impact on patient satisfaction with methadone maintenance treatment by alexan

i

INFLUENCING FACTORS ON METHADONE PHARMACOLOGY

IMPACT ON PATIENT SATISFACTION WITH METHADONE

MAINTENANCE TREATMENT

by

Alexander Khaled Elkader

A thesis submitted in conformity with the requirements

for the degree of Doctor of Philosophy

Graduate Department of Pharmaceutical Sciences

University of Toronto

copy Copyright by Alexander Khaled Elkader (2009)

ii

Influencing Factors on Methadone Pharmacology Impact on Patient Satisfaction with Methadone Maintenance Treatment


Doctor of Philosophy Department of Pharmaceutical Sciences

University of Toronto 2009

Abstract

The methadone maintenance treatment population suffers from high rates of comorbid

psychiatric and substance use disorders Despite a more than 40-year treatment history

not all patients are satisfied with methadone treatment and more than half of the patients

complain of significant inter-dose withdrawal at least some of the time The objectives of

this research were to investigate the pharmacological response to methadone under the

influence of comorbid major depressive disorder and smoking and to identify factors

other than physical withdrawal symptoms that can differentiate patients based on their

complaints of dissatisfaction with treatment In Study 1 seven depressed methadone

maintenance patients experienced more opioid withdrawal symptomatology over a 24-

hour methadone-dosing interval than 10 nondepressed methadone patients Depression

severity was significantly correlated with trough opioid withdrawal severity This

suggests that depression or depressive symptoms are related to reported opioid

withdrawal In Study 2 many factors other than physical opioid withdrawal symptoms

were able to differentiate patients who were satisfied with treatment (holders n=25)

partially satisfied with treatment (partial holders n=35) and not satisfied with treatment

(nonholders n=30) Results suggested that these patient satisfaction groups cluster

differently depending on physical opioid withdrawal mood psychological distress and

iii

personality Nonholders experienced more physical withdrawal symptoms craving for

opioids and negative drug effects Holders had less psychological distress and

experienced less negative mood states than the other groups Partial holders had less

agreeable personalities compared to patients in the other groups In Study 3 opioid and

nicotine withdrawal symptoms and effects were measured in 40 methadone-maintained

patients who were current smokers during trough and peak methadone effects both pre-

and post-nicotine administration Cigarette smoking enhanced opioid withdrawal

suppression during the peak methadone condition methadone attenuated nicotine

withdrawal and methadone and nicotine shared many of the same main effects

suggesting that smoking and methadone effects may be inseparable dimensions In

summary the results of these studies suggest that in addition to physical symptoms

mood related factors are important to opioid withdrawal perception and that the mood

factors and drug interactions can impact on a patientrsquos perception of satisfaction with

methadone treatment

iv

Acknowledgements

To my supervisor Beth Sproule I couldnrsquot imagine learning the ropes from anyone else

You are a patient teacher an ideal role model and a constant source of encouragement

and motivation Being your student has meant always knowing that there would never be

an issue that was unsolvable Thank you for an experience that will never be matched

To Bruna Brands your passion for the work is evident at all times and is a source of

inspiration for me I am grateful for the time that you devoted to me Having you as a

mentor is an experience all students should be so lucky to have

To my advisors Martin Zack and Krista Lanctocirct I thank you for your consistent support

and challenge over the years Having researchers of your quality to advise me has been

an honor

There have been so many students training with me over the years You guys are the

friends that made this place always fun and always home All I can really say is thank

you for the support and that it is a tremendous feeling to look across the table and know

that someone else is having the same experiences Those who go through this together

are friends forever

v

To the rest of my friends you are a second family to me Thanks for being there when

the last thing I wanted to talk about was school I appreciated your understanding all

those times when I couldnrsquot make it I always wanted to be there

To my parents and my sister Susie you guys are incredible I know you went through

this with me I couldnrsquot imagine life without you guys Thank you for everything I love

you guys

vi

Table of Contents

Abstract ii

Acknowledgements iv

Table of Contents vi

List of Tables xii

List of Figures xiii

List of Abbreviations xv

List of Appendices xviii

10 INTRODUCTION 1

11 Statement of Problem 1

12 Overall Purpose of the Study Objectives and Hypothesis 2

121 Purpose 2

122 Objectives 3

123 Overall Hypothesis 3

13 Specific Research Objectives and Hypotheses 4

131

Major Depressive Disorder and Patient Satisfaction in Relation to Methadone Pharmacokinetics and Pharmacodynamics in Stabilized Methadone Maintenance Patients (Study 1)

4

1311 Specific Objectives 4

1312 Specific Hypothesis 4

132

Opioid Withdrawal Scale Modification and Characterization of Between Dose Opioid Withdrawal and Patient Satisfaction in Methadone Maintenance Treatment (Study 2)

5



vii

133 Methadone-Nicotine Interactions in Stabilized Methadone Maintenance Treatment Patients (Study 3)

6



14 Review of the Literature 7

141 Opioid Dependence 7

142 Methadone and Methadone Maintenance Treatment 8

1421 The Canadian Experience 9

143 Methadone Pharmacodynamics 10

144 Methadone Pharmacokinetics 14

1441 Absorption and Distribution 14

1442 Metabolism and Elimination 15

1443 Influence of Enantiomers and BoundUnbound Fractions

16

145 Methadone Concentration-Effect Relationships 18

1451 Pharmacokinetic-Pharmacodynamic Modelling 21

1452 Pharmacokinetic-Pharmacodynamic Modelling of Methadone

22

146 Opioid Withdrawal 23

147 Measuring Opioid Withdrawal 24

148 Patient Satisfaction with Methadone Maintenance Treatment Holders Nonholders and Opioid Withdrawal

28

149 Methadone Mood and Major Depressive Disorder 30

1410 Major Depressive Disorder and the Opioid System 32

14101 Animal Studies 32

14102 Human Studies 33

1411 Smoking and Methadone Maintenance Treatment 35

1412 Smoking Nicotine and the Opioid System 37



viii

1413 Nature of the Interaction Between Smoking and Methadone

41

15 Restatement of Research Hypothesis 42


152 Specific Hypotheses 43

1521


43

1522


44


44

20 METHODS AND MATERIALS 45

21 Major Depressive Disorder and Patient Satisfaction in Relation to Methadone Pharmacokinetics and Pharmacodynamics in Stabilized Methadone Maintenance Patients (Study 1)

45

211 Study Design 45

212 Subject Selection 46

213 Sample Size Justification 47

214 Subject Recruitment 47

215 Assessment Day Procedures 48

216 Study Day Procedures 49

217 Plasma Concentration Determination 50

218 Ethical Considerations 52

219 Data Analysis 52

ix

22 Opioid Withdrawal Scale Modification and Characterization of Between Dose Opioid Withdrawal and Patient Satisfaction in Methadone Maintenance Treatment (Study 2)

55

221 Study Design 55








60

231 Study Design 60









24 Pharmacodynamic Measures 68

241 Objective Measures 68

242 Subjective Measures 68

x

30 RESULTS 76

31 Major Depressive Disorder and Patient Satisfaction in Relation to Methadone Pharmacokinetics and Pharmacodynamics in Stabilized Methadone Maintenance Pateints (Study 1)

76

311 Study Participants 76

312 Pharmacodynamic Results 79

313 Pharmacokinetic Results 84

314 Concentration-Effect Relationship 85


86


322 Subjective Data 87

3221 Patient Satisfaction as a Dichotomy 88

32211 Nonholders 88

32212 Holders 94

32213 Partial Holders 98

3222 Patient Satisfaction as a Continuum 98

3223 Other Measures 101

323 Discriminant Function Analysis 102

324 SubOWS Modification 102


108




xi

40 GENERAL DISCUSSION CONCLUSIONS amp RECOMMENDATIONS

124


124


129


133

44 Overall Discussion and Conclusions 140

45 Clinical Significance 149

46 Recommendations 152

47 Final Comment 155

50 REFERENCES 156

60 PUBLICATIONS 173

Appendices 175

xii

List of Tables

Table Title Page

11 Summary of published opioid withdrawal scales 27

21 Study day schedule MethadoneDepression study 50

31 Patient characteristics from Study 1 78

32 Free (S)-methadone pharmacokinetic parameters 85



35 Methadone Effects Repeated Measures ANOVA 121

xiii

List of Figures

Figure Title Page

11 Methadone chemical structure 11

12 Potential interactions between methadone and nicotine 42

21 Methadone-nicotine interaction study design 64

31 ARCI Dysphoria (LSD subscale Scores) 80

32 SubOWS scores over the dosing interval 81

33 Correlation Trough opioid withdrawal and depression severity 82

34 Pupil diameter over the dosing interval 83

35 Free (S)-methadone levels over the day 84

36 Opioid withdrawal scores (various scales) among groups partial holders resemble holders

90

37 Pain scores among groups partial holders resemble holders 91

38 Opioid craving among groups partial holders resemble holders 92

39 Drug effects (ARCI) among groups partial holders resemble holders 93

310 Psychological distress among groups partial holders resemble nonholders

95

311 Mood states among groups partial holders resemble nonholders 96

312 Neuroticism among groups partial holders resemble nonholders 97

313 Openness and Agreeableness (personality) among groups partial holders different than holders and nonholders

99

314 Pain measures among groups satisfaction resembles a continuum 103

315 Drug effects (ARCI) among groups satisfaction resembles a continuum

104

316 Psychological distress among groups satisfaction resembles a continuum

105

317 Anxiety measures among groups satisfaction resembles a continuum 106

318 Mood states among groups satisfaction resembles a continuum 107

319 Subjective Opioid Withdrawal Scale (SubOWS) scores by cycle and by study day stratified by sex

113

320 Minnesota Nicotine Withdrawal Scale (MNWS) scores by cycle and by study day stratified by sex

114

xiv

321 Effect of Day 115

322 Methadone and Nicotine share main effects 116


324 Methadone and Nicotine have opposing main effects 118

325 QSU scores on the cigarette day 119

326 VAS scores on the cigarette day 120

327 Methadone levels 122

328 Nicotine levels 123


42 Model of overall hypothesis 146

43 Revised model 148

xv

List of Abbreviations

Δmax Maximum change from baseline score

[18F] Radioactive Fluorine

ANOVA Analysis of Variance

ARCI Addiction Research Center Inventory

ARCI-SOW Addiction Research Center Inventory ndash Strong Opioid Withdrawal scale

ARCI-WOW Addiction Research Center Inventory ndash Weak Opioid Withdrawal scale

ASI Anxiety Sensitivity Index

ASN Asparagine

ASP Aspartate

AUC Area Under the plasma concentration vs time Curve

AUEC Area Under the Effect vs time Curve

BG Benzedrine Group

C Concentration

C0 Concentration at time=0

C24 Concentration at time=24 hours

cAMP Cyclic Adenosine Monophosphate

CAMH Centre for Addiction and Mental Health

ClF Clearance rate

CluF Clearance rate of unbound fraction

Cmax Maximum plasma concentration

CNS Central Nervous System

CO Carbon Monoxide

CPP Conditioned Place Preferences

CREB cAMP Response Element-Binding protein

Css Steady-state Concentration

Css(avg) Average Steady-state Concentration

CYP Cytochrome P-450

DSM Diagnostic and Statistical Manual

DSST Digit Symbol Substitution Task

xvi

DTCQ Drug Taking Confidence Questionnaire

E Effect

EC50 Concentration that produces 50 of the maximum Effect

ECT Electroconvulsive Therapy

EDDP 2-ethylidene-15-dimethyl-33-diphenylpyrrolidine

Emax Maximum Effect

FTND Fagerstroumlm Test for Nicotine Dependence

HAMD Hamilton Depression Scale

IC50 Inhibitory Concentration 50 concentration of a substance to produce 50 inhibition of a marker biological process

ICSS Intra-Cranial Self-Stimulation

Ki Inhibition Constant

LSD Lysergic Acid Diethylamide

MANOVA Multivariate Analysis of Variance

MBG Morphine Benzedrine Group

MINI Mini International Neuropsychiatric Interview

MMT Methadone Maintenance Treatment

MNWS Minnesota Nicotine Withdrawal Scale

MSPSS Multidimensional Scale of Perceived Social Support

MTT Manual Tracking Test

N Slope Factor

NAc Nucleus Accumbens

NEO Neo Personality Inventory

NH Nonholder

NMDA M-methyl-D-Aspartate

NOSIE Nicotine and Other Substances Interaction Expectancies scale

NRT Nicotine Replacement Therapy

OCDUS Obsessive-Compulsive Drug Use Survey

OOWS Objective Opioid Withdrawal Scale

po Oral route of administration

PCAG Phenobarbital Chloropromazine Group

PD Pharmacodyamic

PET Positron Emission Tomography

xvii

PH Partial Holder

PK Pharmacokinetic

PK-PD Pharmacokinetic-Pharmacodynamic

POMS Profile of Mood States scale

DepDej DepressionDejection

ppm Parts per million

QSU Questionnaire of Smoking Urges

SCID Structured Clinical Interview for DSM criteria

SCL-90 Hopkins Symptom Checklist-90

SD Standard Deviation

SEM Standard Error of the Mean

SEmax Sigmoid Emax pharmacodynamic model

SF-36 Health Status Questionnaire

SFMPQ McGill Pain Questionnaire ndash short-form

ShOWS Short Opioid Withdrawal Scale

STAI-s State-Trait Anxiety Inventory ndash State subscale

SubOWS Subjective Opioid Withdrawal Scale

SubOWS24 SubOWS score at trough

Tmax Time to maximum plasma concentration

TMD Total Mood Disturbance

VAS Visual Analog Scale

VTA Ventral Tegmental Area

xviii

List of Appendices

Appendix Title Page

1 Patient Informed Consent Form Study 1 175

2 Advertisement Flyer Study 1 183

3 Brief Telephone Screen Study 1 185


5 Patient Satisfaction Screening Guide used in Study 2 193






1

Section 1 INTRODUCTION

11 Statement of Problem

Methadone maintenance treatment (MMT) is the gold standard pharmacotherapy for the

treatment of opioid dependence and has been used for this indication since the mid

1960rsquos1 2 Opioid-dependent patients are a stigmatized group with significant social and

health consequences3 4 These patients have particularly high rates of concurrent

psychiatric and drug use disorders5 6 Despite proven efficacy MMT is not equally

effective for all patients more than half of all patients report experiencing significant

opioid withdrawal some of the time despite attempted clinical dose optimization7 In the

literature patients have been classified as lsquoholdersrsquo or lsquononholdersrsquo depending on their

complaints of opioid withdrawal symptoms with nonholders being patients who

experience significant inter-dose opioid withdrawal frequently or all of the time7 Factors

that influence the pharmacology of methadone may have an impact on response to

methadone treatment

Currently available instruments for measuring opioid withdrawal were designed to assess

symptoms during acute opioid detoxification and rely heavily on physical symptoms of

withdrawal8 In MMT however there may be other important aspects of opioid

withdrawal (eg mood symptoms) that may impact the perception of opioid withdrawal

Characterizing MMT patients according to factors other than physical opioid withdrawal

could be of clinical utility

2

Mood has been related to perceived opioid withdrawal in methadone patients9 Also it is

well know that these patients have high rates of comorbid major depressive disorder10-12

Therefore it is possible that depression could influence methadone pharmacodynamic

responses particularly in patients who complain of opioid withdrawal

Another interesting observation in this population is that cigarette smoking is nearly

universally prevalent in MMT patients13-18 Greater methadone doses have been

associated with increased cigarette smoking and increased nicotine dependence

severity14 19-21 While cigarette smoking and nicotine administration have been

associated with increased methadone self-administration22 23 the pharmacodynamic

influence of smokingnicotine administration on perceived effects of methadone has not

been well studied

12 Overall Purpose of the Study Objectives and Hypothesis

121 Purpose

To identify and evaluate factors that influence pharmacological responses to methadone

in stabilized methadone maintenance treatment patients

3

122 Objectives

To investigate pharmacological responses of methadone in the context of concurrent

major depressive disorder and during the concurrent administration of nicotine in two

experimental trials in stabilized MMT patients

To identify factors other than physical withdrawal symptoms that differentiate MMT

patients based on their satisfaction with treatment and use these factors to modify an

existing opioid withdrawal scale to better reflect the construct of opioid withdrawal in the

context of opioid substitution therapy

123 Overall Hypothesis

Methadone pharmacodynamic responses in methadone maintenance treatment patients

are altered by many factors Specifically methadone pharmacokinetics comorbid

psychiatric statessymptoms and drug interactions are likely to influence perceived

opioid effects and opioid withdrawal symptoms and have an impact on patient

satisfaction with methadone treatment

4

13 Specific Research Objectives and Hypotheses

131 Major Depressive Disorder and Patient Satisfaction in Relation to Methadone

Pharmacokinetics and Pharmacodynamics in Stabilized Methadone Maintenance

Patients (Study 1)

1311 Specific Objectives

Primary To investigate the influence of comorbid major depressive disorder on the

relationship between methadone pharmacokinetics and pharmacodynamics in stabilized

methadone maintenance treatment patients

Secondary To determine what impact patient satisfaction with methadone treatment has

on these relationships in depressed MMT patients

1312 Specific Hypotheses

The relationship between methadone plasma concentrations and negative mood

disturbance will be steeper in depressed methadone patients compared to those without

comorbid depression particularly in nonholders

5

Pharmacodynamic responses to methadone will be different in depressed methadone

maintenance patients compared to nondepressed patients with depressed patients being

more sensitive to negative effects

132 Opioid Withdrawal Scale Modification and Characterization of Between Dose

Opioid Withdrawal and Patient Satisfaction in Methadone Maintenance Treatment

(Study 2)


Primary To modify the Subjective Opioid Withdrawal Scale to include other measures

that differentiate patients based on their satisfaction with methadone maintenance

treatment

Secondary To characterize holder and nonholder populations through the examination

of patient factors that may be related to the experience of opioid withdrawal symptoms in

opioid substitution therapy


Psychological factors will differentiate methadone maintenance treatment patients who

self report as holders partial holders and nonholders as well as or better than physical

opioid withdrawal symptoms alone

6

Modification of the Subjective Opioid Withdrawal Scale to include patient factors other

than physical opioid withdrawal will result in a more sensitive instrument for measuring

perceived opioid withdrawal in methadone maintenance treatment patients

133 Methadone-Nicotine Interactions in Stabilized Methadone Maintenance

Treatment Patients (Study 3)


Primary To elucidate the pharmacodynamic interaction between smoking and

methadone in MMT patients Specifically to determine how smoking alters acute

methadone effectsmethadone withdrawal effects and to determine how methadone alters

acute smoking effects and withdrawal effects from smoking

Secondary To determine if the interaction between methadone and smoking is mediated

by nicotine effects or behaviours related to cigarette smoking

1332 Specific Hypothesis

Methadone effects and nicotine (or smoking) effects interact with each other in different

ways depending on the exposure to both drugs Specifically smoking can alter acute

7

methadone effectsmethadone withdrawal effects and methadone can alter acute smoking

effects and withdrawal effects from smoking

14 Review of the Literature

141 Opioid Dependence

Opioid Dependence like other substance use disorders is typically a long-lasting and

relapsing condition that causes significant distress and disability The illicit opioid using

population is estimated to be approximately 290 to 430 per 100000 of the adult

population aged 15 to 64 in Canada 60000 to 90000 persons24 There are significant

social and health consequences associated with opioid dependence For example in a

study of 114 heroin users in Toronto 52 were in temporary housing 46 had no

employment over the last year and a large percentage of their average monthly income

came from social benefits and illegal activities4 A large proportion of these users (62)

had used emergency services in the previous 12 months half had overdosed on opioids in

their lifetime and many had tested positive for Hepatitis B (28) Hepatitis C (56) or

HIV (7)4

Summary Point

- Opioid dependence is a chronic relapsing condition with significant social

and health consequences

8

142 Methadone and Methadone Maintenance Treatment

An important pharmacotherapy option for opioid dependence is substitution therapy with

an opioid agonist The rationale for substitution treatment is to replace the abused opioid

with a long acting opioid preparation that will attenuate withdrawal symptoms reduce the

craving for opioids avoid the risks associated with needle use and allow the individual to

focus on lifestyle modifications to support recovery from opioid dependence In Canada

methadone and buprenorphine are the only opioids available for this indication with

methadone as the mainstay of treatment

Methadone is a synthetic opioid analgesic developed in Germany prior to World War II

in an attempt to develop an analgesic with minimal abuse liability25 It was patented in

1941 but not used because German physicians did not know how to safely prescribe it26

After the war researchers at the US Public Health Hospital in Lexington Kentucky

found that it had effects similar to morphine but with a longer duration of action26

Methadone has unique pharmacologic properties that makes it suitable for maintenance

treatment A single oral dose in a stabilized patient lasts between 24-36 hours without

producing euphoria sedation or analgesia This allows a patient to function normally

not be impaired when performing tasks and to experience normal pain and emotional

responses Further methadone relieves the persistent craving for opioids (one of the

major causes of relapse) and in sufficient doses ldquoblocksrdquo the opioid effects of normal

street doses of short-acting opioids (eg heroin) Tolerance to methadone develops and

remains steady hence patients can be maintained at the same dose for extended lengths

9

of time26 Finally methadone is a safe drug with minimal side effects27-29 It is important

to note that safety is a relative term in this case A small oral dose (30 - 40 mg) produces

respiratory depression that is sufficient to kill an opioid naiumlve adult even lower doses can

be fatal for children30-33

It wasnrsquot until the mid 1960s that Dole and Nyswander began treating heroin addicts in

New York city with methadone maintenance treatment1 2 Now in the United States

over 150 000 opioid dependent individuals are enrolled in methadone maintenance

programs It is estimated that these services reach one in 10 to one in eight of the 12 to

15 million opioid dependent individuals in the United States34

Summary Points

- Opioid substitution therapy helps stabilize opioid dependence individuals by

minimizing opioid withdrawal and reducing craving which allows a patient

to focus on recovery

- Methadone has unique pharmacology that enables it to be used as a once

daily substitute

1421 The Canadian Experience

In Canada methadone has been used since 1948 as an analgesic and since 1959 to treat

opioid withdrawal symptoms35 In 1963 Halliday and colleagues developed a

lsquoprolongedrsquo opioid withdrawal treatment program35-37 This prolonged approach is

10

similar to the maintenance treatment of Dole and Nyswander1 2 though Halliday did not

necessarily believe that lsquoprolongedrsquo withdrawal treatment was synonymous with

lsquomaintenancersquo36 Also the approach of Halliday and colleagues set a maximum daily

methadone dose of 40 mg35 36 From 1968 to the early 1970s there was an increase in

the number of persons in methadone treatment However there were issues with misuse

and abuse of methadone38 To combat these issues national health authorities prepared

strict treatment guidelines for methadone maintenance39 Following the implementation

of these guidelines and regulations a sharp decrease in patients on MMT was noted38

There was a slight increase in the number of MMT patients in Canada from the early

1980s to mid-199638 40 In 1996 methadone treatment was expanded in Ontario resulting

in an increase in the number of methadone patients in the province from 975 in 1996 to

more than 4000 in 199840 Currently in Canada there are between 25000 and 30000

patients in MMT24 41 with half of the patients concentrated in Ontario and British

Columbia42

Summary Point

- Methadone has a long history in Canada for the treatment of pain and opioid

withdrawal

143 Methadone Pharmacodynamics

Methadone elicits its pharmacodynamic properties through binding to the μ δ and κ

opioid receptors43 The μ opioid receptor is principally responsible for the typical opioid

11

pharmacological effects its activation produces analgesia respiratory depression

physical dependence and tolerance44 45

Methadone possesses a chiral carbon atom in its structure see figure 11 This means that

methadone exists as a racemate of two enantiomeric forms These enantiomers have

identical chemical compositions but differential spatial arrangements about the chiral

carbon with one enantiomer being the mirror image of the other Racemic methadone

consists of (R)- or levo- or (l)-methadone and (S)- or dextro- or (d)-methadone

Figure 11 Methadone Chemical Structure

Figure 11 Methadonersquos chemical structure The chiral carbon is circled in the structure This is the stereo-centre of the molecule

(R)-methadone is thought to account for most if not all of methadonersquos opioid activity

In vitro binding studies have demonstrated that the IC50 for (R)-methadone was 10 times

lower than for (S)-methadone in whole rat brain homogenates46 An approximate 10-fold

difference in affinity has been found between the two enantiomers at the bovine micro1 and micro2

receptors IC50 values for the bovine micro1 receptor which mediates supraspinal analgesia

were 30 and 264 nmolL for (R)- and (S)-methadone respectively At the bovine micro2

(R)-Methadone (S)-Methadone

12

receptor which mediates spinal analgesia the IC50 values were 69 and 88 nmolL for

(R)- and (S)-methadone respectively47 In human analgesia (R)-methadone is

approximately 50 times as potent as (S)-methadone48

In a blinded study by Dole and Nyswander stabilized methadone maintenance patients

were switched from (RS)-methadone to (S)-methadone2 49 Initially these patients were

unaware of the switch because there was no difference in taste and immediate effects

however after 24 hours they began to experience symptoms of withdrawal and after three

days they believed without suggestion that their medication was altered2 49 Once this

occurred they were switched back to (RS)-methadone and opioid withdrawal symptoms

quickly resolved2 49 In another study in humans both objective and subjective opioid

effects were not detected after the administration of 15-90mg of (S)-methadone to non-

tolerant formerly opioid-dependent subjects50 In the same study subcutaneous

administration of 30-90 mg (S)-methadone failed to improve withdrawal symptomatolgy

in opioid-dependent subjects abruptly withdrawn from morphine50 In a study of healthy

male volunteers the effects of 75 mg oral (S)-methadone on respiratory depression and

pupil diameter were not significantly different from placebo However the oral

administration of 75 mg (R)-methadone or 15 mg (RS)-methadone caused sustained

respiratory depression and miosis51 (S)-methadone doses between 50 and 100 mg

induced mild respiratory depression51 High doses (650-1000 mgday) of (S)-methadone

to dependent patients induced opioid subjective effects partially suppressed withdrawal

and caused mild physical dependence52 However patients consistently denied

experiencing subjective opioid effects52 In another study (R)- and (S)-methadone levels

13

were measured concurrently with mood states and opioid withdrawal symptoms over a

24-hour dosing interval in stabilized methadone maintenance patients53 (S)-methadone

was associated with negative mood states and opioid withdrawal in a manner opposite to

(R)-methadone53 Also a greater (S)(R)-methadone ratio was associated with negative

mood states in patients on a methadone dose of greater than 100 mgday53

Methadone is also a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA)

receptor The Ki values for methadone and dextromethorphan an established NMDA

receptor antagonist are similar54 55 NMDA receptor antagonism attenuates and reverses

the development of tolerance to morphine without altering its analgesic properties55

Both (R)- and (S)-methadone have similar affinities for the NMDA receptor with Ki

values of 34 and 74 micromolL respectively Methadone is also a strong inhibitor of

serotonin and norepinephrine uptake56 Ki values for inhibition of serotonin are 0014

and 0992 micromolL and for inhibition of norepinephrine are 0702 and 127 micromolL for

(R)- and (S)-methadone respectively It has been suggested that methadonersquos

antagonistic properties at the NMDA receptor and inhibitory action on serotonin and

norepinephrine uptake may contribute to its antinociceptive properties56

Summary Points

- Methadone effects are largely mediated by the μ-opioid receptor

- Methadone is a chiral compound with (R)-methadone accounting for the

majority of methadonersquos μ opioid effects

- (S)-methadone may be related to aversive effects of methadone

14

144 Methadone Pharmacokinetics

1441 Absorption and Distribution

Different oral formulations of methadone (tablet liquid and disk) do not produce

differences in Area Under the plasma concentration vs time Curve (AUC) peak plasma

concentrations and trough plasma concentrations57 The oral bioavailability of

methadone tablets has been estimated between 70 and 80 for doses ranging from 10 to

60 mg58-61 There is considerable inter-individual variation in these estimates (range 36-

100)58-61 As well the oral bioavailability of methadone is different at treatment

initiation compared to later on in treatment In a study of six patients at the start of

MMT oral bioavailability fell from 95plusmn9 at the start of treatment to 81plusmn10 on day

2560 This may be explained by auto-induction of methadone metabolism Tmax for

methadone ranges from 25 to 4 hours after administration59 62-64

Methadone is a lipophillic drug with a volume of distribution greater than physiologic

volumes At steady-state the volume of distribution ranges from 14 to 67 Lkg60 64-66

Methadone is highly bound to plasma proteins including albumin67 68 lipoproteins68 and

α1-acid glycoprotein68 69 with the latter accounting for the majority of the protein

binding68 70 71

15

Summary Point

- Methadone has high oral bioavailability large volume of distribution and is

highly protein bound

1442 Metabolism and Elimination

Methadone is extensively metabolized mostly in the liver but intestinal Cytochrome

P450 (CYP) 3A4 also likely plays a role The main metabolite 2-ethylidene-15-

dimethyl-33-diphenylpyrrolidine (EDDP) is the product of N-demethylation followed by

spontaneous cycling (the product of the N-demethylation is unstable and hence

lsquospontaneouslyrsquo forms a cyclic compound to increase its stability) 72 More recent in

vitro studies suggest that in addition to CYP3A4 CYP2B6 and CYP2C19 are involved in

N-demethylation of methadone with CYP2B6 playing the greatest role73 In addition to

methadone 9 metabolites have been identified in urine and 3 metabolites have been

identified in feces74-76 Metabolites other than EDDP individually account for little of the

metabolism of methadone74 Mean plasma clearance rates range from 53 to 217

mlmin58-61 64-66 77-82 There is considerable inter-individual variability in estimates of the

plasma clearance rate The elimination half-life of methadone also demonstrates

considerable inter-individual variability Reported estimates of methadone half-life range

from 15 to 207 hours51 58-66 78-86

In a population pharmacokinetic study of 35 MMT patients the elimination half-life was

significantly shorter at steady-state compared to treatment induction with half-life

16

estimates of 48 hrs at steady-state compared to 128 hours at treatment induction87 This

was confirmed in another study of 12 subjects half-life decreased from 55 hours at

treatment induction to 22 hours on day 2686 This again may be accounted for by auto-

induction of methadone metabolism resulting in an increased clearance rate

When evaluating pharmacokinetic influences in MMT it is important to consider steady-

state pharmacokinetics As noted above methadone pharmacokinetics are different under

single-dose and steady-state conditions Auto-induction of methadone metabolism leads

to decreased estimates of half-life and oral bioavailability60 86 87

Summary Points

- Methadone is metabolized by CYP3A4 CYP2B6 and CYP2C19

- Methadone has a long elimination half-life

- Methadone pharmacokinetics are altered at steady-state

- There is considerable inter-individual variability in methadone

pharmacokinetic parameters


In a pharmacokinetic study evaluating the individual enantiomers (R)-methadone was

significantly different then (S)-methadone for a number of pharmacokinetic parameters

(R)-methadone values for Cmax and Tmax were 83 and 129 those of (S)-methadone

respectively77 The ratio of (R)- to (S)-methadone at Tmax was significantly lower than at

17

the trough condition A significant difference was detected at one hour after methadone

administration and remained detectable until 4 hours after methadone administration77

When accounting for protein binding additional differences in pharmacokinetic

parameters were apparent Free (R)-methadone plasma concentrations at trough (pre- and

post-dose) and peak were 170 to 175 those of free (S)-methadone77 For free (R)-

methadone AUC CSS and plasma clearance (CLuF) were 167 158 and 59 of the

values obtained for free (S)-methadone77

The significantly lower clearance of free (R)-methadone indicates that (R)-methadone has

a lower intrinsic clearance Further evidence of this is the significantly greater portions

of (S)-EDDP and (R)-methadone found in urine compared to the corresponding

enantiomers77

Methadone metabolism shows stereoselectivity both CYP2B6 and CYP2C19 but not

CYP3A4 have different preferences for (R)- and (S)-methadone N-demethylation

CYP2B6 demonstrates preference for metabolizing (S)-methadone and CYP2C19

demonstrates preference for metabolizing (R)-methadone73

Information about how methadone disposition changes over time is currently lacking In

one study Mitchell et al investigated pharmacokinetic fluctuation in five MMT patients

with two separate 24-hour testing sessions separated by a minimum of one year88

Average dose-corrected (R)-methadone steady state levels changed between sessions

ranging from a 51 decrease to a 466 increase These differences were not

18

consistently related to changes in methadone dose88 (S)(R)-methadone ratios increased

12 between sessions suggesting different long term changes in the pharmacokinetics of

each enantiomer88

Summary Points

- There are differences in pharmacokinetics between methadone enantiomers

- There is a greater exposure to free (R)-methadone and it is cleared more

slowly

145 Methadone Concentration-Effect Relationships

A number of studies have attempted to find a minimum plasma concentration for

effective maintenance therapy The results of these studies have been conflicting In

some studies a threshold concentration could not be determined89-92 While other studies

have reported a threshold for effective MMT ranging between 50 and 600 ngmL49 93-97

Most of these studies focused on trough plasma concentrations only this may not be

sufficient as demonstrated by the work of Dyer et al described below92 Further none of

these studies examined the effects of chirality on the relationship between concentration

and effect Due to differences in pharmacokinetic and pharmacodyamic properties of

(R)- and (S)-methadone it may be useful to quantify both (R)- and (S)-methadone plasma

concentrations when investigating the pharmacokinetics of methadone

19

Dyer et al92 investigated the relationship between methadone plasma concentration and

effects in 18 methadone-stabilized patients where serial methadone blood concentration

determinations were made over one 24-hour dosing interval Results indicated that there

was a significant inverse relationship between plasma methadone concentrations and

withdrawal severity Specifically withdrawal severity was significantly correlated with

the maximum hourly rate of decline in plasma concentration (r = 067) for all subjects92

In a subsequent study Dyer et al found a relationship between methadone plasma

concentrations and total mood disturbance (an index of negative mood from the Profile of

Mood States (POMS) scale) negative mood varied with the rate of decline in methadone

plasma concentration9

In a study by Hiltunen et al 50 methadone maintenance subjects were enrolled into two

groups satisfied and dissatisfied patients dissatisfied patients felt their dose was too

low98 Well-being was rated using the Objective Opioid Withdrawal Scale (OOWS)99

and an augmented version of the Subjective Opioid Withdrawal Scale (SubOWS)99 100

A correlation analysis between methadone plasma concentrations ((R)- (S)- and (RS)-

methadone) and total scores of positive opioid effects SubOWS items and OOWS items

was carried out for dissatisfied subjects only98 For (RS)-methadone scores on the

SubOWS items were significantly correlated to methadone plasma concentrations at 2

hours For (R)-methadone plasma concentrations were significantly correlated with

SubOWS effects at 2 and 8 hours98 Results suggest that relating (R)-methadone plasma

levels to effects of methadone may be more useful than racemic methadone levels

20

In a study by Eap et al101 trough (R)- (S)- and (RS)-methadone plasma concentrations

were measured in 180 methadone maintenance patients The aim of this study was to

determine whether (R)-methadone concentrations were related to therapeutic response

(measured by opioid-free urine samples over a two month period prior to blood

sampling) Patients were classified as responders if they had only opiate-free urine

samples and non-responders if they had one or more opiate-positive urine samples

Thresholds from 100 to 500 ngml were tested for (R)- and (S)- methadone (in increments

of 50 ngml) while thresholds from 100 to 1000 ngml were tested for (RS)-methadone

(in increments of 100 ngml)101 Sensitivity (responders above threshold concentration

divided by all responders) and specificity (non-responders below threshold divided by all

non-responders) as well as χ2 and p-values were calculated for all experimental

thresholds For (R)-methadone a significant χ2 value was reported for 200 250 and 300

ngml with the highest p-value at 250 ngml101 For (RS)-methadone a significant χ2

value was reported for 400 ngml) Significance was not reported for any of the tested

(S)-methadone thresholds101 At the (R)- methadone threshold of 250 ngml the

specificity was 93 therefore only 7 of the non-responders had (R)-methadone plasma

concentrations above this threshold101 At the (RS)-methadone threshold of 400 ngml

the specificity was 81 therefore 19 of non-responders had plasma concentrations

above the threshold101 These results support the premise that (R)-methadone plasma

concentrations may have greater predictive capabilities than racemic methadone levels

21

Summary Points

- No minimum effective trough methadone plasma concentration for

withdrawal suppression has been identified

- Withdrawal severity is proportional to rate of decline in plasma

concentration

- (R)-methadone may be more predictive of methadone opioid effects

1451 Pharmacokinetic-Pharmacodynamic Modelling

A major goal of clinical pharmacology is to understand dose-effect relationships in the

therapeutic use of drugs Pharmacodynamic models relate drug concentrations to drug

effect102 Simple models include the fixed effect model (where an observed effect is

absent or present) the Emax model (simplest model capable of describing drug effect over

the whole range of possible concentrations) the linear model (drug effect is proportional

to concentration) and the Sigmoid Emax (SEmax) model (similar to the Emax model a more

generalizable form ie the Emax model is the simplest form of the SEmax model)102

The SEmax model is of particular utility in evaluating pharmacodynamic relationships

mediated by receptors The model is explained by the following equations (1 ndash when

drug effect is to increase a measure and 2 ndash when drug effect is to decrease a measure)

22

1 E = Emax bull CN 2 E = Emax - Emax bull CN EC50

N + CN EC50N + CN

Where E is the drug effect C is the plasma concentration Emax is the maximum

attainable effect EC50 is the concentration that produces 50 of the maximum effect and

N is the sigmoidicity factor (slope factor) Assumptions using this approach for

pharmacokinetic-pharmacodynamic modelling include equilibrium between brain and

plasma concentrations no delay between changes in concentration and effect tolerance

to drug effects would have occurred previously and would be stable and that the drug

effects are caused by the parent drug and not contributed to by an active metabolite

Summary Point

- SEmax model may be particularly suitable for investigating methadone PK-

PD relationships


Pharmacokinetic-pharmacodynamic modelling has been utilized to investigate

concentration-effect relationships for methadone In two studies Inturrisi et al related

sedation and pain relief to methadone plasma concentrations in cancer and chronic pain

patients after intravenous injection or infusion of methadone79 103 They found large

inter-individual variability in the Pharmacokinetic-Pharmacodynamic (PK-PD)

relationships and suggested a clinical utility of PD-modelling for individualization and

optimization of analgesic methadone use in chronic pain populations79 103 Dyer et al

23

used this model to link methadone concentrations to effects in methadone maintained

patients9 92 But the model could not be applied to all subjects Estimates of EC50 and

slope for pain relief were similar to those reported by Inturrisi et al103 The Dyer studies

suggest that the relationship between methadone and its effects in MMT patients is steep

indicating that small changes in methadone plasma concentrations could lead to robust

differences in methadone effects9 92

Summary Point

- SEmax model ably related analgesia opioid withdrawal and sedation to

methadone plasma concentrations

146 Opioid Withdrawal

Withdrawal from opioids (including methadone) is a characteristic syndrome consisting

of any or all of the following symptoms aching muscles and joints insomnia nausea

mood changes tachycardia lacrimation stuffy nose sweating gooseflesh loss of

appetite tremor yawning restlessness fever increased respiratory rate increased blood

pressure weight loss pupil dilation irritability and anxiety104 105 While not life-

threatening opioid withdrawal is associated with a very miserable phenotype therefore

an opioid-dependent individual suffering from opioid withdrawal may seek out opioids to

alleviate the extreme discomfort In the case of an opioid substitution therapy patient

experiencing opioid withdrawal there is an increased risk of relapse and dissatisfaction

with treatment

24

Opioid withdrawal symptoms following abrupt cessation of opioid use may be

qualitatively different from withdrawal symptoms routinely associated with substitution

therapy (ie those that occur towards the end of the dosing interval) Also inter-

individual differences in opioid withdrawal perceptions and acceptance are also important

to consider As such differences in the relative salience of physical and psychological

symptoms of withdrawal may need to be accounted for at the individual patient level and

may depend on the context of opioid use

Summary Points

- Opioid withdrawal can be extremely uncomfortable but not life threatening

- Opioid withdrawal experienced in the context of abrupt opioid cessation or

opioid substitution therapy may have clinically relevant differences

147 Measuring Opioid Withdrawal

Opioid withdrawal is usually measured using three methods self-report clinician

observation and objective measurement Self-report involves a patientrsquos own

interpretation of withdrawal symptoms as such it is a subjective measure and can vary

based on individual patient factors Self-report is the most direct measure of withdrawal

however reliability may be reduced as patients may not score items consistently

Clinician observation involves a trained observer rating various signs of withdrawal as

such it is considered more reliable than self-report This method is indirect therefore it

25

may lack sensitivity when quantifying lower levels of opioid withdrawal Objective

measurement of opioid withdrawal is accomplished by the measurement of physiological

changes that are linked to opioid withdrawal There are limited physiological markers for

opioid withdrawal eg heart rate blood pressure and pupil dilation This type of

measurement can be made very reliably however physiological measures can be altered

by other factors than opioid withdrawal For example heart rate can be altered by a

patientrsquos activities prior to measurement and hence care should be taken in the

interpretation of these objective measurements These three methods for quantifying

opioid withdrawal have been used alone or in combination

Self-report may be of particular use when assessing opioid withdrawal in the context of

opioid substitution therapy as this may provide a special case in which psychological

modifiers of withdrawal are more important Seventy years ago Kolb and Himmelsbach

importantly noted that some patients experiencing opioid withdrawal show many

objective signs of withdrawal but complained little while others may show no objective

signs but present as restless in pain and nervous105 This suggests that factors other than

physical withdrawal may influence the perception of opioid withdrawal and consequently

patient satisfaction with treatment

To date 16 opioid withdrawal scales have been published 7 99 104-116 These scales are

strongly rooted in physical symptoms of withdrawal with many of the scales based upon

the work of Kolb and Himmeslbach104 105 Of the withdrawal scales 13 had full

validity and reliability testing 19 had only reliability testing 56 had only validity

26

testing and 38 had no form of reliability of validity testing (see table 11) Fifty percent

were developed using patients in detoxification programs and 38 were developed based

on a naloxone challenge during development and validation The majority of scales

(63) are based on self-report8 Of the available scales the best is the Subjective Opioid

Withdrawal Scale (SubOWS) although it is based on self-report and consists of physical

symptoms of withdrawal it has full validity and reliability testing and it is short and

easily understood by patients8 See table 11 for scale descriptions

Summary Points

- Self-report is the optimal method for measuring opioid withdrawal in the

context of substitution therapy

- Factors other than physical opioid withdrawal may relate to perceived

satisfaction with treatment

- SubOWS is the best available opioid withdrawal scale

27

Table 11 Various opioid withdrawal scales Overview of available opioid withdrawal scales including description of the population of development length method of quantification validity testing and reliability testing The SubOWS is the best available scale for measuring opioid withdrawal It is has full validity and reliability testing and is a short self-report tool It was developed in detoxification patients and may lack sensitivity in describing psychological aspects of opioid withdrawal

Scale Acronym Method of Quantification of

Items Validity Reliability

Patient Population (development)

Himmelsbach Scale (1938)

- Clinician Observation - Objective Measurement

14 None None Opioid Addicts

Opiate Withdrawal Scale (long form) (1968)

OPWL - Self Report 59 Yes None Opioid Addicts

Opiate Withdrawal Scale (short form) (1968)

OPW - Self Report 29 Yes None Opioid Addicts

Strong Opioid Withdrawal Scale (1970)

SOW - Self Report 80 Yes None Patients 10 days into Opioid Taper

Weak Opioid Withdrawal Scale (1970)

WOW - Self Report 84 Yes None Detoxification patients

Wang (1974)

- Clinician Observation 10 Yes None Treatment seeking patients (confirm dependence)

Judson (1980)

- Clinician Observation 17 None None Treatment seeking patients (confirm dependence)

Subjective Opiate Withdrawal Scale (1987)

SOWS (SubOWS)

- Self Report 16 Yes Yes Detoxification Patients

Objective Opiate Withdrawal Scale (1987)

OOWS - Clinician Observation 13 Yes Yes Detoxification Patients

Opiate Withdrawal Scale (1987)

OWS - Self Report 32 Yes None Detoxification Patients

Adjective Rating Scale (1988)

ARS - Self Report 2016 None None Detoxification Patients

Clinical Institute Narcotic Assessment (1988)

CINA - Clinician Observation - Objective Measurement

13 None Yes Treatment seeking patients (confirm dependence)

Short Opiate Withdrawal Scale (1990)

SOWS (ShOWS)

- Self Report 10 Yes None Detoxification Patients

Subjective Opiate Withdrawal Questionnaire (1991)

SOWQ - Self Report 20 None None Detoxification Patients

Methadone Symptom Checklist (1997)

MSC - Self Report 48(16) None None Methadone Maintenance Treatment Patients

Clinical Opiate Withdrawal Scale (1998)

COWS - Clinician Observation - Objective Measurement

11 None None Prior to Buprenorphine Induction

Table 11 Summary of published opioid withdrawal scales

28

148 Patient Satisfaction with Methadone Maintenance Treatment Holders

Nonholders and Opioid Withdrawal

In MMT the term patient satisfaction can have multiple meanings Often client

satisfaction with a treatment program relates to patient perception of the level of support

they receive the level of respect they receive and if the program has the services the

patient believes they need117 Others in the field have related satisfaction to the

methadone dose Hiltunen et al have previously labelled MMT patients as satisfied or

dissatisfied (with dissatisfied patients reporting that they believed their methadone dose

was too low)98 As mentioned previously not all patients in MMT respond equally to

treatment Despite attempts at dosage optimization clinically as many as 53 of

patients experience significant and unacceptable symptoms of inter-dose withdrawal at

least some of the time and 34 of patients experience this frequently or all of the time7

Dyer and White termed those who complained of withdrawal frequently or all the time as

lsquononholdersrsquo and the rest of patients were termed lsquoholdersrsquo7 In this body of work

patient satisfaction with treatment is believed to be more than satisfaction with the

methadone dose Rather it is a reflection of the level of opioid withdrawal that a patient

experiences how they perceive it and how it impacts their quality of life

In a subsequent study by Dyer et al the impact of methadone pharmacokinetics on holder

status was investigated in 18 patients Of the 18 patients nine experienced significant

withdrawal towards the end of the dosing interval and these patients were termed

nonholders while the other nine patients did not experience significant withdrawal and

29

were termed holders92 The mean trough plasma methadone concentrations were similar

Peak plasma concentrations occurred at approximately three hours in both groups92

Other pharmacokinetic factors compared were dose mean peak to trough plasma

concentration ratio and area under the concentration time curve (AUC) these were also

not significantly different between groups92 However the maximum hourly rate of

decline in methadone plasma concentration was significantly higher in the nonholder

group compared to the holder group92 Hence Dyer et al concluded that holders and

nonholders differ in methadone pharmacokinetics Not on usual pharmacokinetic

parameters but rather on a relative rate of decline in plasma methadone levels in intervals

from peak to trough However they were unable to exclude pharmacodynamic

determinants as potential contributors to the difference between the groups92

In a similar study of 14 methadone-stabilized patients (seven holders and seven

nonholders) the pharmacokinetics and pharmacodynamics of methadone and a slow

release oral morphine product were compared in an open-label cross-over design As in

the previous study described above there were no significant differences in Cmax or

trough plasma concentrations between groups For methadone patients who self-reported

as nonholders the number of self-reported opioid withdrawal symptoms prior to dosing

was less when they received the sustained-release oral morphine product compared to

methadone118 This implies that for some nonholders a switch to an alternate opioid can

be clinically beneficial

30

Hanna and colleagues examined the effect of time on methadone pharmacokinetics and

pharmacodynamics in 6 nonholder methadone maintenance treatment patients119

Pharmacokinetic and pharmacodynamic assessments were made serially over a 24-hour

dosing interval on three occasions separated by 7-16 day intervals during this time

methadone doses remained stable119 Overall between-subject variability was greater

than within-subject variability119 As such it was reported that nonholder methadone

patients responded consistently to methadone and had stable plasma levels of methadone

over the course of 1-2 months119

Summary Points

- Patient satisfaction classifications may be related to opioid withdrawal

complaints or the perception of having too low a dose of methadone

- In this thesis satisfaction is related to dose adequacy perceived opioid

withdrawal and impact of opioid withdrawal on quality of life

- Patient lsquodissatisfactionrsquo or lsquononholdingrsquo can be related methadone

pharmacokinetics

149 Methadone Mood and Major Depressive Disorder

In a study by Dyer et al the relationship between mood states and patient satisfaction

(holder status) in methadone maintenance patients was evaluated9 They found that mood

disturbance as measured by the Profile of Mood States (POMS)120 scale was associated

with nonholder status9 Specifically in this population of non-psychiatric patients

31

nonholders had significantly more mood disturbance than holders with maximum

differences during trough methadone conditions and minimum differences during peak

methadone conditions9 Furthermore they reported that negative mood varied with the

rate of decline in methadone plasma concentration9 A steep concentration-effect

relationship was reported indicating that small changes in concentration could lead to

significant mood changes and because nonholders had a faster rate of decline in plasma

concentration these mood changes could be exaggerated compared to holders9

These mood-related findings are important because opioid addiction is also associated

with high prevalence rates of psychiatric disorders Regier et al estimated the lifetime

prevalence of psychiatric disorders among those with an opioid use disorder to be 656

More importantly lifetime prevalence of depression in methadone maintenance patients

has been reported as high as 4312 However current rates of depression in this

population vary greatly from study to study depending on the method used to identify

major depression Studies that use stringent DSM-IIIR and DSM-IV criteria estimate a

prevalence of 194-2310 11 Concurrent depression is regularly associated with negative

impacts on the treatment outcomes of other diseases and illnesses121 This is also the case

with MMT122-125

Summary Points

- Nonholders have more mood disturbance than holders

- There is a high prevalence of depression in MMT patients

- Concurrent depression impacts negatively on MMT outcomes

32

1410 Major Depressive Disorder and the Opioid System

There is a body of evidence suggesting a neurobiological interaction between opioid

pathways and major depressive disorder 1) Opioids have been implicated in the

pathogenesis of depressive illness126 and 2) Endogenous opioid peptides and receptors

are abundant in regions associated with the regulation of mood and behaviour such as the

anterior cingulate prefrontal cortex and amygdala127-131

14101 Animal Studies

In an animal study the influence of opioid agonists antagonists as well as the

endogenous opioid system was investigated utilizing the learned helplessness animal

model of depression132 In this paradigm animals are exposed to inescapable shocks and

then re-exposed to the same shocks with a route of escape Animals that do not escape

from the second exposure have learned helplessness and constitute what is considered to

be a valid model of depression133-135 The administration of opioid agonists and

endogenous opioid catabolism inhibitors to depressed animals resulted in a reversed

escape deficit The administration of an opioid antagonist resulted in an increased

helplessness response132 136 Further work by this group suggests that the δ-opioid

receptor is involved in the effects produced by endogenous opioids (enkephalins) on

learned helplessness137 Specifically a δ-opioid agonist was able to reverse the escape

deficit and a δ-opioid antagonist was able to inhibit the positive opioid effect137 Broom

et al also implicated the δ-opioid system in depression by demonstrating anti-depressant

effects of δ-opioid agonists in the forced swim test but they found no effects with a κ-

33

opioid agonist nor a μ-opioid morphine138 Filliol et al developed knock-out mice for

each μ- δ- and κ-opioid receptors and used them to investigate models of depression

and anxiety139 Kappa knock-out mice did not have an altered phenotype compared to

wild-type mice hence κ-opioid receptors may not have a role in the influence of

depressive phenotypes Mu and δ knock-out mice had opposing phenotypes with δ

knock-outs experiencing consistent depressive-like responses in the behavioural tasks139

Naloxone-treated δ knock-out mice responded as wild-type mice suggesting that

endogenous μ-opioid activity and hence μ-opioid receptors may be partly responsible for

mood-related changes in δ knock-out mice

Summary Points

- Opioid agonists lead to anti-depressive effects while antagonists increased

depressive effects in animal models of depression

14102 Human Studies

It has been suggested that depressed patients may have a deficiency in endogenous opioid

activity and that manic patients may have an excess of endogenous opioid activity140

Clinical trials have indicated that opioid compounds have limited anti-depressant

activity141-143 Also there is evidence that suggests that some of the effects of

electroconvulsive therapy (ECT) (an effective treatment for refractory depression) may

be mediated by opioid peptides144 ECT resulted in increased plasma concentrations of β-

endorphin145-147 Zubieta et al using Positron Emission Tomography (PET) showed that

endogenous μ opioid receptor activation in the thalamus and dorsal anterior cingulate is

involved in attenuation of pain-specific affective responses148 In a human study the

34

prolactin response (mediated by opioid receptor stimulation) was measured in depressed

and control subjects following the administration of morphine The prolactin response in

the control group was normal and significantly larger than that exhibited in the depressed

group149 This was replicated by two other investigators150 151 and subsequently disputed

by Zis et al who used a longer sampling time in their study152 In another human study

depressed and control patients were randomized to receive either 6 mg hydromorphone

po or placebo Depressed subjects who received hydromorphone experienced

significantly attenuated negative opioid symptoms compared to the controls This trend

was even more pronounced in the severely depressed (Hamilton Depression Scale

(HAMD) gt 24) subgroup As well psychomotor function was improved in depressed

patients compared to controls as measured by a Manual Tracking Test (MTT)

(plt001)153 In an fMRI study 21 MMT patients were studied and brain perfusion data

was correlated with BDI scores A significant inverse relationship was noted with BDI

scores and prefrontal activation suggesting that reduced fronto-limbic activity is

associated with depressive symptoms in methadone maintenance treatment patients154

Affect dysregulation is an important risk factor for addiction155 and could be an important

factor in understanding the comorbidity between opioid dependence and depression154

Summary Points

- Opioid agonists have anti-depressive activity in humans

- Depressed patients may have altered responses to acute opioid

administration

35

1411 Smoking and Methadone Maintenance Treatment

Smoking rates in alcohol and illicit drug using populations are greater than the general

population The prevalence of tobacco smoking in methadone maintenance treatment

patients ranges from 85-9813-18 In long-term studies of opioid dependent populations

tobacco smoking is a significant predictor of morbidity and mortality156 157 Although

MMT patients report a high level of interest in quitting smoking16 18 19 158-160 low levels

of sustained smoking cessation are the norm

In a study by Frosch et al methadone patients were divided as non-smokers tobacco-

chippers and heavy smokers Methadone doses were higher in the heavy smokers group

compared to the combination of the other two groups161 Further methadone has been

shown to increase smoking rates in a dose-dependent manner14 20 21 and patients on

higher methadone doses tend to have greater Fagerstroumlm Test for Nicotine Dependence

(FTND) scores a marker of nicotine dependence severity159 Also methadone

administration led to dose-related increases in smoking satisfaction14 Similarly

buprenorphine has been related to increased cigarette smoking rates after the start of

treatment compared to pre-treatment162 163

There is very little research on the influence of nicotine on methadone effects Spiga et al

investigated the influence of nicotine (ad libitum smoking 0- 2- and 4-mg nicotine gum)

on methadone self-administration23 Methadone self-administration was increased during

ad libitum smoking and when 4-mg nicotine gum was available The authors suggested

36

that nicotine may enhance the reinforcing effects of methadone or that nicotine may serve

as a conditioned stimulus to methadone self-administration In another study by Spiga et

al the influence of nicotine and methadone availability on self-administration was

evaluated in methadone maintenance patients using a behavioural economics approach22

Patients were willing to do more work to receive methadone when nicotine was available

by cigarette puff than when cigarette puffs were not concurrently available Methadone

did not alter the level of work a patient was willing to do to receive nicotine through a

cigarette puff suggesting that methadonersquos reinforcing properties are increased in the

presence of nicotine while nicotinersquos reinforcing properties are not altered by

methadone22

Methadone patients report that they smoke more near the time of their methadone dose

they report experiencing more pleasing effects when the drugs are taken together and less

methadone-induced sedation164 Richter et al monitored smoking patterns in methadone

maintenance patients They found that smoking rates are greatest relative to the time of

methadone dosing administration regardless of the time of waking Results suggested

that methadone may reduce variability in regular smoking patterns and create a signature

smoking pattern common to methadone patients who smoke165 Methadone patients also

believe that drug use increases their smoking rates but that smoking does not trigger them

to use drugs166 Despite this belief smoking has been related to increased positive urine

screens Specifically Stopshaw et al conducted a smoking abstinence study in

methadone maintenance treatment patients and showed that smoking abstinence led to

significantly more opioid clean urine samples167 and Frosch et al reported higher levels

37

of illicit drug use (cocaine or opioid positive urine samples) in smokers compared to

tobacco-chippers or non-smokers161

Summary Points

- Smoking is nearly universally prevalent in the MMT population

- Methadone increases smoking and is associated with higher nicotine

dependence scores

- Methadonersquos reinforcing properties increased when nicotine is available by

cigarette

- MMT patients may have a signature smoking pattern related to the timing of

their methadone dose

1412 Smoking Nicotine and the Opioid System


Nicotine is known to affect the endogenous opioid system Nicotine administration leads to

increased levels of β-endorphin in rats168 In an isolated perfused mouse brain preparation

direct administration of nicotine to the hypothalamus produced dose-related increases in

β-endorphin levels169 Similarly after nicotine administration in the guinea pig and rat

plasma enkephalin levels were increased170 171 After chronic nicotine administration in

mice little change in hypothalamic β-endorphin levels were found however upon

termination of nicotine dosing significant reductions in β-endorphin levels were

38

reported172 In rat brain nicotine also stimulated enkephalin release in nucleus

accumbens (NAc) and amygdala173

Phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding

proteins (CREB) has been associated with rewarding effects of nicotine174

Environmental cues (eg conditioned place preference (CPP) chamber) previously paired

with nicotine delivery can be an important part of the incentive to maintain smoking

behaviour In fact CREB phosphorylation is increased following exposure to

environments with a prior association to rewarding effects associated with nicotine

increases are similar in magnitude to those seen with actual nicotine exposure174

Naloxone administration 24 hours after the nicotine dose blocked conditional increases of

phosphorylated CREB in the VTA and NAc174 In chronic nicotine administration

paradigms naloxone increases Intra-Cranial Self Stimulation (ICSS) thresholds and

causes a conditioned place aversion (CPA) in rats175 176 Pre-treatment of rats with the μ-

opioid receptor antagonist β-funaltrexamine abolished anxiolytic-like effects of nicotine

on the elevated plus maze task177 After chronic nicotine exposure nicotine physical

withdrawal could be precipitated by injections of opioid antagonists176 178 179 Also the

nicotine abstinence syndrome precipitated with naloxone was reversible with subsequent

morphine injection180 Interestingly neuropeptide F which precipitates withdrawal in

opioid-dependent rats was able to precipitate nicotine abstinence syndrome181 In a study

of the cross-tolerance between morphine- and nicotine-induced CPP it was found that

both naloxone and mecamylamine (a nicotinic receptor antagonist) were able to reduce

CPP of morphine and nicotine182 As well mecamylamine-precipitated nicotine

withdrawal was attenuated with pre-injection of morphine183 A potential explanation is

39

that chronic periodic nicotine administration leads to prolonged release of endogenous

opioid peptides and nicotine withdrawal results in decreased tone in opioid receptors184

In a knock-out study rewarding effects of nicotine measured with a CPP test were noted

in wild-type but not μ knock-out mice185 In another knock-out study the role of the μ-

opioid receptor in the development of tolerance to nicotine effects was examined

Chronic administration of nicotine induced tolerance to antinociceptive effects in both

wild-type and μ knock-out mice but the knock-out mice developed tolerance more

quickly186 This suggests that release of endogenous opioids by stimulation of the

nicotinic acetylcholine receptors may occur and that the endogenous opioid system may

be involved in nicotine pharmacodynamic effects including tolerance to antinociceptive

effects

Summary Points

- Nicotine administration leads to the release of endogenous opioids in brain

regions related to reward

- Opioid activity is required in order to experience the rewarding effects of

nicotine

14122 Human Studies

In human studies after 12-hour nicotine abstinence smoking high nicotine content

cigarettes increased plasma β-endorphin levels compared to baseline levels187 188 Also

40

the administration of naloxone was found to reduce the number of cigarettes smoked by

dependent smokers as well as block the pleasurable response to smoking189 This

suggests that opioid peptides are released during smoking and may play a role in smoking

maintenance184 In an open-label pharmacogenetic study of transdermal nicotine versus

nicotine nasal spray the role of the μ-opioid receptor Asn40Asp variant was examined190

Of 320 smokers of European ancestry individuals carrying the Asp40 variant

(heterozygous AsnAsp or homozygous AspAsp N=82) were significantly more likely

than those homozygous for the Asn allele (AsnAsn N= 238) to be abstinent after

treatment190 This difference was significant in the transdermal nicotine group not the

nicotine spray group In the transdermal nicotine group 52 of the Asp carrier group vs

33 of the Asn group were abstinent at the end of the eight weeks of treatment

(OR=24)190 Also smokers with the Asp40 variant reported less withdrawal symptoms

and less mood disturbance during the first two weeks of nicotine replacement therapy190

A subsequent study by the same group showed that carrying the Asp40 variant was

associated with reduced reinforcing values of nicotine (cigarette puffs) in women191

Summary Points

- Smoking resulted in the release of endogenous opioids in humans

- Opioid antagonists blocked the rewarding effects of smoking

- Patients with a functional mutation at the μ-opioid receptor were more likely

to be abstinent from smoking at the end of a nicotine replacement therapy

smoking cessation trial

41


There is currently no evidence to suggest that an interaction between methadone and

nicotine would be pharmacokinetic in nature The metabolic pathways that are induced

by the polycyclic aromatic hydrocarbons in tobacco smoke (ie CYP1A1 CYP1A2

CYP2E1) or that metabolize nicotine (ie CYP2A6)192 are different than the enzymes

involved in methadone metabolism or that are influenced by methadone (ie primarily

CYP3A4)193

Based on the evidence presented above a synergistic or additive pharmacodynamic

interaction between nicotine and methadone is probable MMT patients who smoke will

during the course of a day experience agonist effects and withdrawal effects of both

nicotine and methadone Hence interactions where agonist effects of one drug interact

with agonist effects of the other where abstinence effects of one drug interact with

abstinence effects of the other and where agonist effects of one drug interact with

abstinence effects of the other are all possible See figure 12 for a model describing

potential interactions between methadone and nicotine

Summary Points

- There is no evidence to suggest that nicotine-methadone interactions would

be pharmacokinetic in nature pharmacodynamic interactions more likely

- Interactions between methadone and nicotine are likely complex and

variable over the course of the day

42

Figure 12 Potential interactions between methadone and nicotine

Figure 12 Model representing potential interactions between methadone and nicotine The (+) sign represents agonist effects present the (-) sign represents withdrawal effects present There can be additivesynergistic interactions (boxes 1 and 4) or mixed interactions with agonist effects of one drug interacting with withdrawal effects of the other (boxes 2 and 3) A methadone patient who is a smoker will experience different interactions at different points of the day depending on their smoking and methadone schedules Patients are likely to start the day in box 4 then move between box 3 and 4 while they smoke prior to their methadone dose After the methadone dose patients will move between box 1 and 2 while they smoke until methadone effects begin to dissipate and they return to boxes 3 and 4

15 Restatement of Research Hypothesis





Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)

Methadone (-) Nicotine (+)

Methadone (-)

Nicotine (-)

Methadone Agonist Effects

Methadone Withdrawal

Nicotine Withdrawal

Nicotine Agonist Effects

1

43

2

43

responses to methadone including opioid effects opioid withdrawal and their impact on

patient satisfaction with methadone treatment


1521 Major Depressive Disorder and Patient Satisfaction in Relation to

Methadone Pharmacokinetics and Pharmacodynamics in Stabilized Methadone

Maintenance Patients (Study 1)

Specific Hypotheses







44

1522 Opioid Withdrawal Scale Modification and Characterization of Between

Dose Opioid Withdrawal and Patient Satisfaction in Methadone Maintenance

Treatment (Study 2)

Specific Hypotheses









Specific Hypothesis





45

Section 2 METHODS AND MATERIALS


Pharmacokinetics and Pharmacodynamics in Stabilized Methadone


211 Study Design

This was a non-interventional study of the relationship between steady state methadone

pharmacokinetics and pharmacodynamics The study procedure was the same for all

subjects and consisted of one assessment day to determine eligibility and group

assignment and one 25-hour study session over two consecutive days Stabilized

methadone patients were recruited based on depression status (with or without major

depressive disorder) and patient satisfaction with treatment (holdernonholder) On the

first study day subjects arrived one hour before they drank their regular dose of

methadone and remained for 12 hours for blood sampling and to complete

pharmacodynamic assessments Subjects returned home at the end of the first study day

and again on the second day arrived one hour before their methadone dose to complete

the 24-hour testing cycle Subjects were discharged after they had completed the last

cycle and had taken their dose of methadone

46

212 Subject Selection

Subjects were eligible for participation if they were able to provide informed consent (see

appendix 1 for consent form) were 18 years or older and were stabilized in treatment

(ie enrolled in a methadone maintenance treatment program for at least the last 6

months and prescribed the same dose of methadone for at least the previous one month)

To be included in the depressed group subjects had to be currently suffering a major

depressive episode confirmed with the Structured Clinical Interview for DSM-IV criteria

(SCID) Depressed subjects being treated with antidepressants were included if they

continued to take their medication and had been on the same dose of the antidepressant

for a sufficient period of time to arrive at a steady-state condition (ensuring that any

pharmacokinetic interaction with methadone would have been stabilized)

The identification of holders and nonholders was made by self-report Subjects were

asked whether they thought that their daily methadone dosage was sufficient to maintain

them for one full dosing interval (24 hours) Those who said yes were placed in the

holder group those who said no were placed in the nonholder group If a subject was

unsure heshe was asked to select the most appropriate group based on perceived

withdrawal symptomatology over the past month

All subjects were asked to abstain from caffeine and alcohol from 12 hours before the

study day and for the duration of the study session Subjects were asked to continue

47

taking any other regular medications A SCID was conducted with all participants

Subjects suffering from other current psychiatric disorders (other than anxiety disorders)

or other current substance use disorders (other than nicotine) were excluded from

participation

213 Sample Size Justification

For this preliminary study a sample size of 20 subjects was proposed 5 subjects in each

of the 4 groups (depressed holders nondepressed holders depressed nonholders

nondepressed nonholders) In the Dyer etal study120 the mean Total Mood Disturbance

score in holders (20plusmn 5 25 coefficient of variation) was significantly lower than in

nonholders (65plusmn10 15 coefficient of variation) estimated from the graphs This study

had a power of 80 for a 2-tailed test to detect a minimum difference of 20 points

between depressed nonholders and nondepressed holders assuming a 15 coefficient of

variation in each group and an α = 01 for this preliminary study with 5 subjects in each

group

214 Subject Recruitment

Subjects were recruited from the Centre for Addiction and Mental Health (CAMH) and

other methadone clinics in the Greater Toronto Area using posted flyers (see appendix 2

for recruitment flyer) Of the 226 individuals who responded to the advertisement 174

were able to be contacted 85 passed the brief telephone screen (see appendix 3 for the

48

telephone screen) and were willing to come for an assessment and 40 assessments were

completed A total of 22 subjects were eligible to participate following the assessment

and were enrolled in the study five did not complete the study Of those who did not

complete the study three were not able to have an intravenous catheter stably inserted

due to venous problems one decided not to participate after enrolment and one failed to

report for the study session

215 Assessment Day Procedures

All potential subjects who passed the brief screen attended an assessment session in order

to determine study eligibility and group assignments as outlined in the subject selection

section above Subjects were asked to come to the CAMH clinical laboratory prior to

taking their methadone dose so that patient satisfaction determination during the trough

methadone condition could be assessed All potential subjects then gave a urine sample

for toxicology screening and were then given their methadone dose Afterwards

potential subjects were asked a series of questions about demographics general health

current medications drug use history drug treatment history and methadone

maintenance treatment history At this point the SCID interviews were conducted

Subjects who were deemed ineligible were discharged at that point without completing

the assessment Finally the 21-item Hamilton depression scale (HAMD)194 was given to

assess the severity of depression

49

216 Study Day Procedures

Subjects arrived at the CAMH clinical laboratory one hour prior to their regular

methadone dosing time At this point all subjects were asked to provide a urine sample

for toxicology screening and to submit to an alcohol breathalyzer test A 22-gauge

intravenous catheter was inserted into a vein on the subjectsrsquo forearm Prior to

methadone dosing a baseline blood sample was obtained for methadone concentration

determination vital signs were measured a pupil diameter measurement was made and

subjects were asked to respond to computerized versions of the Addiction Research

Center Inventory (ARCI)195-197 short-form the POMS120 the Subjective Opioid

Withdrawal Scale (SubOWS)99 the Digit-Symbol Substitution Task (DSST)198 199 and

the Manual Tracking Test (MTT)200 for assessment descriptions see section 24

Following the baseline assessments subjects consumed their regular methadone dose

Additional vital signs and blood samples were collected at 05 1 15 2 3 4 5 6 8 10

12 and 24 hours after methadone dose administration Blood samples were centrifuged

the serum was separated and stored at -80degC until analysis The ARCI POMS

SubOWS DSST and MTT were administered serially at 1 2 3 4 5 6 8 10 12 and 24

hours after methadone administration After the 12th hour cycle the catheter was

removed and subjects were excused for the evening Subjects returned the following

morning to complete the 24th hour cycle the final blood sample was obtained by

venipuncture A urine sample for toxicology screening and a breathalyzer measurement

were again obtained See table 21 for study scheduling chart All subjects continued to

take their regular prescribed daily dose of methadone Subjects with take-home dose

50

privileges brought their regular dose with them the rest received their regular daily dose

at the CAMH pharmacy study personnel observed all methadone dose administrations

Subjects were provided with a lounge to relax in between study cycles and were allowed

to smoke cigarettes between study cycles when time permitted All subjects were

provided with a light breakfast lunch and dinner

Day 1 Day 2 Time (hr) 0 05 1 15 2 3 4 5 6 8 10 12 24

Blood Sample X X X X X X X X X X X X X

Vital Signs X X X X X X X X X X X X X

Urine Sample X X

Breathalyzer X X

Pupilometer X X X X X X X X X X X

ARCI X X X X X X X X X X X

POMS X X X X X X X X X X X

SubOWS X X X X X X X X X X X

DSST X X X X X X X X X X X

MTT X X X X X X X X X X

X

Table 21 Study schedule subjects reported for two consecutive study days on day one they went home following the 12th hour cycle They returned the following day one hour prior to the regular time of their methadone administration 217 Plasma Concentration Determination

Concentrations of (R)- and (S)-methadone were determined in plasma using an LCQ

liquid chromatographmass spectrometer (LCMS) with an electrospray interface (ESI)

operating in the positive ionization mode (ThermoFisher Mississauga ON) The

methadone enantiomers were separated on an AGP Chiral 100 mm x 400 mm 5 μm id

column (Chrom Tech Ltd Apple Valley MN) Optimal separation was achieved with a

mobile phase comprised of a 10 mM ammonium acetate buffer with a pH adjusted to 55

and isopropanol in a ratio of 928 (vv) One hundred microlitres of plasma was

Table 21 Study day schedule MethadoneDepression study

51

combined with 100 μL of internal standard (deuterated methadone) solution consisting of

300 ngmL deuterated methadone and 100 μL of 500nM sodium bicarbonate The

mixture was extracted with 750 μL hexane 500 μL of which was dried off and the

remaining residue was reconstituted with 100 μL of mobile phase Twenty microlitres of

this extract was injected into the LCMS with a flow rate of 08 mLmin The mz

monitored was 310 for methadone and 319 for deuterated methadone Retention times

for (R)- and (S)- methadone were 67 and 80 min respectively Calibration curves over

the range of 50 to 500 ngml were used to quantify each enantiomer Intra-assay

variability was 5 for both enantiomers and inter-assay variability was 6 for (R)-

methadone and 10 for (S)-methadone The limit of quantitation was 50 ngmL

Quantitation of free enantiomers was made using the same instrumentation with an

altered sample preparation Serum samples were thawed and brought to room

temperature Immediately after thawing 400 μl of serum was filtered through Centrifree

Micropartition devices (Millipore Billerica MA) to separate free from protein-bound

methadone Samples were then centrifuged at 1500 x g to minimize effects of

temperature and pH on ligand binding Two hundred microlitres of protein-free filtrate

was extracted twice with hexane (as above) After solvent evaporation the residue was

reconstituted with 60 μl of mobile phase and 20 μL were injected Calibration curves

over the range of 5-50 ngmL were used to quantify each of the free enantiomers

Racemic methadone concentrations were calculated by adding the concentrations of the

two enantiomers determined separately

52

218 Ethical Considerations

This study was approved by the CAMH Research Ethics Board and all participants

provided written informed consent prior to participating in the study All data were kept

strictly confidential Subjects were identified by subject number and initials not by

name The clinical research laboratory at CAMH is located near the Addiction Medicine

Clinic at the 33 Russell Street site For subjects currently experiencing depressive

symptoms we informed (when permitted) their treating physician of the diagnosis of

depression in order that they could be followed-up and treated as necessary Subjects

who did not give their permission were offered information on resources and urged to

discuss their feelings with their physician Subjects were paid $15000 Canadian for their

time and participation upon completion of the study Subjects deemed ineligible at the

assessment were paid $2500 Canadian Subjects who arrived and were not able to

complete the study because of venous problems (intravenous catheters) were paid $5000

Canadian

219 Data Analysis

The peak (Cmax) and trough (C0 and C24) plasma concentrations as well as the time to

peak plasma concentration were calculated from visual inspection of the data Area

Under the plasma concentration versus time Curve (AUC) from 0 to 24 hours was

calculated by the linear trapezoidal rule The average steady-state plasma concentration

(Css) was calculated by dividing the AUC by the dosing interval Average clearance

53

(ClF) was calculated by dividing the dose by the AUC Peaktrough ratios were

calculated by dividing Cmax by C24 The maximum rate of decline in concentration from

peak to trough was calculated by evaluating rates of decline in concentration at all

sampling time points These parameters were calculated for total and unbound (RS)-

(R)- and (S)-methadone plasma concentration levels

Area under the Effect versus time Curve (AUEC) was calculated for all

pharmacodynamic measures using the linear trapezoidal rule The maximum change

from baseline was also calculated for all measures Composite scales were derived from

ARCI subscales by summing positive drug effect subscales (euphoria stimulation abuse

potential) together and negative drug effect subscales (sedation dysphoria) together A

Cronbachrsquos alpha201 was conducted to confirm internal consistency when constructing the

composite measures Summary ARCI statistics and trough SubOWS scores were

correlated with HAMD scores The 24-hour SubOWS score was chosen for this

correlation because this score was the most accurate measure of 24-hour post methadone

withdrawal

A Sigmoid Emax model was used to relate plasma concentrations and effects of

methadone This was a stepwise procedure of four steps Step 1 Plot the mean

normalized data and determine initial estimates for fitting in step two Step 2 Fitting the

mean normalized data with initial estimates obtained in step one In this step initial

estimates for fitting in step three were obtained Step 3 Fitting all data at once with

54

initial estimates obtained in step two In this step initial estimates for fitting is step four

were obtained Step 4 Fit individual data with initial estimates obtained in step three

Descriptive statistics were used to characterize the participants An ANOVA was used

with depression and holder status as the factors No interactions were found Hence

results are reported from independent samples t-tests in order to better illustrate

differences between groups for pharmacokinetic pharmacodynamic and modeling

endpoints

The primary outcome variable in this study was the total mood disturbance score This

was to be the primary focus of the pharmacodynamic modelling proposed Secondary

outcome variables were SubOWS ARCI MTT DSST and other POMS scale scores

Also pharmacokinetic parameters were secondary outcome measures

As mentioned previously this study was powered to detect differences between patients

distributed amongst four groups with five subjects in each group However because the

sample size was insufficient for this subjects were placed in two dichotomous groupings

(depressednondepressed and holdernonholder) Differences between depressed and

nondepressed methadone maintenance patients on the pharmacodynamic measures and

differences between holders and nonholders on pharmacokinetic and pharmacodynamic

measures were secondary objectives

55


Opioid Withdrawal and Patient Satisfaction in Methadone Maintenance

Treatment (Study 2)

221 Study Design

In this non-interventional study perceived opioid withdrawal was investigated in

stabilized methadone maintenance patients with varying degrees of satisfaction with

treatment Holder and nonholder methadone maintenance treatment patients were

characterized using measures of physical opioid withdrawal craving pain mood states

drug effects pain personality quality of life self-efficacy and social support during the

approximate trough methadone condition In order to modify the SubOWS candidates

from the characterization measures were selected Selection was based on the ability to

distinguish between holders and nonholders


Subjects were eligible for participation if they were 18 years of age or older were able to

provide informed consent (see appendix 4 for consent form) and were stabilized in

treatment (ie enrolled in a methadone maintenance program for 6 months or longer and

prescribed the same dose for the previous one month or longer) Also all subjects were

required to abstain from caffeine and alcohol from 12 hours before the study day until the

study was completed

56

After enrolment subjects were divided into three patient satisfaction groups Holders

(none or little opioid withdrawal with no significant impact on quality of life) Partial

Holders (mild to moderate opioid withdrawal with some impact on quality of life) and

Nonholders (moderate to severe opioid withdrawal with significant impact on quality of

life) Group assignment was accomplished with a guided self-report screening interview

The guided self-report process consisted of a series of questions with a focus on the

impact of opioid withdrawal that a subject experienced and a classification guide see

appendix 5


Due to the nature of this study there was no primary outcome measure In general with

an alpha of 005 this study would have 80 power to detect an effect size of 060 on a

two-tailed test with 43 subjects in each group using a dichotomous categorization

(holders and nonholders) Therefore a total sample size of 90 subjects was targeted


Subjects were recruited from the CAMH and other methadone clinics in the Greater

Toronto Area with posted flyers (see appendix 6 for study flyer) Of the 205 individuals

who responded to the advertisement 183 were able to be contacted 90 subjects passed

the brief telephone screening (see appendix 7) and were eligible and willing to participate

57

in the study All but one of the study participants completed the entire study day

protocol This one subject was not comfortable answering the questions and left after

completing half of the study measures partial data from this subject were included in this

analysis



methadone dosing time and were asked to provide a urine sample for toxicology

screening and to submit to an alcohol breathalyzer test Subjects were administered the

Mini International Neuropsychiatric Interview(MINI)202 to screen for psychiatric

disorders

Subjects then completed a battery of subjective assessments (see below) divided into 2

blocks Assessments that are subject to acute changes (block 1) were administered during

the trough methadone condition and those that were more stable (block 2) were

administered after a 30-minute break during which time subjects received their daily

methadone dosage Subjects with take-home dose privileges brought their regular dose

with them the rest received their regular daily dose at the CAMH pharmacy study

personnel observed all methadone dose ingestions During the break subjects were

provided with a lounge to relax in as well as a light meal Questionnaires in each block

were presented in a random order

58

For details about subjective assessments see section 24 Block one assessments

consisted of the Subjective Opioid Withdrawal Scale (SubOWS)99 Short Opioid

Withdrawal Scale (ShOWS)107 108 Addiction Research Center Inventory ndash Weak and

Strong Opioid Withdrawal Scales (ARCI-WOW and ARCI-SOW)110 Addiction

Research Center Inventory (ARCI)195-197 Profile of Mood States (POMS)120 State-Trait

Anxiety Inventory state subscale (STAI-s)203 Short-Form McGill Pain Questionnaire

(SFMPQ)204-206 and the Hopkins Symptom Checklist 90 (SCL-90)207 208 Block two

assessments consisted of the Neo Personality Index (NEO)209 210 Obsessive Compulsive

Drug Use Survey (OCDUS)211 The Health Status Questionnaire (SF-36)212 Drug-

Taking Confidence Questionnaire (DTCQ)213 Anxiety Sensitivity Index (ASI)214 and the

Multidimensional Scale of Perceived Social Support (MSPSS)215 216


This study was approved by the CAMH Research Ethics Board and all subjects provided

written informed consent prior to participatation The clinical research laboratory at

CAMH is located proximally to the Addiction Medicine Clinic and the Opioid Clinic

where physicians and therapists were available All data were kept strictly confidential

and were identified by subject number and initials not by name Subjects received

$3000 Canadian for their time and participation

59

227 Data Analysis

Descriptive statistics were used to characterize the sample A multivariate analysis of

variance (MANOVA) was conducted for each construct that was measured using

multiple scales ie opioid withdrawal (SubOWS ShOWS ARCI-WOW and ARCI-

SOW) and anxiety (STAI-s ASI) or for each scale comprised of multiple subscales (eg

ARCI POMS) Significant measures were reported using univariate ANOVAs and post-

hoc tests Discriminant function analyses were also preformed for each construct or scale

that was comprised of multiple subscales Measures that most highly correlated with

significant discriminant functions from each analysis were selected for an overall

combined discriminant function analysis to determine which measures were the best

discriminators of the patient satisfaction groups Measures that were selected by the

discriminant function analysis would be used for SubOWS modification

As mentioned in the sample size justification section due to the nature of this study there

were no primary outcome variables

60



231 Study Design

This was a double-blind randomized within-subject placebo-controlled trial to

investigate methadone nicotine interactions in stabilized methadone maintenance

treatment patients Subjects attended the CAMH clinical laboratory for three identical

study days with the only exception being the method in which nicotine was administered

on each day On day one subjects received nicotine by their regular brand of cigarette

after this subjects entered the randomized phase of the study and received 4-mg (2x2-

mg) Nicorettereg gum or matching placebo on days two and three



appendix 8 for consent form) 18 years or older were stabilized in treatment (ie enrolled

in a methadone maintenance treatment program for at least the last three months and

prescribed the same dose of methadone for at least the previous two weeks) and had no

plans to quit smoking or request a change of methadone dose during the course of the

study

61

All subjects were asked to abstain from caffeine alcohol and smoking (and all nicotine

products) from 12 hours before each study day and for the duration of each study session

Subjects were asked to continue taking any other regular medications A Mini

International Neuropsychiatric Interview (MINI)202 was conducted to screen out potential

subjects with current psychiatric disorders and substance use disorders Subjects were

excluded if they suffered from concurrent psychiatric disorders (other than anxiety

disorders) or other current substance use disorders Subjects were also screened for their

level of nicotine dependence with the Fagerstrom test for Nicotine Dependence217

subjects were excluded if they scored less than six


In order to calculate an appropriate sample size four subjects were piloted in a one-day

study looking at the effects of cigarette smoking on methadone effects (similar to the

design proposed here) These preliminary data indicated reductions in opioid withdrawal

symptoms (SubOWS) following the first cigarette administration prior to methadone

dosing (from 12 plusmn 3 to 9 plusmn 2) and increases in positive mood (POMS-rew) following the

second cigarette administration during the time of peak methadone concentrations (from

24 plusmn 15 to 32 plusmn20) Based on this pilot data this study would have been able to detect a

significant difference between conditions with a power of 80 for a two-tailed test with

alpha=005 with a total of 40 subjects

62


Subjects were recruited from CAMH and other methadone clinics in the Greater Toronto

Area with posted flyers (see appendix 10 for study flyer) Of the 141 individuals

responded to the advertisement 122 were able to be contacted 82 passed the brief

telephone screen (see appendix 11 for the telephone screen) and were willing to come for

an assessment and 60 assessments were completed A total of 53 subjects were eligible

to participate following the assessment and were enrolled in the study 13 did not

complete the study Of those who did not complete the study six failed to arrive for the

first study day four were unable to abstain from smoking one was arrested after the first

study day one dropped out after the first study day and one was released because of

suspected hypertension


Potential research subjects were assessed for eligibility based on the following smoking

drug-use and methadone treatment history the MINI the Fagerstroumlm test for nicotine

dependence (FTND) and a urine sample for toxicology and pregnancy testing The

FTND is the most widely used tool to establish a patientrsquos level of nicotine dependence

Possible scores range from 0 to 11 A score of 6 or higher indicates a high level of

nicotine dependence217 In addition subjects had their demographics recorded and

completed the Nicotine and Other Substance Interaction Expectancies questionnaire

(NOSIE) The NOSIE was constructed to measure patient perceptions of the effects of

63

smoking on other illicit drug use and vice versa The scale consists of 4 factors effect of

drugs on smoking effect of smoking on drug use smoking to cope with drug urges and

difficulty of concomitantly quitting smoking and drugs The 20 items are scored on a 5-

point Likert Scale Ranging from never (1) to always (5)166 218 Subjects were also

classified as holders partial holders and nonholders with the guided self-report screening

process developed in Study 2


On study days subjects arrived at the CAMH clinical laboratory one hour prior to their

regular methadone dosing time At this point all subjects were asked to provide a urine

sample for toxicology screening and to submit to an alcohol breathalyzer test and carbon

monoxide (CO) breath test Subjects were required to score zero on the alcohol breath

test and no greater than 10 ppm on the CO breath test in order to confirm 12 hours

abstinence from smoking and alcohol use Subjects had vital signs monitored and were

asked to respond to the Addiction Research Center Inventory Cole-short form195-197

Profile of Mood States120 Subjective Opioid Withdrawal Scale99 Questionnaire of

Smoking Urges219 Minnesota Nicotine Withdrawal Scale220 and a Visual Analog Scale

for smoking effects221 on 4 separate cycles The first two cycles were pre- and post-

nicotine administration during the trough methadone condition The second two cycles

were pre- and post-nicotine administration during the peak methadone effects condition

Nicotine administration on the first study day was by cigarette subjects were allowed 10

minutes to smoke one of their regular brands of cigarette Nicotine administration on the

64

subsequent days was the active and placebo gum subjects were instructed to chew the

gum for 30 minutes using the lsquochew-chew-parkrsquo method (described in the product

monograph) chewing the gum in this method requires an individual to chew the gum

twice and then station the gum between the gums and the wall of the mouth for 30

seconds this is repeated for 30 minutes Subjects received their regular methadone dose

following cycle two Methadone administration was followed by a three-hour break (to

reach approximate peak methadone effects) during which time smoking was prohibited

Blood samples were collected for methadone and nicotine plasma concentration

determination during cycles two and four See figure 21 for study design Subjects were

provided with a lounge to relax in during the break as well subjects received a light

meal

Figure 21 Methadone-nicotine interaction study design Study procedures were identical between study days with the exception of the nicotine administration type Subjects completed identical study cycles pre and post nicotine administrations at both the trough (cycles 1 and 2) and approximate peak (cycles 3 and 4) methadone conditions Subjects received either 10 minutes to smoke one of their regular brands of cigarette or chewed the gum (active or placebo) for 30 minutes using the recommended method The three-hour break was to allow for approximate peak methadone effects

Cycle 1 (-) Methadone

(-) Nicotine

Cycle 2 (-) Methadone (+) Nicotine

Cycle 3 (+) Methadone

(-) Nicotine


(+) Nicotine

3 hr 1030 min 1030 min

Nicotine Administration


Methadone Administration

Figure 21 Methadone-nicotine interaction study design

65

237 Plasma Concentration Determination

Concentrations of methadone were determined in plasma using an LCQ liquid

chromatographmass spectrometer (LCMS) with an electrospray interface (ESI)

operating in the positive ionization mode (ThermoFisher Mississauga ON) Methadone

was separated on a Kromasil C18 100 mm x 210 mm 35 μm id column (CSC

Montreal QC) Optimal separation was achieved with a mobile phase comprised of

acetonitrile and 01 formic acid in a ratio of 6040 (vv) Fifty microlitres of plasma

was combined with 100 μL of internal standard (deuterated methadone) solution

consisting of 300 ngmL deuterated methadone and 100 μL of 500nM sodium

bicarbonate The mixture was extracted with 750 μL hexane 200 μL of which was dried

off and the remaining residue was reconstituted with 500 μL of mobile phase Ten

microlitres of this extract was injected into the LCMS with a flow rate of 02 mLmin

The mz detected was 310 for methadone and 319 for deuterated methadone The

retention time for methadone was 26 min Calibration curves over the range of 50 to

1500 ngml were used to quantify each enantiomer Intra-assay variability was 5 inter-

assay variability was 5-6 The limit of quantitation was 50 ngmL

Concentrations of nicotine cotinine and hydroxyl-cotinine were analyzed according to

the method of Giesbrecht et al222 This method was originally developed for measuring

very low levels of nicotine metabolites in urine (for studying environmental exposure to

smoking in non-smokers) However the same method was used for determining nicotine

and metabolite levels in serum with the following exceptions A sample volume of 100

66

μL was used Standard curves were constructed from 5-1500 ngmL for each analyte

Retention times for hydroxycotinine cotinine and nicotine were 074 min 10 min and

24 min respectively The transitions monitored were hydroxycotinine 193 to 80

deuterated hydroxycotinine 196 to 80 cotinine 177 to 80 deuterated cotinine 180 to 80

nicotine 163 to 84 and deuterated nicotine 167 to 84


This study was approved by the CAMH Research Ethics Board and received a letter of no

objection from Health Canada Natural Health Products Directorate Written informed

consent was obtained from each participant of the study All data were kept strictly

confidential and was identified by subject number and initials not by name The CAMH

clinical research laboratory is located proximally to the Addiction Medicine Clinic

Upon completion of the study subjects received $22500 Canadian for their time and

participation Subjects who dropped out prior to completion were paid on a prorated

basis at the rate of $5000 per completed study day

239 Data Analysis

Descriptive statistics were used to characterize participants Pharmacodynamic data was

analyzed with repeated measures ANOVAs with methadone status (two levels ndash

prepost) nicotine status (two levels ndash prepost) and study day (three levels ndash cigarette

day nicotine gum day and placebo gum day) as within-subject factors Methadone

67

pharmacokinetic data was analyzed with repeated measures ANOVAs with methadone

(two levels ndash prepost) and study day (3 levels ndash cigarette day nicotine gum day and

placebo gum day) as within-subject factors Nicotine cotinine and hydroxy-cotinine

pharmacokinetic data were analyzed with repeated measures ANOVAs with nicotine

status (two levels ndash post first nicotine administration (cycle two)post second nicotine

administration (cycle four)) and day (three levels ndash cigarette day nicotine gum day and

placebo gum day) as within-subject factors Sex was used as a between-subjects factor in

the ANOVAs Order effects were analyzed using order of nicotine gumplacebo gum

administration as a between subjects factor in the ANOVAs Holder status (holderpartial

holdernonholder) effects on results were tested as a between-subject factor in the

ANOVAs

The primary outcome measure of this study was the SubOWS score Secondary outcome

measures were scores on the ARCI MNWS POMS QSU and VAS (smoking effects)

assessments tools Methadone and nicotine plasma levels were also secondary outcome

measures in this study

68

24 Pharmacodynamic Measures

241 Objective Measures

Vital Signs Heart rate blood pressure oxygen saturation skin temperature and

respiratory rate were taken using a Criticare (model number 507EP) vital signs monitor

Pupil Diameter Pupil diameter was measured with a pupillometer The pupillometer is

a specialized camera that uses an infrared light source to acquire an image that is

captured to a research computer and quantified The pupillometer has been used in

opioid research conducted in our laboratory223

242 Subjective Measures

Subjective Opioid Withdrawal Scale (SubOWS) The SubOWS is a 16-item symptom

checklist for opioid withdrawal Items comprise typical signs and symptoms of opioid

withdrawal Each item is scored on a 5-point scale from 0 (not at all) to 4 (extremely)99

A typical subject is able to complete this scale in one minute

Short Opioid Withdrawal Scale (ShOWS) The ShOWS is 10-item symptom checklist

for opioid withdrawal Each item is scored on a 4-point scale from 0 (nil) to 3 (severe)

and is used to rate opioid withdrawal over the previous 24-hour period108 The ShOWS is

a short form version of the Opiate Withdrawal Scale (OWS)107 A factor analysis was

69

completed and the OWS was shortened to 20 items After removing confusing and

redundant items the OWS was condensed to the 10-item ShOWS108 A typical subject is

able to complete this scale in less than one minute

Addiction Research Center Inventory ndash Weak and Strong Opioid Withdrawal Scale

(ARCI-WOW and ARCI-SOW) An opioid withdrawal scale was developed from the

items of the ARCI109 It was noted that this scale was accurate for when assessing strong

opioid withdrawal symptoms but not necessarily reflective of weak subjective opioid

withdrawal symptoms Hence new scales were developed The ARCI-WOW items were

selected because they differentiated a group of no-withdrawal control subjects (opioid-

dependent patients one month after admission to an inpatient detoxification program)

from subjects expected to be feeling weak opioid withdrawal (opioid-dependent patients

three days after admission to an inpatient detoxification program)110 The ARCI-SOW

items were selected because they differentiated opioid addicts on the 10th day of a taper

from heroin or morphine from their own baseline110 A typical subject is able to complete

either of these measures in four to five minutes

Addiction Research Center Inventory (ARCI) The ARCI scale was developed by the

Addiction Research Center It is the most commonly used scale for assessing the effects

of different psychotropic drug classes The full ARCI consists of 550 truefalse

statements196 The Coleshort form of the ARCI was used it is a combination of the 49-

item ARCI short form197 and the 66-item ARCI-Cole195 Because of overlap the

Coleshort form version of the ARCI consists of 76 truefalse questions that comprise 12

70

subscales (five from the short form and seven from the ARCI-Cole) The ARCI short

form consists of five subscales assessing euphoria sedation dysphoria and stimulation

Of the five subscales three were most useful for studying methadone The Morphine

Benzedrine Group (MBG) assesses morphine-like and stimulant effects Its content

reflects feelings of pleasantness contentedness and happiness as such it is commonly

called the ldquoeuphoriardquo scale The Pentobarbital Chlorpromazine Alcohol Group (PCAG) is

sensitive to a variety of CNS depressant drugs Its content reflects feelings of sedation

and apathy It is commonly called the ldquosedationrdquo scale The Lysergic Acid Diethylamide

(LSD) scalersquos (named after the hallucinogen) contents reflect feelings of dysphoria and

sensory and somatic disturbance It is commonly called the ldquodysphoriardquo scale197 The

ARCI-Cole was derived from ARCI List 116 A factor analysis was carried out by Cole

et al and three factors seemed most important these were sedation euphoria and

dysphoria195 These factors were broken down into somatic and psychic symptoms to

comprise the following subscales Sedation-Motor Sedation-Mental Unpleasantness-

Physical Unpleasantness-Dysphoria Stimulation-Motor and Stimulation-Euphoria As

well a composite scale for abuse potential was created with items that correlated

significantly (r=032) with street value of the drug (based on assignment of monetary

value by study subjects)195 A typical subject is able to complete this scale in five

minutes

Profile of Mood States (POMS) The POMS is an adjective checklist used for assessing

drug-induced changes in mood Subjects indicate how they feel using a five-point scale

from ldquonot at allrdquo to ldquoextremelyrdquo The version used is comprised of 72-items

71

corresponding to 8 mood clusters and 2 derived mood clusters These mood clusters

include anxietytension depression anger fatigue vigor confusion friendliness and

elation Derived measures are arousal (sum of anxiety and vigor - sum of confusion and

fatigue) and positive mood (elation ndash depression)120 A typical subject is able to complete

this scale in four minutes

Obsessive Compulsive Drug Use Survey (OCDUS) The OCDUS measures two

factors of opioid craving over the previous one-week period 1) thoughts about heroin

and interference and 2) desire and control211 The scale has 10 items framed around

heroin Subjects were asked to substitute the word heroin with methadone A typical

subject is able to complete this scale in less than one minute

The Health Status Questionnaire (SF-36) The SF-36 is a quality of life measure

suitable for self-administration It has been shown to be valid in groups reporting

different levels of ill-health It assesses eight health concepts physical functioning role

limitations due to physical health problems social functioning bodily pain general

mental health (psychological distress and psychological well-being) role limitations due

to emotional problems vitality (energyfatigue) and general health perceptions212 A

typical subject is able to complete this scale in five minutes

Drug-Taking Confidence Questionnaire (DTCQ) The DTCQ is a 50-item self-report

questionnaire to assess situation specific coping self-efficacy for using a particular

substance The scale consists of eight subscales Unpleasant emotions physical

72

discomfort pleasant emotions testing personal control urgestemptation to use conflict

with others social pressure to use and pleasant times with others Items are graded on a

6-point scale ranging from not at all confident to very confident213 Subjects were asked

to respond to the items with opioids as the substance of interest A typical subject is able

to complete the DTCQ in four minutes

State-Trait Anxiety Inventory (STAI) A 40-item self-report assessment that

differentiates between state and trait anxiety The STAI is comprised of two 20-item

subscales one for state and one for trait anxiety203 The subscale for state anxiety (STAI-

s) was used A typical subject is able to complete the STAI-s in two minutes

Short-Form McGill Pain Questionnaire (SFMPQ) This instrument is designed to

provide quantitative measures of clinical pain that are sensitive to change It contains 15

descriptors (11 sensory 4 affective) which are rated for intensity as well as measures for

current and average pain intensity204-206 A typical subject is able to complete the

SFMPQ in four minutes

Anxiety Sensitivity Index (ASI) The ASI is a 16-item questionnaire in which

participants indicate on a 5-point Likert scale (from very little to very much) the degree

to which they fear anxiety symptoms214 A typical subjects are able to complete the ASI

in two minutes

73

Hopkins Symptom Checklist 90 (SCL-90) This is a 90-item self-report symptom

inventory designed to reflect current psychological symptom patterns of psychiatric and

medical patients It is interpreted in terms of 9 primary symptom dimensions

somatization obsessive-compulsive interpersonal sensitivity depression anxiety

hostility phobic anxiety paranoid ideation and psychoticism Normative data are

available on non-patients and psychiatric outpatients207 208 A typical subject is able to

complete the SCL-90 in five minutes

Neo Personality Index (NEO) This is a self-report instrument for measuring five major

personality factors neuroticism extroversion openness agreeableness and

conscientiousness each containing six subfactors There are 240 items and a subject can

strongly agree agree be neutral disagree or strongly disagree Normative data are

available The NEO has been extensively evaluated for reliability and validity in both

normal and clinical populations209 210 A typical subject is able to complete the NEO in

30 minutes

Multidimensional Scale of Perceived Social Support (MSPSS) This is a short self-

report measure where subjects indicate the extent of their agreement with a series of

statements related to the social support they receive from family friends and significant

others This scale provides a more direct measure of social support than just marital and

employment status215 216 A typical subject is able to complete the MSPSS in one

minute

74

Visual Analog Scales ndash Smoking (VAS) Visual analog scales are often used to assess

momentary changes in effect224 Twenty-six scales related to smoking were presented to

subjects Subjects select how much they agree or disagree with the statement by

selecting where to intersect a 100-point line anchored by two opposing options This

scale has been used in previous studies in our laboratory221 A typical subject is able to

complete the 26 VAS in two minutes

Questionnaire of Smoking Urges (QSU) The QSU is a 32-item scale consisting of four

subscales desire to smoke anticipation of positive outcome relief of withdrawal or

negative affect and intention to smoke Also the items of the QSU can be divided into

two factors Factor one is related to intention and desire to smoke for positive outcomes

associated with smoking and Factor two is related to the relief of negative affect or

withdrawal by smoking Items of the QSU are scored on a 7-point Likert scale ranging

from strongly disagree (1) to strongly agree (7)219 The QSU can be completed in three

minutes by a typical subject

Minnesota Nicotine Withdrawal Scale (MNWS) This is a brief 8-item self-report

instrument based on DSM-IV symptoms of nicotine withdrawal220 Items are rated on a 5-

point Likert scale It has been shown to be sensitive to acute changes in smoking A

typical subject is able to complete the MNWS in one minute

Digit Symbol Substitution Test (DSST) This is a computerized psychomotor test that

requires subjects to replicate a template pattern on a blank numbered template There are

75

10 different symbols comprised of different combinations of blank and filled squares

These 10 symbols are randomly paired with the numbers 0-9 The subject is randomly

given a number between 0 and 9 that is associated with a specific symbol from the

legend Replication is accomplished by clicking the appropriate squares in the blank

template with a computer mouse Subjects have 90 seconds to make as many

substitutions as possible The number of correct substitutions is used as a measure of

psychomotor function198 199

Manual Tracking Test (MTT) The MTT is a computerized test that requires the

subject to navigate a virtual airplane over a set pathway that shifts across the screen using

a computer mouse Each assessment consists of three 20-second trials The mean

percent time spent over the pathway is used as a measure of psychomotor function200

76

Section 3 Results




311 Study Participants

A total of 17 subjects completed the study protocol There were no differences in

baseline characteristics between subject groupings (depressed vs nondepressed and

holders vs nonholders) with two exceptions Depressed subjects were confirmed to be

significantly more depressed than nondepressed subjects as evidenced by HAMD POMS

depressiondejection subscale and POMS total mood disturbance scores As well

depressed subjects were significantly heavier however the dose relative to weight was

not different between the depressed and nondepressed groups While not significant

nonholders tended to have more negative mood disturbance and depressiondejection

though there was no difference between holders and nonholder for depression severity

(HAMD) For a summary of patient characteristics see table 31 Urine screens were

positive for benzodiazepines in 24 of cases for cannabinoids in 18 of cases and for

cocaine in 6 of cases and there were no differences between subject groupings All

those with positive urine screens reported their last use as 3 or more days ago with the

exception of one participant who after questioning reported using cannabis on the night

prior to the study None of the subjects had a positive urine screen for other opioids on

77

the study days All but one subject were current tobacco smokers The prevalence of

anxiety disorders according to DSM-IV criteria were social phobia 12 panic disorder

6 obsessive compulsive disorder 6 and post traumatic stress disorder 6

Again there were no differences between subject groupings Three of the 10 subjects in

the control group had a history of major depression but were not suffering current

symptomatology (HAMD lt7) Two of the depressed subjects were currently taking

antidepressants (one paroxetine and one sertraline) Removing patients currently taking

antidepressants from the analysis did not affect study findings

78

Table 31 Summary of patient characeristics ns = not significant HAMD = score on the 21-item Hamilton Depression Scale POMS ndash DepDej = score on DepressionDejection subscale of the Profile Of Mood States scale at baseline and POMS ndash TMD = score on the composite measure of Total Mood Disturbance derived from the Profile of Mood States at baseline Scores are reported as mean (SD)

Total Nondepressed Depressed p Holder Nonholder p N 17 10 7 12 5

Sex 12M5F 8M2F 4M3F 0475 11M1F 1M4F 0019 Smokers 94 90 100 0873 92 100 0826

Age (years)

387 (105) 366 (118) 419 (81) 0326 396 (106) 368 (113) 0634

Height (cm)

1735 (95) 1724 (93) 1750 (102) 0593 1758 (95) 1678 (71) 0112

Weight (kg)

855 (277) 723 (126) 1044 (332) 0013 900 (308) 820 (212) 0751

Dose (mg)

988 (544) 895 (636) 1121 (385) 0836 892 (514) 1220 (603) 0271

Time on Dose (mo)

91 (99) 121 (120) 48 (27) 0093 93 (105) 86 (93) 0807

Time in Treatment (mo)

370 (402) 500 (480) 185 (135 0115 422 (467) 245 (147) 0426

HAMD 99 (95) 27 (23) 193 (59) lt0001 82 (87) 138 (109) 0229

POMS - DepDej 162 (144) 97 (84) 246 (167) 0035 139 (103) 212 (217) 0307

POMS - TMD 386 (323) 231 (182) 584 (367) 0024 329 (233) 510 (477) 0458

Table 31 Patient characteristics from Study 1

79

312 Pharmacodynamic Results

Depressed subjects experienced significantly more negative opioid effects specifically

dysphoric effects as measured with the LSD subscale of the ARCI Both AUEC and

maximum change from baseline (Δmax) scores were significantly higher in depressed

subjects (AUEC 141plusmn323 vs -310plusmn467 plt004 and Δmax 07plusmn39 vs -27plusmn26

plt004 respectively) See figure 31 Depressed subjects did not score higher on any

ARCI positive effects subscales (MBG BG amphetamine mental stimulation and abuse

potential) compared to nondepressed subjects

Depressed subjects experienced more opioid withdrawal symptoms compared to

nondepressed subjects This was observed in the higher scores for opioid withdrawal

symptoms as measured by the Subjective Opioid Withdrawal Scale (SubOWS) (AUEC

327plusmn959 vs -742plusmn667 plt002) See figure 32a for comparison of SubOWS scores

over the 24-hour dosing interval in depressed and nondepressed methadone maintenance

treatment patients Similarly currently depressed patients tended to have higher

SubOWS scores compared to patients who were not currently depressed but had a past

history of major depressive disorder (n=3) (AUEC 327plusmn959 vs -408plusmn221 p=024)

Nonholders did not score significantly higher on the SubOWS compared to holders see

figure 32b

80

ARCI Dysphoric Effects (AUEC)

14

-31

-60

-40

-20

0

20

40

ARCI Dysphoric Effects (Δmax)

07

-27

-4

-2

0

2

4

a)

b)

Nondepressed

Nondepressed

Depressed

Depressed

Figure 31 Depressed MMT patients experience more dysphoric opioid effects (LSD subscale) This was noted with both the a) AUEC and b) Δmax LSD summary scores Error reported as SEM

plt004

plt004

Figure 31 ARCI Dysphoria (LSD subscale Scores)

81

SubOWS Score vs Time (hr)

0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sc

ore

Depressed NonDepressed

Figure 32 SubOWS scores over one 24-hour dosing interval in a) depressed vs nondepressed and b) holder vs nonholder methadone patients Depressed patients had significantly more opioid withdrawal at all time points There were no differences between holders and nonholders Error reported as SEM


0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sco

re

Holder Nonholder

a)

b)

Figure 32 SubOWS scores over the dosing interval

82

Hamilton depression scores were significantly correlated with trough SubOWS scores (r

= 070 plt0004) see figure 33 There was a significant correlation between HAMD and

the AUEC of a composite measure of negative ARCI subscales (LSD PCAG motor

sedation mental sedation unpleasantness-physical unpleasantness-dysphoria α=085) (r

= 050 plt005)

Figure 33 Trough SubOWS scores were significantly correlated with HAMD scores

Trough SubOWS Score vs HAMD Score

0

10

20

30

40

0 5 10 15 20 25 30

HAMD Score

Su

bO

WS

Sco

re

Figure 33 Correlation Trough opioid withdrawal and depression severity

r=070 plt0004

83

There were no differences between groups in pupil diameter Pupillary miosis was

evident in all subjects see figure 34

There were no differences detected in psychomotor function (both DSST and MTT)

between groups

Pupil Diameter (mm) vs Time (hr)

3

4

5

6

0 6 12 18 24

Time (hr)

Pu

pil D

iam

ter

(mm

)

Figure 34 Pupil diameter vs time Pupil diameter decreased with maximal miosis at 3 hours post methadone dose Afterwards pupil diameter rebounds to baseline levels Error reported as SEM

Figure 34 Pupil diameter over the dosing interval

84

313 Pharmacokinetic Results

There were no differences in pharmacokinetic parameters for methadone both as a

racemate and as individual enantiomers (total and free levels) between depressed and

nondepressed patients The same was true for holders and nonholders with the exception

of free (S)-methadone (see figure 35) Nonholders had significantly higher C24 Css Cmax

and AUC compared to holders (see table 32 for a summary)

Unbound (S)-Methadone Conc (ngml) vs Time (hr)

0

5

10

15

20

0 6 12 18 24

Time (hr)

(S)-

Me

tha

do

ne

(n

gm

l)

Holder

Nonholder

Figure 35 Unbound (S)-methadone levels over one 24-hour dosing interval in holder and nonholder methadone maintenance treatment patients Nonholder patients have greater exposure to unbound (S)-methadone over the entire dosing interval This is demonstrated by the significantly higher Cmax Css C24 and AUC in nonholders compared to holders Error reported as SEM

Figure 35 Free (S)-methadone levels over the day

85

Parameter Unit Holder Nonholder p C24 ngml 27 (17) 61 (27) 0008 Css ngml 41 (25) 76 (40) 0044

Cmax ngml 75 (42) 146 (71) 0030 AUC hr ngml 994 (606) 1829 (948) 0044

There were no differences between holders and nonholders in terms of maximum rates of

decline in plasma methadone concentrations for total and unbound (RS)- (R)- or (S)-

methadone

314 Concentration-Effect Relationship

The Sigmoid Emax model did not fit enough of the data to justify the modelling

Furthermore accounting for both protein binding and chirality did not lead to the

production of better fitting models

Table 32 Unbound (S)-methadone pharmacokinetic parameter estimates for holders and nonholders C24 = trough concentration at 24 hours Css = average Steady-State concentration Cmax = peak concentration and AUC = Area Under the plasma concentration vs time Curve Scores reported as mean (SD)

Table 32 Free (S)-methadone pharmacokinetic parameters

86



Treatment (Study 2)


A total of 90 subjects 25 holders 35 partial holders and 30 nonholders completed the

study protocol Partial holders had been enrolled in methadone maintenance treatment

for significantly less time than the patients in the other two groups Nonetheless partial

holders were in treatment for an average of more than four consecutive years and on their

current dose for nearly eight months a period of time assumed to be sufficient for the

clinical optimization of the patientsrsquo doses Also a disproportionately greater number of

males were enrolled in the partial holder group (2411) See table 33 for a summary of

patient characteristics Urine screens were positive for cannabinoids in 32 of cases for

benzodiazepines in 21 of cases for cocaine metabolite in 16 of cases for opioids in

10 of cases for cocaine in 6 of cases and for amphetamine in 1 of cases There

were no differences amongst groups for positive urine samples The majority (94) of

the participants were current smokers The prevalence of psychiatric disorders according

to the MINI screening were Agoraphobia (28) major depressive disorder (20)

social phobia (16) panic disorder (11) bipolar disorder (11) post traumatic stress

disorder (10) schizophrenia (psychotic disorder) (9) generalized anxiety disorder

(9) dysthymia (6) obsessive compulsive disorder (3) and bulimia (3) There

were no differences amongst groups for psychiatric disorders with the exception of

87

agoraphobia being more prevalent in nonholders (holders 18 partial holders 20 and

nonholders 47 p=0018) Although rates of depression among the groups did not differ

statistically differences amongst the groups were noted (holders 4 partial holders 25

and nonholders 26 p=0064)

322 Subjective Data

Study results suggest that patient satisfaction groups differed from each other in a

dichotomous manner for some measures and over a continuum for other measures When

patient satisfaction suggested a dichotomous differentiation between groups three

patterns emerged 1) Nonholders were different from the other groups 2) partial holders

were different and 3) holders were different

Holder Partial Holder

Nonholder p

N 25 35 30

Sex (FM) 1213 1124 1317 0271

Age (yr) 395 (83) 407 (85) 398 (83) 0857

Height (cm) 1706 (102) 1711 (79) 1745 (97) 0209

Weight (kg) 788 (243) 771 (258) 760 (147 0892

Time in Treatment (mo) 680 (495) 501 (47) 784 (476) 0045

Time on Dose (mo) 83 (121) 78 (112) 79 (100) 0984

Dose (mgday) 730 (461) 808 (386) 995 (446) 0062

Table 33 Study 2 patient demographics Values reported as mean (SD) There are no differences between groups in demographics with the exception that partial holders were in treatment for significantly less time than the other groups and the ratio of men to women was greatest in the partial holder group


88

3221 Patient Satisfaction as a Dichotomy

32211 Nonholders

Nonholders had more opioid withdrawal pain opioid craving and unpleasant drug

effects compared to holders and partial holders

Opioid Withdrawal Nonholders (NH) scored higher than partial holders (PH) and

holders (H) on the SubOWS (NH 220plusmn88 vs PH 122plusmn82 vs H 93plusmn100 plt0001)

the ShOWS (NH 132plusmn56 vs PH 84plusmn46 vs H 70plusmn43 plt0001) the ARCI-WOW

(NH 591plusmn151 vs PH 476plusmn172 vs H 429plusmn149 p=0001) and the ARCI-SOW

(NH 240plusmn78 vs PH 168plusmn89 vs H 154plusmn82 plt0001) Post-hoc tests showed that

the difference between groups was driven by nonholders vs holderspartial holders See

figure 36

Pain There were significant differences amongst patient satisfaction groups for current

pain (NH 19plusmn12 vs PH 13plusmn10 vs H 120plusmn09 p=0015) and past month average

pain intensity (NH 67plusmn23 vs PH 50plusmn27 vs H 50plusmn27 p=0013) according to the

short form of the McGill Pain Questionnaire Post hoc tests showed that the difference

amongst groups was driven by nonholders vs holderspartial holders See figure 37

89

Craving Past week craving measured by the Obsessive Compulsive Drug Use Survey

(OCDUS) tended to be different amongst patient satisfaction groups This was evident

for the OCDUS total score (NH 114plusmn88 vs PH 64plusmn66 vs H 65plusmn62 p=0016) the

thoughts and interference subscale (NH 69plusmn56 vs PH 40plusmn47 vs H 38plusmn36

p=0023) and the desire and control subscale (NH 45plusmn36 vs PH 24plusmn26 vs H

28plusmn28 p=0022) Post hoc tests showed that the differences amongst groups were

driven by the nonholders vs partial holders The difference between nonholders and

holders approached significance (OCDUS total score p=0056 thoughts and interference

p=0055 and desire and control p=012) See figure 38

Drug Effects Many subscales of the ARCI tended to be different amongst groups LSD

(NH 77plusmn32 vs PH 54plusmn34 vs H 52plusmn29 p=0005) Unpleasantness-Dysphoric (NH

36plusmn18 vs PH 24plusmn21 vs H 18plusmn18 p=0002) Unpleasantness-Physical (NH 40plusmn25

vs PH 21plusmn21 vs H 16plusmn21 plt0001) and Stimulation-Abuse Potential (NH 36plusmn29

vs PH 56plusmn23 vs H 64plusmn23 plt0001) Post hoc tests showed that differences amongst

groups were driven by nonholders vs holderspartial holders See figure 39

90

Subjective Opioid Withdrawal Scale

104 122

220

0

10

20

30

40

Holders Partial Holders Nonholders

Su

bO

WS

Sco

re

ARCI - Weak Opioid Withdrawal

591

476429

0

20

40

60

80


AR

CI-

WO

W S

co

re

Short Opioid Withdrawal Scale

132

8470

0

5

10

15

20


Sh

OW

S S

co

re

ARCI - Strong Opioid Withdrawal

154 168

240

0

10

20

30

40


AR

CI-

SO

W S

co

re

Figure 36 Opioid withdrawal scores among groups a) SubOWS b) ShOWS c) ARCI-WOW and d) ARCI-SOW Partial holders resemble holders and differences are driven by holderspartial holders vs nonholders

a) b)

c) d)

plt0001 plt0001

p=0001 plt0001

Figure 36 Opioid withdrawal scores (various scales) among groups partial holders resemble holders

91

SFMPQ - Average Pain Intensity

50 50

67

0

2

4

6

8

10


Avera

ge P

ain

In

ten

sit

y

SFMPQ - Current Pain

193

126120

0

1

2

3

4


Cu

rren

t P

ain

Figure 37 a) Average and b) Current pain among groups Partial holders resemble holders and differences are driven by holderspartial holders vs nonholders

a) b)

p=0013 p=0015

92

OCDUS Total Score

65 64

114

0

5

10

15

20

25


OC

DU

S T

ota

l S

co

re

OCDUS - Desire and Control

2824

45

0

2

4

6

8

10


Desir

e a

nd

Co

ntr

ol

Sco

re

OCDUS - Thoughts and Interference

69

4038

0

5

10

15

Holders Partial Holders NonholdersTh

ou

gh

ts a

nd

In

terf

ere

nce S

co

re

Figure 38 Past week craving among groups a) Thoughts about methadone and how these thoughts interfere with normal functioning b) Desire for and control over desire for methadone and c) Total craving score Partial holders resemble holders and differences are driven by partial holders vs nonholders

a) b)

c)

p=0022

p=0016

Figure 38 Opioid craving among groups partial holders resemble holders

p=0023

93

ARCI - LSD

52 54

77

0

4

8

12


LS

D S

co

re

ARCI - Unpleasantness - Physical

1621

40

0

2

4

6

8


Ph

ys

ica

l S

co

re

ARCI - Unpleasantness - Dysphoria

36

2418

0

2

4

6


Dy

sp

ho

ria

Sc

ore

ARCI - Stimulation - Abuse Potential

6456

36

0

2

4

6

8

10


Ab

us

e P

ote

nti

al S

co

re

Figure 39 Drug effects among groups a) LSD-dysphoria b) Unpleasantness-dysphoria c) Physical unpleasantness and d) Abuse potentialdrug liking Partial holders resemble holders and differences are driven by holderspartial holders vs nonholders

a) b)

c) d)

p=0005 p=0002

plt0001 plt0001

Figure 39 Drug effects (ARCI) among groups partial holders resemble holders

94

32212 Holders

Holders had less psychological distress and mood disturbance compared to partial holders

and nonholders

Psychological Distress There were significant differences amongst groups on many

subscales of the psychological distress Symptom Checklist-90 Obsessive-Compulsive

(NH 153plusmn81 vs PH 123plusmn73 vs H 66plusmn51 plt0001) Interpersonal Sensitivity (NH

114plusmn72 vs PH 95plusmn67 vs H 54plusmn65 p=0007) Depression (NH 211plusmn115 vs PH

176plusmn111 vs H 113plusmn95 p=0005) Anxiety (NH 115plusmn73 vs PH 93plusmn69 vs H

53plusmn58 p=0004) AngerHostility (NH 49plusmn37 vs PH 55plusmn49 vs H 16plusmn15

plt0001) Paranoid Ideation (NH 69plusmn42 vs PH 62plusmn41 vs H 37plusmn37 p=0013) and

Global Severity Index (NH 13plusmn07 vs PH 10plusmn06 vs H 06plusmn05 p=0001) For the

Obsessive-Compulsive AngerHostility subscales and Global Severity Index differences

among groups were driven by nonholderspartial holders vs holders see figure 310 For

the rest of the subscales the difference between groups was driven by nonholders vs

holders with the difference between partial holders and holders approaching

significance Interpersonal Sensitivity (p=0076) Depression (p=0084) Anxiety

(p=0078) and Paranoid Ideation (0059)

Mood Profile Of Mood States subscales tended to be different amongst groups

Specifically holders had lower scores on negative mood subscales (TensionAnxiety

(NH 133plusmn57 vs PH 112plusmn64 vs H 72plusmn52 p=0001) AngerHostility (NH

95

SCL-90 - ObsessiveCompulsive

153

123

66

0

5

10

15

20

25


Ob

se

ssiv

eC

om

pu

lsiv

e S

co

re

SCL-90 - AngerHostility

4955

160

4

8

12


An

ge

rH

os

tility

Sc

ore

SCL-90 - Global Severity Index

06

1013

00

05

10

15

20

25


Glo

bal

Severi

ty In

dex S

co

re

Figure 310 Psychological Distress among groups a) obsessivecompulsive based psychological distress b) Angerhostility based psychological distress and c) Global estimate of psychological distress Partial holders resemble nonholders and differences driven by holders vs partial holdersnonholders

a) b)

c)

plt0001

p=0001

Figure 310 Psychological distress among groups partial holders resemble nonholders

plt0001

96

POMS - DepressionDejection

79

172197

0

10

20

30

40

Holders Partial Holders NonholdersD

ep

ressio

nD

eje

cti

on

Sco

re

POMS - AngerHostility

101112

51

0

5

10

15

20

25


An

ger

Ho

sti

lity

Sco

re

Figure 311 a) Tensionanxiety b) Angerhostility c) Confusion d) Depressiondejection and e) Positive mood among groups Partial holders resemble nonholders and differences are driven by holders vs partial holdersnonholders

b)

d)

POMS - TensionAnxiety

72

112

133

0

5

10

15

20


Ten

sio

nA

nx

iety

Sc

ore

a)

p=0001 p=0009

POMS - Confusion

52

80

97

0

4

8

12

16


Co

nfu

sio

n S

co

re

c)

p=0001

p=0002

Holders Nonholders Partial Holders

Figure 311 Mood states among groups partial holders resemble nonholders

p=0002

POMS - Positive Mood

-15 -116 -155

-40

-30

-20

-10

0

10

20

An

ge

rH

osti

lity

Sc

ore

e)

96

p=0002


97

101plusmn64 vs PH 112plusmn96 vs H 51plusmn53 p=0009) DepressionDejection (NH

197plusmn137 vs PH 172plusmn132 vs H 79plusmn104 p=0002) and Confusion (NH 97plusmn50 vs

PH 80plusmn42 vs H 52plusmn39 p=0001)) and lower scores on Positive Mood composite

subscale (NH -155plusmn150 vs PH -116plusmn151 vs H -15plusmn125 p=0002) Post hoc tests

confirmed that differences were driven by holders vs nonholderspartial holders See

figure 311

Personality On the Neuroticism factor (N-Factor) of the NEO personality inventory

there were significant differences amongst groups (NH 633plusmn123 vs PH 609plusmn100 vs

H 540plusmn88 p=0006) Post hoc tests showed that differences were driven by holders vs

nonholderspartial holders See figure 312 Sub-factors (angerhostility depression

self-consciousness and vulnerability) of the N-Factor support these findings

NEO - Neuroticism Factor

540

609633

40

60

80


N-F

ac

tor

Sc

ore

s

Figure 312 NEO neuroticism factor scores among groups Partial holders resemble nonholders and differences driven by holders vs partial holdersnonholders)

Figure 312 Neuroticism among groups partial holders resemble nonholders

p=0006

98

32213 Partial Holders

Partial holders had less open and less agreeable personalities compared to holders and

nonholders

Personality On the Openness factor (O-Factor) and Agreeableness factor (A-Factor) of

the NEO personality inventory there were significant differences amongst groups O-

Factor (NH 537plusmn100 vs PH 469plusmn92 vs H 536plusmn102 p=0008) and A-Factor (NH

442plusmn86 vs PH 380plusmn106 vs H 476plusmn117 p=0002) Post hoc tests confirmed that

differences were driven by partial holders vs holders and partial holders vs nonholders

see figure 313 Sub-factors of the O-Factor and A-Factor were generally not

significantly different between groups differences were more attributable to the overall

factor scores (for the O-Factor the actions sub-factor was significant for the A-Factor

the straightforwardness and altruism sub-factors were significant)

3222 Patient Satisfaction as a Continuum

Scores on measures of pain sedation psychological distress anxiety and mood

resembled a continuum with partial holders results falling in between nonholder and

holders scores in a stepwise fashion

Pain There were significant differences amongst groups for subscales of the short form

of the McGill Pain Questionnaire Lower patient satisfaction groups showed higher

99

NEO - Openness Factor

536

469

537

30

50

70


O-F

acto

r S

co

res

NEO - Agreeableness Factor

476

380

442

30

50

70


A-F

acto

r S

co

res

Figure 313 NEO a) Openness and b) Agreeableness factor scores among groups Partial holders act as their own group and differences are driven by partial holders vs holders and partial holders vs nonholders

a) b)

Figure 313 Openness and Agreeableness (personality) among groups partial holders different than holders and nonholders

p=0008 p=0002

100

scores on the sensory (NH 136plusmn79 vs PH 111plusmn70 vs H 82plusmn73 p=0027) affective

(NH 54plusmn27 vs PH 39plusmn25 vs H 26plusmn27 p=0001) and total pain (NH 190plusmn99 vs

PH 150plusmn88 vs H 108plusmn94 p=0006) subscales Post hoc tests suggest that these

differences were driven by nonholders vs holders with a stepwise increase in pain scores

as patient satisfaction decreased See figure 314

Drug Effects On the ARCI the PCAG (NH 100plusmn41 vs PH 79plusmn36 vs H 63plusmn38

p=0002) Sedation-Motor (NH 53plusmn32 vs PH 35plusmn30 vs H 28plusmn27 p=0007) and

Sedation-Mental (NH 75plusmn33 vs PH 57plusmn31 vs H 46plusmn30 p=0004) subscales were

significantly different amongst groups Post hoc tests showed that differences among

groups were driven by nonholders vs holders with a stepwise increase in sedation scores

from holder to partial holder to nonholder See figure 315

Psychological Distress According to the Symptom Checklist 90 Somatization (NH

169plusmn89 vs PH 132plusmn83 vs H 90plusmn74 p=0003) Phobic Anxiety (NH 69plusmn62 vs

PH 49plusmn59 vs H 25plusmn42 p=0018)cedil Psychoticism (NH 92plusmn68 vs PH 66plusmn59 vs H

36plusmn47 p=0003) and Positive Symptom Distress Index (NH 18plusmn05 vs PH 17plusmn04

vs H 14plusmn04 p=0024) were significantly different amongst groups and the differences

were driven by nonholders vs holders with a stepwise increase in psychological distress


Anxiety Anxiety as measured by the state subscale of the State-Trait Anxiety Index

(STAIs) and Anxiety Sensitivity Index (ASI) was different amongst groups Lower

101

patient satisfaction groups were associated with greater scores on the STAIs (NH

523plusmn103 vs PH 461plusmn104 vs H 413plusmn108 p=0001) Differences were more

strongly associated with negatively worded anxiety items (NH 213plusmn65 vs PH

177plusmn61 vs H 146plusmn50 p=0001) than positively worded anxiety items (NH 311plusmn52

vs PH 283plusmn60 vs H 267plusmn73 p=0035) ASI scores also tended to be greater in

lower patient satisfaction groups (NH 304plusmn150 vs PH 250plusmn110 vs H 223plusmn82

p=0052) Differences were driven by nonholders vs holders with a stepwise increase in

reported anxiety as patient satisfaction decreased See figure 317

Mood On the POMS groups differed on the Fatigue subscale (NH 124plusmn64 vs PH

94plusmn58 vs H 68plusmn53 p=0003) and Arousal composite subscale (NH -29plusmn96 vs PH

14plusmn76 vs H 31plusmn85 p=0028) Differences were driven by nonholders vs holders

with stepwise increases in fatigue and stepwise decreases in arousal as patient satisfaction

decreased See figure 318

3223 Other Measures

Multivariate ANOVAs were not significantly different nor did they approach significance

among groups for measures of quality of life (SF-36) self-efficacy (DTCQ) and

perceived social support (MSPSS) As such there were no differences detected amongst

groups for these measures

102

323 Discriminant Function Analysis

According to the discriminant function analyses the measures that were the best

discriminators of patient satisfaction groups from each of the constructs or scales with

multiple subscales were The SubOWS score SCL-90-ObsessiveCompulsive score

STAI-s (negative wording) NEO-Agreeableness score NEO-Neuroticism score and

SFMPQ-Affective pain score These measures were used in the final discriminant

function analysis The analysis yielded two significant functions (plt0001 and p=0004

respectively) On the first function SubOWS score had the strongest canonical

correlation This function accounted for 62 of the variance in the analysis Only the

NEO-Agreeableness score exhibited a strong canonical correlation with the second

discriminant function this function accounted for 38 of the variance in the analysis

324 SubOWS Modification

Because SubOWS scores were significantly (plt0001) different between holders and

nonholders and based on the results of the discriminant function analysis a decision was

made that it would not be useful to go forward with the SubOWS modification

103

SFMPQ - Sensory Pain

82111

136

0

5

10

15

20

25


Sen

so

ry P

ain

Sco

re

SFMPQ - Total Pain

108151

190

0

10

20

30

40


To

tal P

ain

Sco

re

SFMPQ - Affective Pain

5439

26

0

2

4

6

8

10


Aff

ecti

ve P

ain

Sco

re

Figure 314 Scores for a) sensory b) affective and c) total pain among groups Scores for partial holders fall between holders and nonholders differences driven by holders vs nonholders

a) b)

c)

Figure 314 Pain measures among groups satisfaction resembles a continuum

p=0027 p=0001

p=0006

104

ARCI - PCAG

6379

100

0

5

10

15


PC

AG

Sco

re

ARCI - Sedation-Motor

28 3553

0

2

4

6

8

10


Se

da

tio

n-M

oto

r S

co

re

ARCI - Sedation-Mental

4657

75

0

4

8

12


Sed

ati

on

-Men

tal S

co

re

a) b)

c) Figure 315 Scores for ARCI drug effects a) Sedation-PCAG b) Motor sedation and c) Mental sedation among groups Scores for partial holders fall between holders and nonholders differences driven by holders vs nonholders

p=0002 p=0007

p=0004

Figure 315 Drug effects (ARCI) among groups satisfaction resembles a continuum

105

SCL-90 - Phobic Anxiety

2549

69

0

5

10

15


Ph

ob

ic A

nxie

ty S

co

re

SCL-90 - Psychoticism

3666

92

0

4

8

12

16


Psych

oti

cis

m S

co

re

SCL-90 - Somatization

90132

169

0

10

20

30


So

mati

zati

on

Sco

re

SCL-90 - Positive Symptom Distress Index

145 166 178

0

1

2

3


PS

DI

Sco

re

a) b)

c) d)

Figure 316 Scores for psychological distress a) Phobic-anxiety based distress b) Psychoticism based distress c) somatization based distress and d) average distress severity among groups Scores for partial holders fall between holders and nonholders differences driven by holders vs nonholders

p=0018 p=0003

p=0003 p=0024

Figure 316 Psychological distress among groups satisfaction resembles a continuum

106

STAI Positve Anxiety

267 283311

20

30

40


Po

sit

ive

An

xie

ty S

co

re

STAI - Negative Anxiety

150 177213

0

5

10

15

20

25

30


Neg

ati

ve A

nxie

ty S

co

re

STAI Total Anxiety

523461427

30

40

50

60

70


To

tal A

nx

iety

Sc

ore

Anxiety Sensitivity Index

223 250311

0

10

20

30

40

50


AS

I S

co

re

Figure 317 Anxiety Scores a) STAI-s negatively worded items b) STAI-s positively worded items c) Total STAI-s score and d) Anxiety sensitivity index scores among groups Scores for partial holders fall between holders and nonholders differences driven by holders vs nonholders

a) b)

c) d)

Figure 317 Anxiety measures among groups satisfaction resembles a continuum

p=0001 p=0035

p=0001 p=0052

107

POMS - Fatigue

12494

68

0

5

10

15

20


Fa

tig

ue

Sc

ore

POMS - Arousal

-2914

31

-15

-10

-5

0

5

10

15

Aro

us

al S

co

re

Figure 318 Mood state scores a) Fatigue and b) Arousal among groups Scores for partial holders fall between holders and nonholders differences driven by holders vs nonholders

a) b)

Figure 318 Mood states among groups satisfaction resembles a continuum

p=0003 p=0028


108




A total of 40 subjects completed the 3-day study protocol Patients were stabilized in

methadone treatment and were heavy smokers see table 1 for a summary of patient

characteristics Urine screens suggested recent use of cannabinoids in 45 of cases of

cocaine in 8 of cases of oxycodone in 8 of cases of morphine in 8 of cases of

codeine in 8 of cases of heroin in 5 of cases and of benzodiazepines in 3 of cases

Recent use of cannabis did not influence study results The prevalence of potential

anxiety disorders in our population according to MINI screening interview were

Agoraphobia 10 social phobia 8 panic disorder 5 obsessive compulsive disorder

5 and generalized anxiety disorder 5

Characteristic Mean (SD)

N 40

Sex 17F23M

Age (yr) 406 (83)

Methadone Dose (mg) 811 (384)

Time on Dose (mo) 110 (218)

Time in Treatment (mo) 734 (658)

Cigarettes per Day 205 (80)

Fagerstroumlm Test for Nicotine Dependence 73 (11)

Age First Smoked (yr) 126 (23)

of Serious Quit Attempts 13 (18)

Baseline Carbon Monoxide (ppm) 80 (24)

Table 34 Subjects were stabilized in their methadone treatment and heavy smokers


109

On the Nicotine and Other Substance Interaction Expectancies questionnaire (NOSIE)

questionnaire subjects rated how they believed smoking and drug use interacted with

each other on four domains The mean scores on the four subscales were ldquosubstance use

increases smokingrdquo (200plusmn36 range 5-25) ldquosmoking increases substance userdquo (61plusmn25

range 3-15) ldquosmoke to cope with substance use urgesrdquo (131plusmn51 range 9-45) and

ldquoreceptive to quitting smoking during drug treatmentrdquo (173plusmn40 range 7-35) These

results indicate that these patients believed that substance use increased their smoking

habits but that smoking did not trigger them to using drugs They also show that the

participants did not believe that they smoked to cope with urges to use drugs and that

patients did not necessarily think that quitting smoking and receiving treatment for

another drug-use disorder were incompatible goals


There was a main effect of methadone to decrease SubOWS scores (plt0001) and a

daymethadone interaction (p=0031) associated with decreased opioid withdrawal on the

cigarette day There was a significant effect of gender on SubOWS scores (p=0025)

with women having greater SubOWS scores particularly during the trough methadone

condition See figure 319 for opioid withdrawal scores across days and cycles between

sexes

There was a main effect of nicotine (plt0001) and methadone (p=0001) to decrease

MNWS scores Effects were driven by the scores on the cigarette day as indicated by

110

daynicotine (p=0003) and daymethadone (p=0004) interactions There was a

significant effect of gender on MNWS scores (p=0036) with women having greater

MNWS scores particularly during the trough methadone condition See figure 320 for

nicotine withdrawal scores across days and cycles between sexes

There was a significant effect of day for POMS-friendliness (p=0015) POMS-elation

(p=0017) VAS-pleasant feelings in mind (p=0026) and VAS-pleasant bodily

sensations (p=0024) The effect of day was such that for all cycles including the pre-

nicotine administration cycles patients rated these measures higher on the cigarette day

Also associated with the smoking day there was an effect of day such that patients rated

POMS-angerhostility (p=0018) lower on all cycles See figure 321 for the effect of

day on the discussed measures across days and cycles

Methadone and nicotine shared many of the same main effects Methadone and nicotine

increased ARCI-stimulation-euphoria (p=0001 and p=0025 for methadone and nicotine

respectively) ARCI-stimulation-abuse potential (plt0001 and plt0001) ARCI-BG

(plt0001 and p=0005) and VAS-pleasant bodily sensations (p=0002 and p=0004)

scores Also methadone and nicotine decreased VAS-irritability (p=0003 and p=0044)

VAS-restlessness (p=0001 and p=0048) VAS-depression (p=0008 and p=0011) and

POMS-angerhostility (p=0049 and p=0035) Figures 322 (methadone and nicotine had

main effects to increase scores) and 5 (methadone and nicotine had main effects to

decrease scores) describe effects of methadone and nicotine on the cigarette day only for

clarity

111

Methadone and nicotine had main effects in the opposite direction for VAS-increased

thinking speed (plt0001 and p=0026 methadone and nicotine respectively) VAS-

difficulty concentrating (p=0025 and p=0031) with nicotine increasing thinking speed

and decreasing difficulty concentrating scores See figure 323 for scores on the cigarette

smoking day

There were main effects of nicotine and day associated with reduced QSU scores This

was evident for all QSU subscales and factors desire to smoke (plt0001 and plt0001

for nicotine and study day (nicotine administration type) respectively) intention to

smoke (plt0001 and plt0001) relief of withdrawal or negative effects (plt0001 and

p=0004) anticipation of positive outcome (plt0001 and p=0001) Factor 1 (plt0001 and

p=0001) and Factor 2 (plt0001 and p=0001) The nicotine effects were mediated by

the cigarette day as indicated by the nicotineday interactions (plt0001 for all measures)

There were no effects of methadone on QSU scores See figure 324 for QSU scores on

the cigarette day Nicotine and day also had main effects on VAS-nicotine effects

(plt0001 and p=0001) VAS-good nicotine effects (plt0001 and plt0001) VAS-

cigarette craving (plt0001 and p=0008) and VAS-I feel high (p=0027 and p=0001)

Again these effects were driven by the cigarette day as indicated by nicotineday

interactions (plt003 for all measures) and methadone had no effects on these measures

See figure 325 for scores on the cigarette day

112

Methadone alone had main effects for a number of measures It increased ARCI-MBG

(p=0001) ARCI-amphetamine (p=0002) POMS-vigor (plt0001) POMS-arousal

(p=0002) POMS-positive mood (p=0004) and VAS-increased energy (p=0001) scores

and decreased ARCI-PCAG (plt0001) ARCI-sedation-motor (plt0001) ARCI-sedation-

mental (p=0004) ARCI-unpleasantness-dysphoria (plt0001) POMS-tensionanxiety

(p=0013) POMS-depressiondejection (p=0026) POMS-fatigue (p=0026) POMS-total

mood disturbance (p=0004) VAS-nasuea (plt0001) VAS-sick (plt0001) VAS-

frustrated (p=0022) VAS-GI disturbances (plt0001) VAS-headache (p=0017) VAS-

dizzy (p=0002) and VAS-drowsy (p=0043) scores See table 35 for the values on these

measures on the cigarette day (as an example of the effect size)

Including the order of nicotine gum (active first or placebo first) or holder status

(holderpartial holdernonholder) into the analysis did not influence study findings

113

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS

Subjective Opioid Withdrawal Scale (SubOWS)

Male Female

Figure 319 Subjective Opioid Withdrawal Scale (SubOWS) scores by cycle and by study day stratified by sex

Figure 319 Subjective Opioid Withdrawal Scale (SubOWS) scores by cycle and by study day stratified by sex Women tended to have greater opioid withdrawal scores particularly during the trough methadone condition There was a main effect of methadone to decrease SubOWS scores There was an interaction between study day and methadone suggesting that opioid withdrawal reduction was enhanced on the cigarette-smoking day

114

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS

Minnesota Nicotine Withdrawal Scale (MNWS)

Male Female

Figure 320 Minnesota Nicotine Withdrawal Scale (MNWS) scores by cycle and study day stratefied by sex Women tended to have higher MNWS scores particularly during the trough methadone condition There were main effects of both nicotine and methadone to reduce MNWS scores Effects were driven by scores on the cigarette-smoking day

Figure 320 Minnesota Nicotine Withdrawal Scale (MNWS) scores by cycle and by study day stratified by sex

115

POMS - Friendliness

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

Fri

en

dlin

ess

Cigarette

Nicotine Gum

Placebo

POMS - Elation

0

5

10

15

M-N- M-N+ M+N- M+N+

Ela

tio

n

Cigarette

Nicotine Gum

Placebo

VAS - Pleasant Feeling in Mind

0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t F

eelin

g in

Min

d

Cigarette

Nicotine Gum

Placebo

VAS - Increase in Thinking Speed

0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Incre

ase in

Th

inkin

g S

peed

Cigarette

Nicotine Gum

Placebo

VAS - Pleasant Bodily Sensations

0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t B

od

ily S

en

sati

on

s

Cigarette

Nicotine Gum

Placebo


0

5

10

15

20

M-N- M-N+ M+N- M+N+

An

ger

Ho

sti

lity

Cigarette

Nicotine Gum

Placebo

a)

d)

b)

c)

f) e)

Figure 321 Effect of Day

115

Figure 321 The effect of day There was a significant effect of day to increase positive feelings a) Friendliness b) Elation c) Pleasant feeling in mind d) Increased thinking speed e) Pleasant feeling in body and and to decrease negative feelings f) Anger and hostility On the cigarette day this effect was prevalent at nearly every cycle this is particularly interesting on the cycles before a cigarette was administered (1 and 3) As such this may represent a non-pharmacological effect of cigarette smoking

116

ARCI - Stimulation-Euphoria

3038

50 58

0

4

8

12

Cigartte Day

ST

ME

N

M-N-

M-N+

M+N-

M+N+

ARCI - Abuse Potential

5162

73 78

0

4

8

12

Cigartte Day

ST

AB

PO

T

M-N-

M-N+

M+N-

M+N+


354521 557 621

0

20

40

60

80

100

Cigartte Day

Ple

as

an

t B

od

ily S

en

sa

tio

ns

M-N-

M-N+

M+N-

M+N+

ARCI - BG

44 4865 73

0

4

8

12

Cigartte Day

BG

M-N-

M-N+

M+N-

M+N+

Figure 322 Methadone and nicotine had main effects to increase a) Euphoria b) Drug liking c) Stimulant effects and d) Pleasant bodily sensations Data is shown for the cigarette day only to clearly demonstrate the effect of nicotine and methadone

a)

d)

b)

c)

Figure 322 Methadone and Nicotine share main effects

Cigarette Day Cigarette Day


117

VAS - Irritable

621501 470

364

0

20

40

60

80

100

Cigartte Day

Irri

tab

le

M-N-

M-N+

M+N-

M+N+

VAS - Restless

620532 506

437

0

20

40

60

80

100

Cigartte Day

Re

stl

es

s

M-N-

M-N+

M+N-

M+N+

VAS - I Feel Depressed

404306 299 259

0

20

40

60

80

100

Cigartte Day

I F

ee

l D

ep

res

se

d

M-N-

M-N+

M+N-

M+N+


78 70 6751

0

5

10

15

Cigartte Day

An

ge

rH

osti

lity

M-N-

M-N+

M+N-

M+N+

Figure 323 Methadone and nicotine both decreased a) Irritability b) Restlessness c) Depression and d) angerhostility Data from the cigarette day only to more clearly demonstrate the effects of methadone and nicotine

a)

d)

b)

c)




118


307417 416

510

0

20

40

60

80

100

Cigartte Day

Inc

rea

se

in T

hin

kin

g S

pe

ed

M-N-

M-N+

M+N-

M+N+

VAS - Difficulty Concentrating

4868 4193 4368 3675

0

20

40

60

80

100

Cigartte Day

Dif

fic

ult

y C

on

ce

ntr

ati

ng

M-N-

M-N+

M+N-

M+N+

Figure 324 Methadone and nicotine have main effects in the opposite direction for a) Increased thinking speed and b) Difficulty concentrating Methadone had a negative effect on thinking capabilities while nicotine had a positive effect on thinking Data from the cigarette day only to clearly illustrate effects of nicotine and methadone

a) b)

Figure 324 Methadone and Nicotine have opposing main effects


119

QSU - Anticipation of Positive Outcomes

448354

438341

0

20

40

60

Cigartte Day

AO

PO

M-N-

M-N+

M+N-

M+N+

QSU - Relief of Withdrawal or Negative Effects

387328

387325

0

20

40

60

Cigartte Day

RO

WO

NE

M-N-

M-N+

M+N-

M+N+

QSU - Intention to Smoke

457360

451357

0

20

40

60

Cigartte Day

ITS

M-N-

M-N+

M+N-

M+N+

QSU - Desire to Smoke

457

327449

328

0

20

40

60

Cigartte Day

DT

S

M-N-

M-N+

M+N-

M+N+

QSU - Factor 1

889

684

875

675

50

70

90

110

Cigartte Day

Facto

r 1

M-N-

M-N+

M+N-

M+N+

QSU - Factor 2

542426

536425

20

40

60

80

Cigartte Day

Facto

r 2

M-N-

M-N+

M+N-

M+N+

a) b)

c) d)

e) f)

Figure 325 QSU scores on the cigarette day

119

Figure 325 QSU scores on the cigarette day Nicotine but not methadone decreased craving for cigarettes on all subscales and composite scales of the QSU a) Anticipation of positive outcomes b) relief of withdrawal and negative effects c) intention to smoke d) desire to smoke e) Factor 1 (positive outcomes related) and f) factor 2 (relief of negative affect related)




120

VAS - I Feel a Nicotine Effect

313

593

346

582

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+

VAS - I Feel a Good Nicotine Effect

244

592

224

633

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Go

od

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+

VAS - I Crave a Cigarette

810

498

835

513

0

20

40

60

80

100

Cigartte Day

I C

rave

a C

iga

rett

e

M-N-

M-N+

M+N-

M+N+

VAS - I Feel High

167

352234

340

0

20

40

60

80

100

Cigartte Day

I F

eel

Hig

h

M-N-

M-N+

M+N-

M+N+

Figure 326 Cigarette day data for a) Nicotine effects b) Good nicotine effects c) cigarette craving and d) Feeling high Like QSU scores only nicotine and not methadone was able to increased nicotine effects and feelings of highness and decrease craving

a) b)

c) d)

Figure 326 VAS scores on the cigarette day



121

Measure Cycle 1 Cycle 2 Cycle 3 Cycle 4 p

Increased by Methadone

ARCI-MBG 35 (31) 42 (33) 56 (43) 70 (53) 0001

ARCI-Amphetamine 32 (21) 34 (27) 43 (27) 49 (30) 0002

POMS-Vigor 66 (51) 74 (48) 98 (59) 94 (55) lt0001

POMS-Arousal 08 (99) 12 (88) 38 (119) 41 (84) 0002

POMS-Positive Mood -55 (94) -46 (99) -12 (94) 00 (79) 0004

VAS-Increased Energy 261 (208) 375 (269) 426 (268) 451 (269) 0001

Decreased by Methadone

ARCI-PCAG 80 (38) 79 (40) 55 (36) 51 (37) lt0001

ARCI-Sedation Motor 33 (28) 41 (30) 19 (26) 23 (27) lt0001

ARCI-Sedation Mental 56 (33) 59 (35) 50 (31) 40 (31) 0004

ARCI-Unpleasantness Dysphoria 29 (20) 25 (21) 16 (19) 16 (18) lt0001

POMS-TensionAnxiety 99 (56) 93 (58) 82 (52) 68 (43) 0013

POMS-DepressionDejection 108 (79) 107 (94) 88 (83) 75 (71) 0026

POMS-Fatigue 93 (70) 87 (60) 76 (63) 68 (50) 0026

POMS-Total Mood Disturbance 376 (272) 352 (302) 279 (264) 221 (214) 0004

VAS-Nausea 299 (265) 354 (287) 164 (262) 167 (236) lt0001

VAS-Sick 338 (284) 313 (289) 184 (254) 171 (228) lt0001

VAS-Frustrated 538 (282) 465 (307) 427 (303) 335 (313) 0022

VAS-GI Disturbances 339 (310) 315 (318) 148 (243) 137 (205) lt0001

VAS-Headache 255 (314) 271 (307) 257 (339) 202 (296) 0017

VAS-Dizzy 242 (243) 335 (293) 164 (224) 183 (254) 0002

VAS-Drowsy 528 (252) 494 (272) 463 (289) 431 (394) 0043

Table 35 Methadone Effects Repeated Measures ANOVA

Table 35 Example results where methadone increased or decreased scores on the various measures ARCI = Addiction Research Center Inventory POMS = Profile of Mood States VAS = Visual Analog Scales

122


Methadone plasma concentrations were not different among study days with average

trough concentrations of 3204plusmn2242 ηgmL 33154plusmn2044 ηgmL and 3169plusmn2207

ηgmL on the cigarette day (cig) nicotine gum day (nic) and placebo gum day (pla)

respectively See figure 326 Peak methadone concentrations ranged from 70 ηgmL to

1280 ηgmL across the study days

Nicotine plasma concentrations were significantly greater on the cigarette smoking day

compared to both the active and placebo gum days both at cycle two (cig 185plusmn216

ηgmL vs nic 113plusmn263 ηgmL vs pla 91plusmn219 ηgmL) and at cycle four (cig

234plusmn280 ηgmL vs nic 118plusmn155 ηgmL vs pla 71plusmn129 ηgmL) plt0001 see

figure 327 There was a main effect of nicotine (cycle) on cotinine and hydroxyl-

cotinine concentration with lower plasma levels during cycle 4 compared to cycle 2

(plt0001 p=0001 respectively)

Methadone Plasma Concentration (ηgmL)

0

200

400

600

800

Cigarette Nicotine Gum Placebo Gum

Me

tha

do

ne

Co

nc (η

gm

L)

Cycle 2

Cycle 4

Figure 327 Methdone plasma concentration by study day Cycle 2 is pre-methadone and cycle 4 is post-methadone There were no differences between study days in methadone levels Methadone levels were significantly greater in the post-methadone dose condition 122

123

Nicotine Plasma Concentration (ηgmL)

0

20

40

60


Nic

oti

ne

Co

nc

(η

gm

L)

Cycle 2

Cycle 4


0

5

10

15

20

25

Cigarette Nicotine Gum

Nic

oti

ne

Co

nc

(η

gm

L)

Cycle 1Cycle 2Cycle 3Cycle 4

Figure 328 a) Nicotine plasma concentration by study day Cycle 2 corresponds to the cycle following the first nicotine administration and cycle 4 corresponds to the cycle following the second nicotine administration There was a main effect of day such that nicotine levels were greatest on the cigarette day b) Utilizing the placebo gum day nicotine levels estimates for cycles 1 and 3 were derived for the cigarette and active nicotine gum days This is not meant to represent true values but rather to illustrate the accumulation of nicotine on the cigarette day in comparison to the active gum day

a)

b)

Figure 328 Nicotine levels

124

Section 4 GENERAL DISCUSSION CONCLUSIONS amp RECOMMENDATIONS



Patients (Study 1)

In Study 1 the influence of depression and satisfaction with methadone treatment on

methadone pharmacology was systematically investigated over one dosing interval

Depressed methadone maintenance treatment patients experienced more opioid

withdrawal symptoms and increased dysphoric effects compared to nondepressed

methadone maintenance treatment patients This is consistent with documented negative

impacts of depressive disorder on the course of other diseases and illnesses121 Also

current depression has been associated with poorer methadone maintenance treatment

outcomes122-125 Therefore it is possible that the effect of depression on methadone

maintenance treatment is to contribute to a decrease in patientsrsquo satisfaction with

treatment as reported by an increase in the perceived level of opioid withdrawal

experienced The significant correlation between depression severity (HAMD scores)

and trough methadone condition withdrawal symptoms (SubOWS24) supports this

concept As well trend results showing higher withdrawal scores in currently depressed

participants compared to those who are currently not depressed but have a past history of

major depressive disorder lends further support Specifically the negative impact of

major depressive disorder on methadone pharmacodynamics appears to be related to

current negative mood symptomatology It is also possible that depressed methadone

maintenance treatment patients are more sensitive to negative experiences in general

125

This is supported by our findings that depressed methadone maintenance treatment

patients had more dysphoric effects over the dosing interval compared to nondepressed

methadone maintenance treatment patients and that depression severity (HAMD scores)

and the AUEC of a composite scale of negative ARCI subscales were significantly

correlated

Overall our results may suggest that treating depressive symptomatology in methadone

maintenance treatment patients with concurrent major depressive disorder may lead to

better patient satisfaction with methadone treatment Effective treatment of depression is

particularly important as current depression prevalence rates in this population are 20

or more and past 6 months depression prevalence rates are more than 4010 11 225

Prevalence estimates of current depressive symptomatology based on Hamilton

depression scores are even higher (50)226 Also in a recent study by Schreiber et al

depression severity was shown to decrease over time in methadone maintenance

treatment227 A more recent study by Galynker et al supports this using

[18F]fluorodeoxyglucose positron emission tomography they show that aberrant mood

processing in the left perigenual anterior cingulate cortex and mid-cingulate cortex is

present in opioid-dependent patients who are long-term abstinent but is absent in

methadone maintained patients suggesting that methadone treatment may improve mood

regulation in methadone maintenance populations228 Interestingly a specific region of

the anterior cingulate cortex the subgenual cingulate region has been targeted in deep

brain stimulation for treatment-resistant depression229 Since depressed patients in our

study were stabilized in methadone treatment for an average of more than 15 years yet

still suffering significant depressive symptomatology (even with two on antidepressants)

126

it is likely that they would benefit from aggressive treatment of depressive symptoms

which may impact positively on treatment satisfaction

While there was no difference in depression severity (HAMD) between holders and

nonholders there was a trend towards increased negative mood on the POMS measures

of depression and mood disturbance in nonholders Surprisingly there was not a

detectable difference between holders and nonholders using the SubOWS Nor were

there any detectable differences between holders and nonholders on other

pharmacodynamic measures studied The likely reason for lack of pharmacodynamic

differences was the small sample size in the nonholder group In terms of opioid

withdrawal other factors are possibly involved It is likely that a patientrsquos perception of

withdrawal is comprised of a combination of physical and psychological withdrawal

symptoms The psychological symptoms associated with opioid withdrawal could have

increased salience during an opioid substitution therapy treatment (eg methadone

maintenance treatment) because physical withdrawal is minimized in this context

Alternatively the method of subject self-report as a means to identify patient satisfaction

groups may have limited the ability to detect differences between the groups Many

subjects considered their situation to be more complicated than a dichotomous

categorization of being lsquoheldrsquo for a full dosing interval or not It is possible that a more

graded identification system that accounts for the complexity of opioid withdrawal would

make it easier for patients to identify their current state This was employed in Study 2

with the help of a guided self report screening process subjects found this system to be

more intuitive

127

Although there were no detectable differences in pharmacodynamic measures between

holders and nonholders there were differences in the pharmacokinetics of unbound (S)-

methadone between holders and nonholders It is interesting that nonholders had higher

unbound (S)-methadone exposure (Cmax C24 Css and AUC) compared to holders (R)-

methadone is considered the active isomer of methadone2 49-52 230 while (S)-methadone

has been associated with limited opioid activity48 50 51 Mitchell and colleagues showed

that (S)-methadone was associated with negative mood states and withdrawal53 It is

plausible that negative mood states associated with increased exposure to (S)-methadone

relates to patient dissatisfaction Mitchell and colleagues also suggested that patients

with an unfavourable subjective effects profile (ie unacceptable negative mood states)

who have had more exposure to (S)- vs (R)-methadone may benefit by a change in

treatment strategy (eg to a different opioid substitution therapy or to (R)-methadone

instead of (RS)-methadone) if available53 Evidence from Study 1 supports this Poor

satisfaction with treatment is often assumed to be related to the elimination rate of

methadone in the individual If this is the case dividing the daily methadone dose may

be appropriate If however poor satisfaction is related to increased exposure to (S)-

methadone then alternate treatment options should be explored

Unfortunately the pharmacodynamic modelling did not produce results that could be

used for comparison with other studies There are many potential explanations for this

Since patients were on their methadone dosage to steady-state the range of methadone

plasma concentrations was limited It is also possible that pharmacodynamic responses

vary little over the dosing interval particularly with stabilized patients These conditions

of flat pharmacokinetic or pharmacodynamic profiles were prevalent in data from Study

128

1 Dyer and colleagues have also had difficulty fitting steady-state data into this model9

92 It is interesting that accounting for both enantiomer and protein binding alone or

together did not lead to a better fitting model

The limitations of this study include the dichotomous classification system between

holders and nonholders This may have limited a subjectrsquos ability to properly self-

identify with one of the two groups It may be that the ability to detect and respond to

opioid withdrawal is sufficiently complex to warrant expanding the grouping criteria A

more even split between the holder vs nonholder groups may have resulted in an

increased power to detect differences The fact that two of the seven patients in the

depressed group were being treated with antidepressants is also a limitation However

all depressed patients were currently symptomatic and those on antidepressants were at a

steady-state condition limiting the impact of antidepressant use on study findings It is

also worth noting that this was a preliminary study (α=01) that was powered to detect

differences among patients grouped based on both depression and holder status

nondepressed holders nondepressed nonholders depressed holders and depressed

nonholders These groupings were not possible because of sample size constraints

Because of this and difficulty with the primary outcome modelling endpoints

interpretations of the findings of Study 1 are based on secondary study outcomes and

dichotomous grouping of patients Multiple comparisons were made in this study

increasing the risk of Type 1 errors Despite these limitations findings from Study 1 are

in agreement with findings from Study 2

129



(Study 2)

In Study 2 methadone maintenance treatment patients were characterized with respect to

patient satisfaction with treatment Many factors were able to differentiate methadone

patients who self-identified as holders partial holders and nonholders Specifically

partial holders resembled holders on measures of opioid withdrawal craving pain

intensity drug liking (ARCI abuse potential) dysphoria and unpleasant drug feelings

On the other hand partial holders resembled nonholders on measures of psychological

distress (globally and specifically on obsessivecompulsive and angerhostility

subscales) negative mood (increased tensionanxiety angerhostility confusion

depressiondejection and decreased positive mood) and neuroticism These separable

dimensions (physical withdrawal vs negative emotionality or intolerance for negative

affect) help to explain the difficulties patients experienced when self-reporting as holders

or nonholders in Study 1 Partial holders would find this particularly difficult Although

they may report equivalently low levels of physical withdrawal as the holder group they

may also be experiencing psychological distress and negative mood symptoms and thus

still be dissatisfied with treatment Findings from the NEO also revealed that partial

holders were less open and less agreeable in general than both holders and nonholders

making partial holders more likely to express dissatisfaction with treatment compared to

the other groups

130

Whereas opioid withdrawal scores can be used effectively to distinguish holders from

nonholders they appear to be of less value in detecting partial holders from holders This

suggests that although physical opioid withdrawal is an important factor in understanding

patient satisfaction with methadone treatment other factors are also important eg mood

and psychological measures

These mood and psychological factors may be particularly important as there is a high

prevalence of psychiatric comorbidity in methadone maintenance patients Mason et al

showed that methadone maintenance treatment patients had an average of 23 current

diagnoses excluding drug abusedependence10 Most common were phobic disorders

(45) antisocial personality (37) any depressive disorder (32) generalized anxiety

disorder (32) and obsessivecompulsive disorder (20)10 Further comorbid

diagnoses are regularly associated with poorer treatment outcomes16 The prevalence of

agoraphobia (assessed with the MINI) was greater in nonholders and that the prevalence

of current depression in partial holders and nonholders tended to be greater than that in

holders Depression in particular has been associated with poor methadone treatment

outcomes122-125

Because partial holders resembled holders with respect to opioid withdrawal

symptomatology craving and drug liking it is not surprising that clinicians may be

suspicious of their complaints of dissatisfaction with treatment Partial holders appear to

have a lower threshold for tolerating these symptoms or functioning despite them

Assessing psychological and mood factors when objective indices do not support

breakthrough withdrawal symptoms could provide a mechanism for validating patient

131

complaints The brief screening guide developed for this study could be of utility when

treating challenging patients

It is interesting that current and average pain intensity scores were higher in the

nonholder group compared to both the partial holders and holders Comorbid pain is

prevalent in methadone treatment patients (37-61)231-233 and has been associated with

more psychiatric disturbance poorer health increased medication use and an increased

likelihood for patients to perceive themselves as under-treated232 It is possible that pain

symptoms are enhancing perceived opioid withdrawal and contributing to patient

dissatisfaction

Pain has often been characterized as a signal detection phenomenon234 whereby the

stimulus (signal) has some objective intensity (eg 2nd degree burn) and the patient has a

response bias (criterion for reporting the signal) that may be conservative (disinclined to

report it lsquostoicrsquo) or liberal (inclined to report it lsquohistrionicrsquo) The present findings

indicate that signal strength and response bias may similarly each contribute to the extent

of relief patients receive from methadone treatment Future studies could benefit by

incorporating procedures from the pain literature to better operationalize the objective

and subjective aspects of opioid withdrawal

Study 2 results suggest that for a number of measures (sensoryaffective pain sedative

drug effects anxiety psychoticism fatigue and arousal) patient satisfaction follows a

continuum Intuitively one would expect this pattern (where partial holders fall between

nonholders and holders) for many measures It is noteworthy that physical opioid

132

withdrawal did not follow this providing further support that patient satisfaction with

treatment is complex

Treating psychological distress and negative mood symptoms in dissatisfied methadone

maintenance treatment patients could lead to improved treatment satisfaction It is

possible that treating these symptoms in partial holders could improve their satisfaction

with treatment and retention Nonholders however may derive less benefit as it seems

that physical opioid withdrawal and craving may play a greater role in patient

dissatisfaction for them although the measurable constructs that suggested patient

satisfaction followed a continuum suggest that nonholders could derive some benefit

particularly on those constructs

Based on the discriminant function analysis the SubOWS (physical opioid withdrawal)

and the NEO-Agreeableness Factor (agreeable personality) were the most capable of

predicting patient satisfaction group membership These results provide empirical

support for the characterization of sub-groups based on both subjective symptom severity

and on the tendency to tolerate sub-optimal relief

A limitation of this study was measuring the various factors only near the trough

methadone condition It is possible that interesting differences would have been detected

during the peak methadone condition when physical opioid withdrawal is minimal

Utilizing a non-validated screening tool to assign patient grouping was a limitation

however the results suggest that the screening tool supported groupings that were distinct

on many measures The patient population in this study was heterogeneous with

reasonably high levels of comorbid psychiatric disorders and positive urine drug screens

133

While there were few differences amongst the patient satisfaction groups on these

measures there were noted differences in rates of agoraphobia and depression This may

have had an impact on study results The data analysis strategy for this study called for

multiple multivariate analyses While the sample size in this study was large from the

perspective of logistics and feasibility it was not sufficiently large to make all of the

multiple comparisons in one MANOVA As such data was reduced using groupings

based on logical conceptual associations There are inherent limitations to self-reported

data some patients may respond inconsistently However this study was primarily

focused on patientsrsquo perceptions and therefore self-report is an appropriate tool for these

assessments



Study 3 was an investigation of interactions between methadone and nicotine during

withdrawal and agonist effect conditions of each drug It was found that mixed

interactions where agonist effects of one drug interacted with withdrawal effects of the

other occurred specifically on the cigarette day nicotine enhanced opioid withdrawal

suppression (figure 41 box 3) and methadone attenuated nicotine withdrawal (figure 41

box 2) Methadone and nicotine shared many of the same main effects (figure 41 box

1) specifically to increase positive drug effectsfeelings (eg ARCI-stimulation-euphoria

ARCI-stimulation-abuse potential (liking) and VAS-pleasant bodily sensations) and to

decrease negative drug effectsfeelings (eg VAS-restlessness VAS-irritability ARCI-

134

unpleasantness-physical and POMS-angerhostility) Also methadone and nicotine had

opposing main effects for thinking speed and difficulty concentrating (figure 41 box 1)

A possible non-pharmacological effect of cigarette smoking was detected with patients

reporting increased positive feelings (eg POMS-friendliness POMS-elation and VAS-

pleasant feeling in mind) and decreased negative feelings (POMS-angerhostility) on the

smoking day even prior to receiving a cigarette non pharmacological effects of smoking

could interact with agonist or withdrawal effects of methadone (figure 41 boxes 1 and

3) Together the results could help to explain the high smoking prevalence rates in

methadone patients13-18 and may account for methadone patients reporting increased

positive effects when they take both drugs together164

Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

4 3

2


Figure 41 Repeat of Figure 12 Model representing potential interactions between methadone and nicotine The (+) sign represents agonist effects present the (-) sign represents withdrawal effects present There can be additivesynergistic interactions (boxes 1 and 4) or mixed interactions with agonist effects of one drug interacting with withdrawal effects of the other (boxes 2 and 3)

135

Mixed agonist effectswithdrawal effects interactions are of particular interest with the

potential for one drug to alleviate withdrawal associated with the other drug Cigarette

smoking was able to attenuate opioid withdrawal during the peak methadone condition

This supports the finding of Spiga et al22 suggesting that methadone is a more effective

reinforcer when tobacco smoke is concurrently available Methadone attenuated nicotine

withdrawal on the cigarette smoking day Richter et al reported that methadone patients

who smoke smoke the most frequently from the time of their methadone dose until four

hours afterwards regardless of the time of methadone administration and that variability

in smoking pattern is decreased in methadone patients who smoke compared to regular

smokers165 It is possible that methadonersquos ability to attenuate nicotine withdrawal plays

a role in reducing variability associated with smoking patterns and in the development of

a characteristic smoking pattern in methadone maintenance treatment patients It is also

possible that for methadone patients increased positive effects of methadone mediated

by cigarette smoking leads to a greater drive to smoke than the drive associated with

alleviating nicotine withdrawal specifically at the peak methadone condition It is

interesting that nicotine withdrawal but not tobacco craving QSU scores and VAS-

craving was affected by methadone Specifically there was no effect of methadone on

the QSU subscale related to the anticipation of positive outcomes from cigarette

smoking If the signature smoking pattern in methadone patients is related to increased

positive effects it is possible that methadone-maintained smokers would have a greater

score on this subscale compared to regular smokers

There was a significant effect of sex such that women reported significantly more opioid

withdrawal and nicotine withdrawal particularly during the trough methadone condition

136

Sex differences did not influence study findings related to opioid and nicotine

withdrawal This is not supported in the literature although there are some animal

studies that suggest sex differences In rats μ-opioid agonists have lower efficacy in

females in mice males develop greater physical dependence235 236

There was no effect of holder status on study outcomes This suggests that methadone-

nicotine interactions identified in Study 3 are present in all types of methadone

maintenance treatment patient and that smoking may play an important role in stabilized

methadone treatment regardless of satisfaction level with treatment

It is possible that the non-pharmacological effects noted for cigarette smoking were

related to an expectancy to smoke The smoking day was not part of the blinding

process and as such subjects knew they would be smoking a cigarette directly after

responding to the questions during the pre-nicotine cycles In an fMRI study expectancy

has been associated with brain activation in anterior cingulate cortex posterior cingulate

cortex dorsomedial prefrontal cortex dorsolateral prefrontal cortex medial orbital

frontal cortex anterior insula superior temporal gyrus ventral pallidum and dorsomedial

thalamus (areas associated with arousal attention and cognitive control) following the

presentation of smoking cues this was not seen when subjects did not expect to smoke

despite the fact that under both conditions self-reported craving scores were similar237

It was expected that behavioural effects of cigarette smoking would be detected by

comparison with the nicotine gum day However there were no differences between the

placebo gum day and active gum day Further both placebo and active gums did not

decrease cigarette craving It has previously been reported that both placebo nicotine

137

gum and 4-mg nicotine gum were able to decrease smoking craving equally however

both were administered serially for four hours238 There were no differences in nicotine

levels between the active and placebo gum days this could account for the lack of effect

of nicotine gum

NOSIE results suggested that study participants believe that drug use increased their

smoking rate but that smoking didnrsquot alter their use of drugs They also reported that they

do not smoke to cope with urges to use drugs and that smoking cessation treatment and

methadone maintenance treatment are not necessarily incompatible goals These results

are in agreement with the results of Stein et al166 Results from Study 3 do support the

concept that methadone use leads to increased smoking and could be related to an

enhancement of positive effects when the two are combined as discussed previously It

is interesting that subjects did not believe that smoking influenced their use of

methadone It is possible that this is more difficult to report because their use of

methadone is very structured (same dose daily at roughly the same time) Results from

Spiga et al suggested that nicotine can influence methadone self-administration23 Had

these been an opioid abusing population different results may have been noted Although

patients did not believe that smoking helped to attenuate craving during opioid

withdrawal the results of Study 3 do not support this Specifically nicotinesmoking

effects seem to be minimizing urges for opioids as many of the main effects of

methadone and nicotine were similar and because smoking enhanced opioid withdrawal

suppression

138

It is not surprising that patients believed that smoking cessation and methadone

maintenance treatment were possible simultaneously as there is a high level of interest in

smoking cessation among methadone patients16 18 19 158 159 In one study methadone

patients had lower nicotine dependence scores and had greater interest in smoking

cessation compared to active opioid abusers159 There is also evidence that methadone

treatment is associated with positive changes in smoking behaviour Methadone patients

reported smoking fewer cigarettes per day and choosing cigarette brands with lower

nicotine content after starting methadone treatment However they may have

compensated for decreased nicotine content by inhaling smoke more deeply or smoking

more of the cigarette239 These positive changes in methadone patients compared to active

opioid abusers suggest that they may be more responsive to smoking cessation strategies

Because of the very high smoking rates13-18 and the fact that smoking is a major predictor

or morbidity and mortality in methadone maintenance patients156 157 smoking cessation

could lead to significant health improvements in this population There have been trials

to evaluate smoking cessation strategies for patients in opioid substitution therapy

utilizing different behavioural and pharmacotherapeutic options21 167 240-243 Results have

shown negative results or modest success in smoking cessation rates Recently Mooney

et al noted that there continues to be a deficiency of evidenced-based smoking cessation

treatment options in opioid-dependent individuals240

Tailoring smoking cessation strategies for methadone maintenance treatment may be

beneficial based on Study 3rsquos findings Certainly both methadone and nicotine have

similar main effects this suggests that during times of peak methadone condition their

influence on each other is greatest this again supports patientsrsquo self-report of using both

139

drugs to enhance methadone pleasing effects164 In terms of nicotine replacement therapy

(NRT) it would be important to account for this and plan for maximal coverage during

this timeframe Identification of the interactions between methadone and nicotine is also

important in the sense that they provide education targets so that patients could be made

aware of what to expect and so that they could prepare themselves and develop coping

strategies Because methadone attenuated nicotine withdrawal it could be particularly

detrimental to introduce methadone dosage reductions during smoking

cessationreduction attempts Richter et al165 suggest that nicotine directly affects not

only the reinforcing effects of methadone but perhaps the therapeutic value of methadone

and hence it is possible that nicotine could play an important part of the stabilization of

methadone maintenance treatment In fact a significant percentage of methadone clinic

leaders believe that smoking in some way benefited a patientrsquos methadone treatment244

Interactions reported here provide potential mechanisms through which nicotine could

have these effects Hence it could be particularly difficult for methadone maintenance

patients who smoke to quit smoking as nicotine could be playing a role that is central to

their methadone treatment outcomes165 At the same time if the interactions reported here

are involved in the stabilization of methadone treatment for some patients then it may be

prudent to monitor methadone treatment outcomes during smoking cessation attempts

The limitations of this study include the minimal effect of the nicotine gum It was not

possible to attribute interactions to nicotine derived from the nicotine gum as it did not

differ from placebo with respect to the various subjective measures and plasma levels

As such nicotine effects were driven by the cigarette-smoking day Another limitation

was the modest effect size compared to the variability in many nicotine effect measures

140

It is important to note that while modest effects were consistent throughout the data It

is not surprising that nicotine effects were modest considering that they were based on

smoking one cigarette Another limitation of this study was the difference in smoking or

nicotine abstinence time prior to testing at the trough and peak methadone conditions

Patients were required to abstain from smoking for 12 hours before the testing cycles

during the trough methadone condition and only for three hours before the testing cycles

during the peak methadone condition This suggests that patients may have experienced

differential smoking abstinence effects during the pre-nicotine conditions This was

minimized because patients had only a minimal exposure to smoking or nicotine prior to

the testing during the peak methadone effects condition and because QSU and other

craving measures were similar both pre and post cigarette administration during the

trough and peak methadone conditions With a sample size of 40 subjects and three

between-subjects factors (sex holder status and order of nicotine administration) it is

possible that there was insufficient power to detect the impact of these factors

44 Overall Discussion and Conclusions

Results from Study 1 suggest that nonholder methadone patients have increased exposure

of (S)- vs (R)-methadone This supports the concept that differences between holder and

nonholder methadone maintenance patients is related to pharmacokinetic differences and

further supports the emerging concept that (S)-methadone may be responsible for the

negative effects associated with methadone treatment Findings have also shown that

depressed methadone maintenance patients are more sensitive to negative opioid effects

141

Specifically they report increased levels of opioid withdrawal and dysphoria These

findings suggest that identification and treatment of depression in methadone

maintenance populations could lead to improved satisfaction with methadone treatment

Results from Study 2 suggest that patient satisfaction with methadone maintenance

treatment is complex and that some patients do not fit into a dichotomous

holdernonholder grouping system Partial holders resemble satisfied patients when

assessing opioid withdrawal craving drug liking and pain intensity while at the same

time they resemble dissatisfied patients with increased psychological distress negative

mood and neuroticism As suggested earlier it is possible that treating psychological

distress and negative mood in methadone maintenance patients could lead to improved

satisfaction with treatment The brief patient satisfaction screening guide developed for

this study could facilitate this Also the brief screening guide could have research utility

in studies evaluating methadone treatment outcomes Overall the results suggest that

although physical opioid withdrawal symptoms are an important factor in assessing

patient satisfaction with treatment the ability or willingness to tolerate these symptoms

are also important considerations in patients in methadone maintenance treatment

Study 3 shows that interactions between agonist and withdrawal effects of methadone and

nicotine occur specifically by attenuating withdrawal states associated with each other

and by increasing positive effectfeelings and decreasing negative effectfeelings Not

only nicotine effects but also behaviours associated with cigarette smoking appear to

mediate these interactions These interactions may constitute an important component of

stabilized methadone maintenance treatment Studying interactions between methadone

142

and nicotinesmoking can be of utility in advising smoking cessation strategies that are

tailored to methadone maintenance treatment patients

Findings from Study 1 did not support the idea that nonholders have faster maximum

rates of decline in methadone plasma concentrations than holders as suggested by Dyer

et al92 The finding that (S)-methadone exposure was greater in nonholders in Study 1

supports the concept that pharmacokinetics can explain the differences between holders

and nonholders At the same time findings from Study 1 and particularly Study 2

suggest that depression psychological distress and negative mood states are also

important in explaining differences between holders and nonholders In Study 1 there

were no reported differences between holders and nonholders for any pharmacodynamic

measures including opioid withdrawal however there was a trend to greater

depressiondejection and negative mood disturbance on the POMS As discussed

previously this is likely a result of the small sample size in the nonholder group in Study

1 However it supports the findings in Study 2 that suggest that negative mood states

could have an impact on patient satisfaction and opioid withdrawal perception Overall

it would seem that patient satisfaction with methadone maintenance treatment can be

related to pharmacokinetic and pharmacodynamic differences between those satisfied and

those dissatisfied with treatment These factors could be acting separately or together

depending on the individual thus making it difficult or challenging to treat dissatisfied

patients

A model to explain how the three studies presented above align with the overall

hypothesis of this work is presented in figures 42 and 43 In figure 42a the overall

143

hypothesis is presented and figure 42b explains where the individual studies fit into the

model In figure 43 a revised model is presented revisions to the model are based on

study findings

The co-occurrence of depression and smoking or nicotine dependence in methadone

maintenance patients is not surprising based on the prevalence rates of both conditions

alone in the population Clinicians would likely have different opinions on how to best to

treat a methadone patient who presents as depressed and interested in quitting smoking

In a study by Stein et al the association between depression and success in smoking

cessation efforts was studied245 They found that depressed patients were less likely to set

a quit date however there were no differences in motivation to quit smoking245 In

another recent study Wapf et al examined barriers to smoking cessation in methadone

and buprenorphine maintained individuals in Switzerland246 Interestingly they found

that a diagnosis of depression was associated with readiness to quit smoking246 Based on

these findings it would seem that initiating smoking cessation therapy in methadone

maintenance treatment patients suffering from concurrent depression would be beneficial

Variability in the acute response to psychoactive medications is well accepted It is

possible that variability in expectancy of drug effects contributes to this There are well

documented effects from placebo administration in the pharmacotherapy of depression

generally it is accepted that 50 of depressed patients show placebo-associated

improvements in antidepressant clinical trials247 Placebo-associated improvements are

more pronounced in the treatment of depression compared to other psychiatric disorders

which may be linked to high levels of psychological distress and insight in depressed

144

patients248 An fMRI study has shown that placebo treatment in depressed patients was

associated with the activation of the limbic system prefrontal cortex and ventral

striatum regions that were activated with fluoxetine treatment249 These activated regions

are associated with anticipation and reward Placebo response in depressed patients is not

limited to antidepressant medications In experimental studies of dextroamphetamine

effects placebo responses were greater in depressed patients compared to controls250 251

Both Study 1 and Study 2 included depressed participants It is possible that robust

placebo responses seen in depressed participants in general may account for a component

of the variability in responses seen in these studies Study 3 was the only study that

utilized a placebo control Denicotinized cigarettes have been associated with smoking

effects and a reduction in nicotine withdrawal and craving252-256 Also in methadone

maintained patients acute administration of active nicotine gum (4 mg every 30 minutes

for 4 hours) or placebo was associated with equivalent decreases in craving for

nicotine238 In Study 3 the response to placebo and active nicotine gum were not

different However there were differences noted compared to the cigarettes smoking

day Specifically there was an expectancy effect associated with cigarette smoking that

was noted on the cigarette day during the pre-cigarette administration conditions

Methadone has had tremendous success and acceptance in the more than 40 years that it

has been used Nonetheless new challenges for treatment have arisen Patients are both

younger and older than ever before5 The younger patients bring high rates of comorbid

substance abuse as well as the cognitive and emotional dynamics of youth and early

adulthood into the clinics5 Older patients are a great testament to the success of long

term methadone treatment However at the same time older methadone patients suffer

145

from the same ailments as other elderly individuals adding to the challenge of treating

elderly or geriatric patients in methadone treatment5 257 258 As well methadone patients

have a high prevalence of depression and anxiety Marion estimates that 60 of the

patients treated in his New York clinic have treatable depression or anxiety a number

that is much greater than seen previously5 Regardless of whether this estimate is high or

whether the increased prevalence noted is due to better detection systems findings from

the studies presented here suggest the importance of treating these ailments The

prevalence of dissatisfaction with methadone treatment among patients ranges from more

than one third to more than one half7 this is clinically unacceptable improving this

through the treatment of mood and psychological factors andor the switching of patients

to an alternate opioid substitute (ie buprenorphine) as appropriate perhaps should be one

of the next targets set for the improvement of MMT in the future

146

Pharmacokinetics Comorbid Psychiatric Disorders Drug Interactions

Figure 42 Model of overall hypothesis

a)

b)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 1


Figure 42 a) Model representing the overall hypothesis proposed Pharmacokinetics comorbid psychiatric disorders and drug interaction were identified as factors influencing the relationship between methadone effectswithdrawal and patient satisfaction with treatment b) Emphasis (in red) of how Study 1 fits with the overall hypothesis Study 1 examined the influence of pharmacokinetics and major depressive disorder on methadone effects and opioid withdrawal their relationship with satisfaction with methadone treatment as well as satisfaction with treatment directly

147


Figure 42 Model of overall hypothesis - continued

c)

d)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 3


Figure 42 c) Emphasis (in red) of how Study 2 fits with the overall hypothesis Study two was an investigation of opioid withdrawal patient satisfaction and the relationship between them d) Emphasis (in red) of how Study 2 fits with the overall hypothesis Study 3 examined the influence of smoking on methadone effects and opioid withdrawal

Study 2

148

Methadone

Effects

Physical

Psychological

Figure 43 Revised model

Figure 43 Revised model based on study findings Opioid withdrawal is composed of more than physical opioid withdrawal symptoms Study two has demonstrated that psychological factors have impact on perceived opioid withdrawal with many mood and psychological distress factors differentiating the opioid withdrawal based patient satisfaction groups Patient factors seemed to have direct impact on satisfaction with treatment and perceived opioid withdrawal Specifically a number of personality related factors neuroticism agreeableness and openness were able to differentiate patient satisfaction groups in different ways It is unclear if these patient factors are impacting on how methadone effects are perceived However this is likely hence its placement in the model with a dotted line

Patient

Satisfaction

Patient Factors

Opioid Withdrawal Symptoms


149

45 Clinical Significance

To illustrate the clinical implications of these studies the following hypothetical case

which deals with the treatment of a challenging methadone maintenance treatment patient

is presented This case highlights some of the research results presented in this thesis

which could have clinical impact

Case

A 41-year-old methadone maintenance treatment patient comes for her first visit at your

clinic Her file indicates that she has been on methadone continuously for the last 8

years She is on a dose of 100mgday and has been on that dose for the last 2 years She

complains that her dose is not holding her When asked to elaborate she complains of a

consistent lack of motivation and an overall feeling of unpleasantness and uneasiness

Her file indicates that she has made this complaint (not holding) regularly throughout her

methadone treatment Blood samples were obtained for pharmacokinetic assessment of

elimination rate of methadone utilizing the ratio of methadone to EDDP (metabolite)

Her results were in the expected range Her file also notes that her previous physician

had assessed her complaints of opioid withdrawal with a self-report measure known as

the Subjective Opioid Withdrawal Scale (SubOWS) on a few occasions When

questioned about illicit opioid use she denied using any Her urine screens were negative

for opioids but positive for cocaine (30 of the time) Based on the withdrawal and

pharmacokinetic assessments her physician has concluded that her complaints are

unfounded She is a regular cigarette smoker who smokes 25 cigarettesday She

consistently takes her methadone dose between 900AM and 1100AM every day

150

Discussion

It seems that her previous physician was willing to explore her complaints with the

opioid withdrawal and pharmacokinetic assessments However when the results showed

low SubOWS scores and that her methadonemetabolite ratios were indicative of a

normal methadone elimination rate the physician decided the patient was not

experiencing opioid withdrawal and perhaps was not being truthful The lack of opioid in

her urine screens affirmed for her previous physician that the methadone was effective

Applied Lessons

We could try increasing her dose however she is on a reasonably high dose already

(100mgday) and is not experiencing opioid withdrawal symptoms according to the

SubOWS We ordered a pharmacokinetic assessment of the patient as we know that

methadonemetabolite ratios are a poor estimate of elimination rate and that a fast

elimination rate itself would not necessarily relate to a patient being a nonholder We are

specifically interested in exposure to unbound (S)-methadone relative to (R)-methadone

We know that increased exposure to (S)-methadone (determined with (S)-(R)-methadone

ratios) has been associated with aversive methadone effects negative mood states and

has very recently been linked to dissatisfaction with methadone treatment (S)-(R)-

methadone ratios were normal We decide that the patient complaints are not related to

pharmacokinetics of methadone Fortunately we are experienced with opioid withdrawal

literature and assessment tools and know that the SubOWS used by the original

physician while a reliable scale is strongly based on physical symptomatology and may

not be sensitive to opioid withdrawal in the context of methadone maintenance because

151

we understand that perceived opioid withdrawal is likely a combination of physical

withdrawal (what the SubOWS measures) and psychological withdrawal (factors that

influence perceived withdrawal and treatment satisfaction) We decide to try our newly

developed guided self-report screening process that was designed to help characterize

methadone patients based on opioid withdrawal and treatment satisfaction The patient is

screened and classified as a partial holder We know that partial holders appear to be

similar to holders with respect to normal satisfaction signals (opioid withdrawal craving

drug liking) This makes it difficult for any physician to explain treatment complaints in

partial holders We also know that partial holders have significant differences from

holders in terms of negative mood and psychological distress We note her complaints of

negative mood and suggest that she be screened for various psychological disorders or

symptoms and treated appropriately as we know that treating symptoms of depression or

other psychopathologies may lead to improved satisfaction with methadone treatment

We note that she is a regular cigarette smoker and because we have heard of a recent

report that there can be significant interactions between nicotinesmoking and methadone

including the possibility that methadone-nicotine interactions are part of stabilized

methadone treatment for methadone patients who smoke We then ask her if she has

changed smoking habits lately She informs us that she has been smoking a little more

than one pack per day for at least the last 10 years and that she smokes most frequently in

the morning with an increasing rate until between1100 AM and 100PM She estimates

that she smokes about half of her daily total of cigarettes by two hours after ingesting her

methadone dose She indicates that she is interested in quitting smoking or at least

reducing her smoking Her smoking schedule is not unusual for a methadone patient

152

hence she may be smoking with great frequency in an attempt to alleviate opioid

withdrawal until she takes her dose and then she smokes to maximize the effects of

methadone We can ask her if she has started to take any new medications that may be

interacting with nicotine to minimize its effects however we do not expect that this is the

case as she has made regular complaints of not holding throughout her methadone

treatment she is not taking any new medications To help guide her smoking cessation

attempt we inform her that from the time that she wakes up until a few hours after her

methadone dose she is most vulnerable to interactions between methadone and nicotine

She should have a treatment schedule with maximum coverage of nicotine replacement

therapy specifically during that time It will also be important to regularly assess her

methadone treatment progress and satisfaction as her smokingnicotine intake reduces

With a loss of the usual methadone-nicotine interactions that influence her stabilized

methadone treatment adjustments may need to be made

46 Recommendations

A study to examine the effect of treating depression or depressive symptoms in

methadone maintenance treatment patients is a logical progression from results of the

methadonedepression study (Study 1) Positive results from such a study would have

profound treatment implications Results also suggest that a more thorough examination

of (S)-methadone pharmacokinetics and patient satisfaction with treatment should be

undertaken Confirmation of Study 1 findings with a larger sample size would be a good

initial plan If such confirmation occurs it may be of benefit to investigate what

153

percentage of patient dissatisfaction with treatment is related to (S)-methadone exposure

and how holder status (nonholderpartial holder) is associated

It would be interesting to conduct a study with similar design to Study 2 except to

investigate differences in patient factors during the peak methadone condition It is

possible that differences would have been detected during the peak methadone condition

when physical opioid withdrawal is truly at its minimum As with the first study results

from Study 2 suggest that treating factors other than opioid withdrawal (negative mood

and psychological distress factors) could lead to improved treatment satisfaction with

methadone treatment A treatment study to investigate if this is the case would be

valuable This sort of study could be coupled with a study investigating the treatment of

depression on patient satisfaction (mentioned above) Results indicate that separating

patients based on the guided self-report screening process was successful further

validation of this process as a screening tool would be of clinical utility Nonetheless it

would still be useful to develop an opioid withdrawal scale tailored to suit the context of

opioid substitution therapy It would be important to develop a scale from first principles

using established scale development techniques Ideally a novel opioid withdrawal scale

would be multi-factored with physical opioid withdrawal symptoms making up only a

portion of the overall scale score A multi-factor opioid withdrawalpatient satisfaction

scale would be helpful in better characterizing the partial holder group by helping to

identify specific targets for treatment As well it would allow opioid withdrawal to be

measured over a continuum rather than by category as the screening process does

154

The methadone-nicotine interaction study investigated the interaction with minimal

nicotine exposure one cigarette or 4mg of nicotine gum on two occasions each study

day It would be important to do a similar study with a greater exposure to nicotine

Smokers smoke to satiation therefore studying methadone-nicotine interactions under

satiated conditions would better approximate what is happening clinically Specifically

one may expect to find more robust and more significant findings from such a study to

confirm and extend results from Study 3 The study could follow methadone

maintenance treatment patients from induction until they are stabilized specifically

monitoring smoking patterns as this could help to explain the high prevalence rates and to

decide whether the prevalence rates are related to being opioid dependent or if methadone

treatment is actually increasing smoking Recent studies suggest that patients on

methadone have a different smoking pattern than regular smokers specifically they

smoke most at the time of their methadone dose and the most important cigarette of the

day for them is the one directly after the methadone dose not the first in the morning as is

the case with regular smokers Following methadone patients as they start treatment

could confirm these observations

Buprenorphine offers avenues for further studies also Since not holding in methadone

treatment may be related to (S)-methadone exposure as suggested in Study 1 switching

patients with unfavourable (S)-(R)-methadone ratios would be a logical step following

the replication of study findings reported in this thesis and by Mitchell et al53 Also

findings from Study 2 may not extend to buprenorphine maintenance therapy a similar

study to this could help to elucidate if mood and psychological factors are an important

component in buprenorphine therapy Dissatisfaction with buprenorphine treatment has

155

been reported at nearly comparable levels to those reported in methadone maintenance

treatment259 Because buprenorphine is a partial agonist it is not known if dissatisfaction

with treatment is related to inability to treat very high levels of opioid dependence260or if

other factors identified in this thesis could be playing a role

47 Final Comment

Although methadone maintenance treatment has been around since the mid-1960rsquos with

documented effectiveness not all patients are treated to satisfaction Now more than four

decades have passed and new issues with methadone maintenance are being raised

Results from this thesis suggest potential mechanisms to optimize and individualize

methadone maintenance treatment that with future study could become treatment

realities

156

50 REFERENCES

1 Dole VP Nyswander ME A medical treatment for diacetylmorphine (heroin) addiction Journal of the American Medical Association 1965193646-650

2 Dole VP Nyswander ME Rehabilitation of heroin addicts after blockade with methadone New York State Journal of Medicine 1966662011-2017

3 Office of National Drug Control Policy The economic costs of drug abuse in the united states 1992-1998 Washington DC Executive Office of the President (Publication No NCJ-190636) 2001

4 Fischer B Medved W Gliksman L Rehm J Illicit opiates in Toronto A profile of current users Addiction Research 19997377-415

5 Marion IJ Methadone Treatment at Forty Science amp Practice Perspectives 20053(1)25-31

6 Regier DA Farmer ME Rae DS et al Comorbidity of mental disorders with alcohol and other drug abuse Results from the Epidemiologic Catchment Area (ECA) study Journal of the American Medical Association 1990264(19)2511-2518

7 Dyer KR White JM Patterns of symptom complaints in methadone maintenance patients Addiction 199792(11)1445-1455

8 Elkader AK Sproule BA Opioid Withdrawal Scales SOWS OOWS and more SOWS Paper presented at 68th College on Problems of Drug Dependence 2006 Scottsdale Arizona USA

9 Dyer KR White J Foster DJR Bochner F Menelaou A Somogyi AA The relationship between mood state and plasma methadone concentration in maintenance patients Journal of Clinical Psychopharmacology 200121(1)78-84

10 Mason BJ Kocsis JH Melia D et al Psychiatric comorbidity in methadone maintained patients Journal of Addictive Diseases 199817(3)75-89

11 Teesson M Havard A Fairbairn S Ross J Lynskey M Darke S Depression among entrants to treatment for heroin dependence in the Australian Treatment Outcome Study (ATOS) prevalence correlates and treatment seeking Drug and Alcohol Dependence 200578309-315

12 Woody GE Luborsky L McLellan AT et al Psychotherapy for opiate addicts Does it help Archives of General Psychiatry 198340(6)639-645

13 Berger H Schweigler M Smoking characteristics of methadone patients Journal of the American Medical Association 1972222705

14 Chait LD Griffiths RR Effects of methadone on human cigarette smoking and subjective ratings Journal of Pharmacology and Experimental Therapeutics 1984229636-640

15 Stark MJ Campbell BK Cigarette smoking and methadone dose levels American Journal of Drug and Alcohol Abuse 199319(2)209-217

16 Clemmey P Brooner R Chutuape MA Kidorf M Stitzer M Smoking habits and attitudes in a methadone maintenance population Drug and Alcohol Dependence 199744123-132

157

17 Best D Lehmann P Gossop M Eating too little smoking and drinking too much wilder lifestyle problems among methadone maintenance patients Addiction Research 19986489-498

18 Richter KP Gibson CA Ahluwalia JS Schmelzle KH Tobacco use and quit attempts among methadone maintenance clients American Journal of Public Health 200191(2)296-299

19 Frosch DL Stopshaw S Jarvik ME Rawson RA Ling W Interest in smoking cessation among methadone maintained outpatients Journal of Addictive Diseases 1998179-19

20 Schmitz JM Grabowski J Rhoades H The effects of high and low doses of methadone on cigarette smoking Drug and Alcohol Dependence 199434237-242

21 Story J Stark MJ Treating cigarette smoking in methadone maintenance clients Journal of Psychoactive Drugs 199123205-215

22 Spiga R Martinetti MP Meisch RA Cowan K Hursh S Methadone and nicotine self-administration in humans a behavioral economic analysis Psychopharmacology 2005178223-231

23 Spiga R Schmitz J Day II J Effects of nicotine on methadone self-administration in humans Drug and Alcohol Dependence 199850157-165

24 Fischer B Rehm J Kirst M et al Heroin-assisted treatment as a response to the public health problem of opiate dependence European Journal of Public Health 200212228-234

25 Goldstein A Aronow L Kalman S Principles of drug addiction the clinical basis of pharmacology 2nd ed New York John Wiley 1974

26 Lowinson JH Marion I Joseph H et al Methadone Maintenance In Lowinson JH Ruiz P Millman RB Langrod JG eds Substance Abuse a comprehensive textbook 4th ed New York Lippincott Williams amp Wilkins 2005616-633

27 Goldstein A Blind dosage comparisons and other studies in a large methadone program Journal of Psychedelic Drugs 19714177-181

28 Jaffe JH Further experience with methdone in the treatment of narcotic users The International Journal of the Addictions 19705375-389

29 Kreek MJ Plasma and urine levels of methadone New York State Journal of Medicine 1973732773-2777

30 Graham NA Merlo LJ Goldberger BA Gold MS Methadone- and heroin-related deaths in Florida Am J Drug Alcohol Abuse 200834(3)347-353

31 Calman L Finch E Powis B Strang J Methadone treatment Only half of patients store methadone in safe place British Medical Journal Dec 7 1996313(7070)1481

32 Binchy JM Molyneux EM Manning J Accidental ingestion of methadone by children in Merseyside British Medical Journal May 21 1994308(6940)1335-1336

33 Cairns A Roberts IS Benbow EW Characteristics of fatal methadone overdose in Manchester 1985-94 British Medical Journal Aug 3 1996313(7052)264-265

158

34 National Institute on Drug Abuse Heroin abuse and addiction (publication number 00-4165) Rockville MD US Department of Health and Human Services National Institute on Drug Abuse 2000

35 Paulus I Halliday R Rehabilitation and the narcotic addict results of a comparative methadone withdrawal program Can Med Assoc J Mar 18 196796(11)655-659

36 Halliday R Treatment of addiction in British Columbia Jama Nov 8 1965194(6)681

37 Halliday R Management of the Narcotic Addict British Columbia Medical Journal 19635(10)412-414

38 Peachey JE Franklin T Methadone treatment of opiate dependence in Canada Br J Addict Sep 198580(3)291-299

39 Methadone and the care of the narcotic addict report of a Special Joint Committee of CMA AND and the DNHW Food and Drug Directorate Can Med Assoc J Dec 4 1971105(11)1193-1201

40 Brands J Brands B Marsh D The expansion of methadone prescribing in ontario 1996-1998 Addiction Research 20008(5)485-496

41 Popova S Rehm J Fischer B An overview of illegal opioid use and health services utilization in Canada Public Health Apr 2006120(4)320-328

42 Fischer B Cruz MF Patra J Rehm J Predictors of methadone maintenance treatment utilization in a multisite cohort of illicit opioid users (OPICAN) J Subst Abuse Treat Apr 200834(3)340-346

43 Kalant H Opioid analgesics and antagonists In Kalant H Roschlau WHE ed Principles of Medical Pharmacology 6th ed New York Oxford University Press 1998262-277

44 Garrido MJ Troconiz IF Methadone a review of its pharmacokineticpharmacodynamic properties Journal of Pharmacological and Toxicological Methods 19994261-66

45 Matthes HWD Maldonado R Simonin F et al Loss of morphine-induced analgesia reward effect and withdrawal symptoms in mice lacking the micro-opioid-receptor gene Nature 1996383819-823

46 Pert CB Snyder SH Opiate receptor demonstration in nervous tissue Science 19731791011-1014

47 Kristensen K Christensen CB Christrup LL The mu1 mu2 delta kappa opioid receptor binding profiles of methadone stereoisomers and morphine Life Sciences 199556(2)45-50

48 Scott CC Robbins EB Chen KK Pharmacological comparison of the optical isomers of methadone Journal of Pharmacology and Experimental Therapeutics 194893282-286

49 Dole VP Implication of methadone maintenance for theories of narcotic addiction Journal of the American Medical Association 198826080-84

50 Isbell H Eisenman AJ The addiction liability of some drugs of the methadone series Journal of Pharmacology and Experimental Therapeutics 194893305-313

159

51 Olsen GD Wendel HA Livermore JD Leger RM Lynn RK Gerber N Clinical effects and pharmacokinetics of racemic methadone and its optical isomers Clinical Pharmacology amp Therapeutics 197721(2)147-157

52 Fraser HF Isbell H Human pharmacology and addictiveness of certain dextroisomers of synthetic analgesics Bulletin on Narcotics 19621425-35

53 Mitchell TB Dyer KR Newcombe D et al Subjective and physiological responses among racemic-methadone maintenance patients in relation to relative (S)- vs (R)-methadone exposure British Journal of Clinical Pharmacology 200458(6)609-617

54 Ebert B Andersen S Krogsgaard-Larsen P Ketobemidone methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord Neuroscience Letters 1995187165-168

55 Gorman AL Elliott KJ Inturrisi CE The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord Neuroscience Letters 1997223(1)5-8

56 Codd EE Shank RP Schupsky JJ Raffa RB Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics structural determinants and role in antinociception The Journal of Pharmacology and Experimental Therapeutics 1995274(3)1263-1270

57 Gourevitch MN Hartel D Tenore P et al Three oral formulations of methadone A clinical and pharmacodynamic comparison Journal of Substance Abuse Treatment 199917(3)237-241

58 Kristensen K Blemmer T Angelo HR et al Stereoselective pharmacokinetics of methadone in chronic pain patients Therapeutic Drug Monitoring 199618221-227

59 Meresaar U Nilsson MI Holmstrand J Anggard E Single dose pharmacokinetics and bioavailability of methadone in man studied with a stable isotope method European Journal of Clinical Pharmacology 198120(6)473-478

60 Nilsson MI Anggard E Holmstrand J Gunne LM Pharmacokinetics of methadone during maintenance treatment adaptive changes during the induction phase European Journal of Clinical Pharmacology 198222(4)343-349

61 Gourlay GK Cherry DA Cousins MJ A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer Pain 198625(3)297-312

62 Inturrisi CE Verebely K Disposition of methadone in man after a single dose Clinical Pharmacology amp Therapeutics 197213(6)923-930

63 Inturrisi CE Verebely K The levels of methadone in the plasma in methadone maintenance Clinical Pharmacology amp Therapeutics 197213(5 Part 1)633-637

64 Wolff K Hay AW Raistrick D Calvert R Steady-state pharmacokinetics of methadone in opioid addicts European Journal of Clinical Pharmacology 199344(2)189-194

65 Nilsson MI Gronbladh L Widerlov E Anggard E Pharmacokinetics of methadone in methadone maintenance treatment characterization of therapeutic failures European Journal of Clinical Pharmacology 198325(4)497-501

160

66 de Vos JW Geerlings PJ van den Brink W Ufkes JG van Wilgenburg H Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts European Journal of Clinical Pharmacology 199548(5)361-366

67 Olsen JD Methadone binding to human plasma albumin Science 1972176525-526

68 Romach MK Piafsky KM Abel JG Khouw V Sellers EM Methadone binding to orosomucoid (alpha 1-acid glycoprotein) determinant of free fraction in plasma Clinical Pharmacology amp Therapeutics 198129(2)211-217

69 Eap CB Cuendet C Baumann P Binding of d-methadone l-methadone and dl-methadone to proteins in plasma of healthy volunteers Role of the variants of α1-acid glycoprotein Clinical Pharmacology amp Therapeutics 199047338-346

70 Garrido MJ Aguirre C Troconiz IF et al Alpha 1-acid glycoprotein (AAG) and serum protein binding of methadone in heroin addicts with abstinence syndrome International Journal of Clinical Pharmacology and Therapeutics 200038(1)35-40

71 Kremer JM Wilting J Janssen LH Drug binding to human alpha-1-acid glycoprotein in health and disease Pharmacological Reviews 198840(1)1-47

72 Sullivan HR Due SL Urinary metabolites of dl-methadone in maintenance subjects Journal of Medicinal Chemistry 197316909-913

73 Gerber JG Rhodes RJ Gal J Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19 Chirality 200416(1)36-44

74 Anggard E Gunne LM Homstrand J McMahon RE Sandberg CG Sullivan HR Disposition of methadone in methadone maintenance Clinical Pharmacology amp Therapeutics 197517(3)258-266

75 Kreek MJ Bencsath FA Field FH Effects of liver disease on urinary excretion of methadone and metabolites in maintenance patients quantitation by direct probe chemical ionization mass spectrometry Biomedical Mass Spectrometry 19807(9)385-395

76 Kreek MJ Bencsath FA Fanizza A Field FH Effects of liver disease on fecal excretion of methadone and its unconjugated metabolites in maintenance patients Quantitation by direct probe chemical ionization mass spectrometry Biomedical Mass Spectrometry 198310(10)544-549

77 Foster DJ Somogyi AA Dyer KR White JM Bochner F Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients British Journal of Clinical Pharmacology 200050(5)427-440

78 Gourlay GK Wilson PR Glynn CJ Pharmacodynamics and pharmacokinetics of methadone during the perioperative period Anesthesiology 198257(6)458-467

79 Inturrisi CE Colburn WA Kaiko RF Houde RW Foley KM Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain Clinical Pharmacology amp Therapeutics 198741(4)392-401

80 Nilsson MI Widerlov E Meresaar U Anggard E Effect of urinary pH on the disposition of methadone in man European Journal of Clinical Pharmacology 198222(4)337-342

81 Plummer JL Gourlay GK Cherry DA Cousins MJ Estimation of methadone clearance application in the management of cancer pain Pain 198833(3)313-322

161

82 Wolff K Rostami-Hodjegan A Shires S et al The pharmacokinetics of methadone in healthy subjects and opiate users British Journal of Clinical Pharmacology 199744(4)325-334

83 Boulton DW Arnaud P DeVane CL Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate Clinical Pharmacology amp Therapeutics 200170(1)48-57

84 Kreek MJ Hachey DL Klein PD Stereoselective disposition of methadone in man Life Sciences 197924(10)925-932

85 Nakamura K Hachey DL Kreek MJ Irving CS Klein PD Quantitation of methadone enatiomers in humans using stable isotope-labeled [2H3]- [

2H5]- and [2H8]methadone Journal of Pharmaceutical Sciences 198271(1)40-43

86 Verebely K Volavka J Mule S Resnick R Methadone in man pharmacokinetic and excretion studies in acute and chronic treatment Clinical Pharmacology amp Therapeutics 197518(2)180-190

87 Wolff K Rostami-Hodjegan A Hay AW Raistrick D Tucker G Population-based pharmacokinetic approach for methadone monitoring of opiate addicts potential clinical utility Addiction 200095(12)1771-1783

88 Mitchell TB Dyer KR Newcombe D Somogyi AA White JM Fluctuations in (RS)-methadone pharmacokinetics and response among long-term methadone maintenance patients Addiction Biology 200611170-174

89 Horns WH Rado M Goldstein A Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride Clinical Pharmacology amp Therapeutics 197517636-649

90 Bell J Bowron P Lewis J Batey R Serum levels of methadone in maintenance clients who persist in illicit drug use British Journal of Addiction 1990851599-1602

91 Torrens M Castillo C San L del Moral E Gonzalez ML de la Torre R Plasma methadone concentrations as an indicator of opioid withdrawal symptoms and heroin use in a methadone maintenance program Drug and Alcohol Dependence 199852(7)193-200

92 Dyer KR Foster DJR White JM Somogyi AA Menelaou A Boucher F Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients comparison of those who do not experience withdrawal and concentration-effect relationships Clinical Pharmacology amp Therapeutics 199965(6)685-694

93 Holmstrand J Anggard E Gunne LM Methadone maintenance plasma levels and therapeutic outcome Clinical Pharmacology amp Therapeutics 197823175-180

94 Bell J Seres V Bowron P Lewis J Batey R The use of serum methadone levels in patients receiving methadone maintenance Clinical Pharmacology amp Therapeutics 198843623-629

95 Loimer N Schmid R The use of plasma levels to optimize methadone maintenance treatment Drug and Alcohol Dependence 199230241-246

96 Wolff K Hay AWM Raistrick D Plasma methadone measurements and their role in methadone detoxification programs Clinical Chemistry 199238420-425

162

97 Kell MJ Utilization of plasma and urine methadone concentration measurements to limit narcotics use in methadone maintenance patients II Generation of plasma concentration response curves Journal of Addictive Diseases 19951485-108

98 Hiltunen AJ Beck O Hjemdahl P et al Rated well-being in relation to plasma concentrations of l- and d-methadone in satisfied and dissatisfied patients on methadone maintenance treatment Psychopharmacology 1999143(4)385-393

99 Handelsman L Cochrane KJ Aronson MJ Ness R Rubinstein KJ Kanof PD Two New Rating Scales for Opiate Withdrawal American Journal of Drug and Alcohol Abuse 198713(3)293-308

100 Hiltunen AJ Lafolie P Martel J et al Subjective and objective symptoms in relation to plasma methadone concentration in methadone patients Psychopharmacology 1995118(2)122-126

101 Eap CB Bourquin M Martin JL et al Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment Drug and Alcohol Dependence 20006147-54

102 Holford NHG Sheiner LB Understanding the dose-effect relationship Clinical application of pharmacokinetic-pharmacodynamic models Clinical Pharmacokinetics 19816429-453

103 Inturrisi CE Portenoy RK Max MB Colburn WA Foley KM Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain Clinical Pharmacology amp Therapeutics 199047565-577

104 Himmelsbach CK The Morphine Abstinence Syndrome its Nature and Treatment Annals of Internal Medicine 194115829-839

105 Kolb L Himmelsbach CK Clinical studies of drug addiction III A critical review of the withdrawal treatments with method of evaluating abstinence syndromes American Journal of Psychiatry 193894759-797

106 Bickel WK Stitzer ML Bigelow GE Liebson IA Jasinski DR Johnson RE A Clinicial Trial of buprenorphine Comparison with methadone in the detoxification of heroin addicts Clinical Pharmacology amp Therapeutics 19884372-78

107 Bradley BP Gossop M Phillips GT Legarda JJ The Devlopment of an Opiate Withdrawal Scale (OWS) British Journal of Addiction 198782(10)1139-1142

108 Gossop M The Development of the Short Opiate Withdrawal Scale (SOWS) Addictive Behaviors 199015(5)487-490

109 Haertzen CA Meketon MJ Opiate Withdrawal as Measured by the Addiction Research Center Inventory (ARCI) Diseases of the Nervous System 196829(7)450-455

110 Haertzen CA Meketon MJ Hooks NT Jr Subjective Experiences Produced by the Withdrawal of Opiates British Journal of Addiction 197065(3)245-255

111 Judson BA Himmelberger DU Goldstein A The naloxone test for opiate dependence Clinical Pharmacology and Therapeutics 198027(4)492-501

112 Loimer N Linzmayer L Grunberger J Comparison between observer assessment and self rating of withdrawal distress during opiate detoxification Drug amp Alcohol Dependence 199128265-268

113 Peachey JE Lei H Assessment of opioid dependence with naloxone British Journal of Addiction 198883193-201

163

114 Wang RIH Wiessen RL Lamid S Roh BL Rating the presence and severity of opiate dependence Clinical Pharmacology and Therapeutics 197416(4)653-658

115 Wesson DR Ling W The Clinical Opiate Withdrawal Scale (COWS) Journal of Psychoactive Drugs 200335(2)253-259

116 Wesson DR Ling W Jara G And the Committee on Treatment of Opioid Dependence Buprenorphine in pharmacotherapy of opioid addiction implementation in office-based medical practice translating the experience of clinical trials into clinical practice San Francisco California society of addiction medicine 1999

117 Villafranca SW McKellar JD Trafton JA Humphreys K Predictors of retention in methadone programs a signal detection analysis Drug Alcohol Depend Jul 27 200683(3)218-224

118 Mitchell TB White JM Somogyi AA Bochner F Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence Drug and Alcohol Dependence 20037285-94

119 Hanna J Foster DJR Salter A Somogyi AA White JM Bochner F Within- and between- subject variability in methadone pharmacokinetics and pharmacodyamics in methadone maintenance subjects British Journal of Clinical Pharmacology 200560(4)404-413

120 McNair DM Lorr M Droppleman LF Profile of Mood States Manual San Diego Educational and Industrial Testing Service 1981

121 Benton T Staab J Evans DL Medical co-morbidity in depressive disorders Annals of Clincial Psychiatry 200719(4)289-303

122 Rounsaville BJ Weissman MM Crists-Christoph K Wilber C Kleber H Diagnosis and symptoms of depression in opiate addicts Course and relationship to treatment outcome Archives of General Psychiatry 198239(2)151-156

123 Hatsukami D Pickens RW Posttreatment depression in an alcohol and drug abuse population The American Journal of Psychiatry 19821391563-1566

124 Compton WM Cottler LB Jacobs JL Ben-Abdallah A Spitznagel EL The role of psychiatric disorders in predicting drug dependence treatment outcomes The American Journal of Psychiatry 2003160890-895

125 Havard A Teesson M Darke S Ross J Depression among heroin users 12-month outcomes from the Australian Treatment Outcome Study (ATOS) Journal of Substance Abuse Treatment 200630355-362

126 Naber D Opioids in the etiology and treatment of psychiatric disorders In Herz A ed Opioids II Springer 1993781-801

127 Mansour A Khachaturian H Lewis ME Akil H Watson SJ Anatomy of CNS opioid receptors Trends in Neuroscience 198811308-314

128 Devinsky O Morrell MJ Vogt BA Contributions of anterior cingulate cortex to behaviour Brain 1995118(Pt 1)279-306

129 Mansour A Fox CA Akil H Watson SJ Opioid-receptor mRNA expression in tthe rat CNS anatomical and functional implications Trends in Neuroscience 199518(1)22-29

164

130 Marek GJ Aghajanian GK The electorphysiology of prefrontal serotonin systems therapeutic implications for mood and psychosis Biological Psychiatry 199844(11)1118-1127

131 Vogt BA Wiley RG Jensen EL Localization of mu and delta opioid receptors to anterior cingulate afferents and projection neurons and inputoutput model of mu regulation Experimental Neurology 1995135(2)83-92

132 Tejedor-Real P Mico JA Maldonado R Roques BP Gibert-Rahola J Implication of endogenous opioid system in the learned-helplessness model of depression Pharmacology Biochemistry and Behavior 199552(1)145-152

133 Seligman MEP Rossellini RA Kozak M Learned helplessness in the rat Reversibility time course and immunization Journal of Comparative and Physiological Psychology 197588542-547

134 Willner P The validity of animal models of depression Psychopharmacology 1984831-16

135 Willner P Animal models of depression An overview Pharmacology amp Therapeutics 199045425-455

136 Tejedor-Real P Mico JA Maldonado R Roques BP Gibert-Rahola J Effect of mixed (RB 38A) and selective (RB 38B) inhibitors of enkephalin degrading enzymes on a model of depression in the rat Biological Psychiatry 199334100-107

137 Tejedor-Real P Mico JA Smadja C Maldonado R Roques BP Gibert-Rahola J Involvement of δ-opioid receptors in the effects induced by endogenous enkephalins on learned helplessness model European Journal of Pharmacology 19983541-7

138 Broom DC Jutkiewicz EM Folk JE Traynor JR Rice KC Woods JH Nonpeptidic δ-opioid receptor agonists reduce immobility in the forced swim assay in rats Neuropsychopharmacology 200026(6)744-755

139 Filliol D Ghozland S Chluba J et al Mice deficient for δ- and μ-opioid receptors exhibit opposing alterations of emotional responses Nature Genetics 200025195-200

140 Pickar D Cutler NR Naber D Post RW Bunney WEJ Plasma opioid activity and manic-depressive illness Lancet 19801(937)

141 Kline NS CH L Lehman HL Lajita A Laski E Cooper T Beta-endorphin-induced changes in schizophrenics and depressed patients Archives of General Psychiatry 1977341111-1113

142 Darko DF Risch SC Gillin JC Golshan S Association of β-endorphine with specific clinical symptoms of depression American Journal of Psychiatry 19921491162-1167

143 Bodkin JA Zornberg GL Lukas SE Cole JO Buprenorphine treatment of refractory depression Journal of Clinical Psychopharmacology 19951549-57

144 Belenky G Holaday JW The opiate antagonist naloxone modifes the effects of electroconvulsive shock (ECS) on respiration blood pressure and heart rate Brain Research 1979177414-417

145 Emerich HM Hollt V Kissling W et al β-endorphin-like immunoreactivity in cerbrospinal fluid and plasma of patients with schizophrenia and other neuropsychiatric disorders Pharmakopsychiatrie 197912269-276

165

146 Inturrisi CE Alexopoulos G Lipman R Foley K Rossier J Beta-endorphin immunoreactivity in the plasma of psychiatric patients receiving electroconvulsive treatment Annals of the New York Academy of Science 1982398413-422

147 Ghadirian AM Gianoulakis CH Nair NP The effect of electroconvulsive treatment on endorphins in depression Biological Psychiatry 198823459

148 Zubieta J-K Smith YR Bueller JA et al Regional mu opioid receptor regulation of sensory and affective dimensions of pain Science 2001293311-315

149 Extein I Pottash AL Gold MS A possible opioid receptor dysfunction in some depressive disorders Annals of the New York Academy of Science 1982398113-119

150 Judd L Risch SC Janowsky DS Segal DS Huey LY Blunted prolactin response - A neuroendocrine abnormality manifested by depressed patients Archives of General Psychiatry 1982391413

151 Robertson AG Jackman H Meltzer HY Prolactin response to morphine in depression Psychiatry Research 198411353-364

152 Zis AP Haskett Rf Albala A Carroll BJ Lohr NE Prolactin Response to morphine in depression Biological Psychiatry 198520287-292

153 Tremblay L Le M Macdonald A Herrmann N Naranjo C Busto U Hydromorphone probing of the brain reward system in major depressive disorder Paper presented at College on Problems of Drug Dependence 65th Annual Scientific Meeting 2003 Bal Harbour Florida

154 Suh JJ Langleben DD Ehrman RN et al Low prefrontal perfusion linked to depression symptoms in methadone-maintained opiate-dependent patients Drug amp Alcohol Dependence 20089911-17

155 Tarter RE Blackson T Brigham J Moss H Caprara GV The association between childhood irritability and liability to substance use in early adolescence a 2-year follow-up study of boys at risk for substance abuse Drug amp Alcohol Dependence 199539253-261

156 Engstrom A Adamsson C Allebeck P Rydberg U Mortality in patients with substance abuse a follow-up in Stockholm County 1973-84 International Journal of the Addictions 19912691-106

157 Hser YI McCarthy WJ Anglin MD Tobacco use as a distal predictor of mortality among long-term narcotics addicts Preventive Medicine 19942361-69

158 Kozlowski LT Skinner W Kent C Pope MA Prospects for smoking treatment in individuals seeking treatment for alcohol and other drug problems Addictive Behaviors 198914273-278

159 Clarke JG Stein MD McGarry KA Gogineni A Interest in smoking cessation amoung injection drug users The Americal Journal on Addictions 200110159-166

160 Nahvi S Richter K Li X Modali L Arnsten J Cigarette smoking and interest in quitting in methadone maintenance patients Addictive Behaviors 2006312127-2134

166

161 Frosch DL Stopshaw S Nahom D Jarvik ME Associations between tobacco smoking and illicit drug use among methadone-maintained opiate-dependent individuals Experimental and Clinical Psychopharmacology 2000897-103

162 Mello NK Lukas SW Mendelson JH Buprenorphine effects on cigarette smoking Psychopharmacology 198586417-425

163 Mutschler NH Stephen BJ Teoh SK Mendelson JH Mello NK An inpatient study of the effects of buprenorphine on cigarette smoking in men concurrently dependent on cocaine and opioids Nicotine Tob Res May 20024(2)223-228

164 McCool RM Paschall Richter K Why do so many drug users smoke J Subst Abuse Treat Jul 200325(1)43-49

165 Richter KP Hamilton AK Hall S Catley D Cox LS Grobe J Patterns of smoking and methadone dose in drug treatment patients Experimental and Clinical Psychopharmacology 200715(2)144-153

166 Stein MD Anderson BJ Nicotine and drug interaction expectancies among methadone maintained cigarette smokers Journal of Substance Abuse Treatment 200324357-361

167 Stopshaw S Rotheram-Fuller E Yang X et al Smoking cessation in methadone maintenance Addiction 2002971317-1328

168 Conte-Devolx B Oliver C Giuard P et al Effect of nicotine on in vivo secretion of melanocorticotropic hormonesin the rat Life Sciences 1981281067-1073

169 Marty MY Erwin VG Cornell H Zgombick JM Effects of nicotine on beta endorphin alpha-MSH and ACTH secretion by isolated perfused mouse brains and pituitary glands Pharmacology Biochemistry and Behavior 198554317-325

170 Hexxum TD Russett LR Plasma enkephalin-like peptide response to chronic nicotine infusion in guinea pig Brain Research 1987406370-372

171 Pierzchala K Houdi AA Van Loon GR Nicotine-induced alterations in brain regional concentrations of native and cryptic met- and leu-enkaphalin Peptides 198781035-1043

172 Rosecrans JA Hendry JS Hong JS Biphasic effects of chronic nicotine treatment on hypothalamic immunoreactive beta-endorphin in the mouse Pharmacology Biochemisty and Behavior 198523141-143

173 Houdi AA Pierzchala K Marson L Palkovitz M Van Loon GR Nicotine-induced alteration in Tyr-Gly Gly and met-enkaphalin in discrete brain nuclei reflects altered enkephalin neuron activity Peptides 199112161-166

174 Walters CL Cleck JN Kuo YC Blendy JA Mu-opioid receptor and CREB activation are required for nicotine reward Neuron 200546(6)933-943

175 Watkins SS Koob GF Markou A Neural mechanisms underlying nicotine addiction acute positive reinforcement and withdrawal Nicotine and Tobacco Reseach 20002(1)19-37

176 Watkins SS Stinus L Koob GF Markou A Reward and somatic changes during precipitated nicotine withdrawal in rats centrally and peripherally mediated effects Journal of Pharmacology and Experimental Therapeutics 2000292(3)1053-1064

167

177 Balerio GN Aso E Maldonado R Involvement of the opioid system in the effects induced by nicotine on anxiety-like behaviour in mice Psychopharmacology 2005181(2)260-269

178 Malin DH Lake JR Carter VA Cunningham JS Wilson OB Naloxone precipitates nicotine abstinence syndrome in the rat Psychopharmacology 1993112((2-3))339-342

179 Biala G Budzynska B Kruk M Naloxone precipitates nicotine abstinence syndrome and attenuates nicotine-induced antinociception in mice Pharmacological Reports 200557(6)755-760

180 Malin DH Lake JR Newlin-Maultsby P et al Rodent model of nicotine abstinence syndrome Pharmacology Biochemistry and Behavior 199243(3)77--784

181 Malin DH Lake JR Short PE et al Nicotine abstinence syndrome precipitated by an analog of neuropeptide FF Pharmacology Biochemistry and Behavior 199654(3)581-585

182 Zarrindast M-R Faraji N Rostami P Sahraei H Ghoshouni H Cross-tolerance between morphine- and nicotine-induced conditioned place preference in mice Pharmacology Biochemisty and Behavior 200374(2)363-369

183 Ise Y Narita M Nagase H Suzuki T Modulation of opioidergic system on mecamylamine-precipitated nicotine-withdrawal aversion in rats Psychopharmacology 2000151(1)49-54

184 Mathieu-Kia AM Kellogg SH Butelman ER Kreek MJ Nicotine addiction insights from recent animal studies Psychopharmacology 2002162102-118

185 Berrendero F Kieffer BL Maldonado R Attenuation of nicotine-induced antinociception rewarding effects and dependence in mu-opioid receptor knock-out mice Journal of Neuroscience 200222(24)10935-10940

186 Galeote L Kieffer BL Maldonado R Berrendero F Mu-opioid receptors are involved in the tolerance to nicotine antinociception Journal of Neurochemistry 200697416-423

187 Pomerleau OF Fertig JD Seyler LW Jaffe J Neuroendocrine reactivity to nicotine in smokers Psychopharmacology 19838161-67

188 Seyler LW Pomerleau OF Fertig JD Hunt D Parker L Pituitary hormone response to cigarette smoking Pharmacology Biochemistry and Behavior 198624159-162

189 Gorelick DA Rose J Jarvick ME Effect of naloxone on cigarette smoking Journal of Substance Abuse 19881153-159

190 Lerman C Wileyto EP Patterson F et al The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial The Pharmacogenomics Journal 20044(3)184-192

191 Ray R Jepson F Patterson F et al Association of OPRM1 A118G variant with the relative reinforcing value of nicotine Psychopharmacology 2006188355-363

192 Hukkanen J Jacob III P Benowitz N Metabolism and disposition kinetics of Nicotine Pharmacological Reviews 200557(1)79-115

168

193 Eap CB Buclin T Baumann P Interindividual variability of the clinical pharmcokinetics of methadone Clinical Pharmacokinetics 200241(14)1153-1193

194 Hamilton M Development of a Rating Scale for Primary Depressive Illness British Journal of Social and Clinical Psychology 19676278-296

195 Cole JO Orzack MH Beake B Bird M Bar-Tal Y Assessment of the abuse liability of buspirone in recreational sedative users Journal of Clinical Psychiatry 198243(12 [Sec 2])69-74

196 Haertzen CA Hill HE Belleville RE Development of the Addiction Research Center Inventory (ARCI) Selection of Items that are Sensetive to the Effects of Various Drugs Psychopharmacologia 19634155-166

197 Martin WR Sloan JW Sapira JD Jasinski DR Physiologic Subjective and Behavioral effects of amphetamine methamphetamine ephedrine phenmetrazine and methylphenidate in man Clinical Pharmacology amp Therapeutics 197112245-258

198 Wechsler D The measurement and appraisal of adult intelligence Baltimore The Williams and Wilkins Company 1958

199 Mcleod DR Griffiths RR Bigelow GE Yingling J An automated version of the digit-symbol substitution test (DSST) Behavior Research Methods and Instruments 198214463-466

200 Kaplan HL When do professional psychologists need professional programmers tools Behavior Research Methods Instruments and Computers 195917(5)546-550

201 Cronbach LJ Coefficient alpha and the internal structure of tests Psychometrika 195116(3)297-334

202 Sheehan DV Lecrubier Y Sheehan H et al The Mini-International Neuropsychiatric Interview (MINI) The development and validation of a structured diagnostic pyschiatric interview for DSM-IV and ICD-10 Journal of Clinical Psychiatry 199859(suppl 20)22-33

203 Spielberger CD State-Trait Anxiety Inventory A comprehensive bibliography Palo Alto Ca Consultant psychologists Press 1984

204 Melzack R The McGill Pain Questionnaire major properties and scoring methods Pain 1975173-82

205 Melzack R The short-form McGill Pain Questionnaire Pain 198730191-197 206 Grafton KV Foster NE Wright CC Test-retest reliability of the Short-Form

McGill Pain Questionnaire Assessment of intraclass correlation coefficients and limits of agreement in patients with osteoarthritis Clinical Journal of Pain 20052173-82

207 Derogatis LR SCL-90 R (Revised) Version Manual-I Baltimore Johns Hopkins University School of Medicine 1977

208 Derogatis LR Lipman RS Rickels K The Hopkins Symptom Checklist (HSCL) A self-report symptom inventory Behavioral Science 1974191-15

209 Costa PT McCrae RR Normal personality assessment in clinical practice The NEO Personality Inventory Psychological Assessment 199245-13

169

210 Costa PT McCrae RR Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) professional manual Odessa Fl Psychological Assessment Resources Inc 1992

211 Franken IH Hendriksa VM van den Brink W Initial validation of two opiate craving questionnaires the obsessive compulsive drug use scale and the desires for drug questionnaire Addictive Behaviors 200227675-685

212 Ware JE SF-36 Health Survey Manual amp Interpretation Guide Boston The Medical Outcomes Trust 1993

213 Sklar SM Annis HM Turner NE Development and validation of the Drug-Taking Confidence Questionnaire A measure of coping self-efficacy Addictive Behaviors 199722(5)665-670

214 Reiss S Peterson RA Gursky DM McNally RJ Anxiety Sensitivity anxiety frequency and the prediction of fearfulness Behavior Research and Therapy 1986241-8

215 Zimet GD Dahlem NW Zimet SG The Multidimensional Scale of Perceived Support Journal of Personality Assessment 19885230-41

216 Dahlem NW Zimet GD Walker RR The multidimensional scale of perceived social support A confirmation study Journal of Clinical Psychology 199147756-761

217 Heatheron TF Kozlowski LT Frecker RC Fagerstrom KO The Fagerstrom test for nicotine dependene a revision of the Fagerstrom Tolerance Questionnaire British Journal of Addition 1991861119-1127

218 Rohsenow DJ Colby SM Martin RA PM M Nicotine and other substance interaction expectancies questionnaire Relationship of expectancies to substance use Addictive Behaviors 200530629-641

219 Tiffany ST Drobes DJ The development and initial validation of a questionnaire on smoking urges British Journal of Addition 1991861467-1476

220 Hughes JR Hatsukami D Signs and symptoms of tobacco withdrawal Archives of General Psychiatry 198643(3)289-294

221 Cardenas L Tremblay LK Naranjo CA Herrmann N Zack M Busto UE Brain reward system activity in major depression and comorbid nicotine dependence Journal of Pharmacology and Experimental Therapeutics 20023021265-1271

222 Giesbrecht E Kapsh I Ferrence R Selby P Dunn E A sensitive LCMSMS for measuring low concentrations of nicotine metabolites Paper presented at International Association for Therapeutic Drug Monitoring and Clinical Toxicology Annual Scientific Meeting Sept 9-14 2007 Nice France

223 Brands B Marsh D Busto U MacDonald A Comparison of heroin and hydromorphone in opioid users Clinical Pharmacology amp Therapeutics 200475(2)P3

224 Folstein MF Lurian R Reliability validity and clinical application of the visual analogue mood scale Psychological Medicine 19732479-486

225 Brienza RS Stein MD Chen M et al Depression among needle exchange program and methadone maintenance clients Journal of Substance Abuse Treatment 200018331-337

170

226 Peles E Schreiber S Naumovsky Y Adelson M Depression in methadone maintenance treatment patients Rate and risk factors Journal of Affective Disorders 200799213-220

227 Schreiber S Peles E Adelson M Association between improvement in depression reduced benzodiazepine (BDZ) abuse and increased psychotropic medication use in methadone maintenance treatment (MMT) patients Drug Alcohol Depend Jan 1 200892(1-3)79-85

228 Galynker II Eisenberg D Matochik JA et al Cerebral metabolism and mood in remitted opiate dependence Drug Alcohol Depend Oct 8 200790(2-3)166-174

229 Johansen-Berg H Gutman DA Behrens TE et al Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression Cereb Cortex Jun 200818(6)1374-1383

230 Judson BA Horns WH Goldstein MD Side effects of levomethadone and racemic methadone in a maintenance program Clinical Pharmacology amp Therapeutics 197620(4)445-449

231 Rosenblum A Joseph H Fong C Kipnis S Cleland C Portenoy RK Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities Journal of the American Medical Association 2003289(18)2370-2378

232 Jamison RN Kauffman J Katz NP Characteristics of methadone maintenance patients with chronic pain Journal of Pain Symptom Management 200019(1)53-62

233 Peles E Schreiber S Gordon J Adelson M Significantly higher methadone dose for methadone maintenance treatment (MMT) patients with chronic pain Pain 2005113340-346

234 Rollman GB Signal detection theory pain measures empirical validation studies and adaptation-level effects Pain 19796(1)9-21

235 Barrett AC Cook CD Terner JM Craft RM Picker MJ Importance of sex and relative efficacy at the mu opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids Psychopharmacology (Berl) Nov 2001158(2)154-164

236 Kest B Palmese CA Hopkins E Adler M Juni A Assessment of acute and chronic morphine dependence in male and female mice Pharmacol Biochem Behav Sep 200170(1)149-156

237 McBride D Barret SP Kelly JT Aw A Dagher A Effects of expectancy and abstinence on the neural response to smoking cues in cigarette smokers An fMRI study Neuropsychopharmacology 2006312728-2738

238 Davies GM Wilner P James DL Morgan MJ Influence of nicotine gum on acute craving for cigarettes Journal of Psychopharmacology 200418(1)83-87

239 Baran-Furga H Chmielewska K Bogucka-Bonikowska A Habrat B Kostowski W Bienkowski P Self-reported effects of methadone on cigarette smoking in methadone-maintained subjects Substance Use and Misuse 2005401103-1111

240 Mooney ME Poling J Gonzalez G Gonsai K Kosten T Sofuoglu M Preliminary study of buprenorphine and bupropion for opioid-dependent smokers The Americal Journal on Addictions 200817287-292

171

241 Richter KP McCool RM Catley D Hall M Ahluwalia JS Dual pharmacotherapy and motivational interviewing for tobacco dependence Journal of Addictive Diseases 20052479-90

242 Stein MD Weinstock MC Herman DS Anderson BJ Anthony JL Niaura RA A smoking cessation intervention for the methadone-maintained Addiction 2006101599-607

243 Stopshaw S Jarvik ME Ling W Rawson RA Contingency management for tobacco smoking in methadone-maintained opiate addicts Addictive Behaviors 199621409-412

244 Richter K Good and bad times for treating cigarette smoking in drug treatment Journal of Psychoactive Drugs 200638(3)311-315

245 Stein MD Weinstock MC Anderson BJ Anthony JL Relationship of depression to smoking outcomes in a methadone-maintained population J Addict Dis 200726(1)35-40

246 Wapf V Schaub M Klaeusler B Boesch L Stohler R Eich D The barriers to smoking cessation in Swiss methadone and buprenorphine-maintained patients Harm Reduct J 2008510

247 Diederich NJ The placebo treatments in neurosciences New insights from clinical and neuroimaging studies Neurology 200871677-684

248 Khan A Kolts RL Rapaport MH Krishnan KR Brodhead AE Browns WA Magnitude of placebo response and drug-placebo differences across psychiatric disorders Psychol Med May 200535(5)743-749

249 Mayberg HS Silva JA Brannan SK et al The functional neuroanatomy of the placebo effect Am J Psychiatry May 2002159(5)728-737

250 Tremblay LK Naranjo CA Cardenas L Herrmann N Busto UE Probing brain reward system function in major depressive disorder Archives of General Psychiatry 200259409-416

251 Balducci X Sproule BA Chayab L Herrmann N Busto UE Naranjo CA Probing the brain reward system in major depressive disorder alcohol dependence and co-morbid individuals Paper presented at Collegium Internationale Neuro-PsychopharmacologicumCanadian College of Neuropsychopharmacology 2006 Chicago IL

252 Buchhalter AR Schrinel L Eissenberg T Withdrawal-suppressing effects of a novel smoking system comparison with own brand not own brand and de-nicotinized cigarettes Nicotine and Tobacco Research 20013111-118

253 Dallery J Houtsmuller EJ Pickworth WB Stitzer ML Effects of cigarette nicotine content and smoking pace on subsequent craving and smoking Psychopharmacology 2003165172-180

254 Donny EC Houtsmuller E Stitzer ML Smoking in the absence of nicotine behavioral subjective and physiological effects over 11 days Addiction 2007102324-334

255 Pickworth WB Fant RV Nelson RA Rohrer MS Pharmacodynamic effects of new de-nicotinized Nicotine and Tobacco Research 19991357-364

256 Rezaishiarz H Hyland A Mahoney MC OConnor RJ Cummings KM Treating smokers before the quit date can nicotine patches and denicotinized cigarettes reduce craving Nicotine and Tobacco Reseach 200791139-1146

172

257 Lofwall MR Brooner RK Bigelow GE Kindbom K Strain EC Characteristics of older opioid maintenance patients Journal of Substance Abuse Treatment 200528(3)265-272

258 Rosen D Smith ML Reynolds CF 3rd The prevalence of mental and physical health disorders among older methadone patients Am J Geriatr Psychiatry Jun 200816(6)488-497

259 Lopatko OV White JM Huber A Ling W Opioid effects and opioid withdrawal during a 24 h dosing interval in patients maintained on buprenorphine Drug amp Alcohol Dependence 200369317-322

260 Elkader A Sproule B Buprenorphine clinical pharmacokinetics in the treatment of opioid dependence Clin Pharmacokinet 200544(7)661-680

173

60 PUBLICATIONS

Refereed Papers

1 Elkader A Sproule BA Buprenorphine Clinical Pharmacokinetics in the treatment of Opioid Dependence Clinical Pharmacokinetics 2005 44(7)661-680

2 Elkader AK Brands B Selby P Sproule BA Major Depressive Disorder and Patient Satisfaction in Relation to Methadone Pharmacokinetics and Pharmacodynamics in Stabilized Methadone Maintenance Patients Journal of Clinical Psychopharmacology Accepted

3 Elkader AK Brands B Zack M Callaghan R Sproule BA Characterization of Between Dose Opioid Withdrawal and Patient Satisfaction in Methadone Maintenance Treatment Drug and Alcohol Dependence Submitted

4 Elkader AK Brands B Selby P Sproule BA Methadone-Nicotine Interactions in Stabilized Methadone Maintenance Treatment Patients Journal of Clinical Psychopharmacology Accepted

Under Internal Review

1 Elkader AK Sproule BA SOWS OOWS COWS and More SOWS A

Review of Opioid Withdrawal Scales Journal Selection Drug and Alcohol Dependence

Abstracts

1 Dunn EJ Giesbrecht E Brands B Elkader A Sproule B A novel HPLC method suitable for the routine determination of buprenorphine concentrations in serum 66th Annual meeting of the College on Problems of Drug Dependence San Juan Puerto Rico June 12-17 2004 (Poster)

2 Elkader A Sproule BA Brands B Selby P Influence of Major Depressive Disorder on the Pharmacokinetic-Pharmacodynamic Relationships of Methadone Harvey Stancer Research in Psychiatry Day University of Toronto Toronto Ontario June 16 2005 (Oral)

3 Elkader AK Sproule BA Selby P Brands B The influence of major depressive disorder on the pharmacokinetic-pharmacodynamic relationships of methadone 67th Annual scientific meeting of the College on Problems of Drug Dependence Orlando Florida June 18-23 2005 (Poster)

4 Elkader AK Sproule BA Selby P Brands B Methadone maintenance patients with comorbid major depressive disorder experience more negative opioid effects Can J Clin Pharmacol 200613(1) 3rd Annual Canadian Joint Therapeutics Congress Toronto Ontario May 10 - 13 2006 (Poster)

174

5 Elkader AK and Sproule BA SOWS OOWS and more SOWS 68th Annual scientific meeting of the College on Problems of Drug Dependence Scottsdale Arizona June 17-22 2006 (Poster)

6 Elkader A Sproule BA Brands B Callaghan R Patient satisfaction with opioid substitution therapy More than withdrawal 69th Annual scientific meeting of the College on Problems of Drug Dependence Quebec City Quebec June 16-21 2007 (Poster)

7 Sproule B Elkader A First exposures in prescription opioid abusers 69th Annual scientific meeting of the College on Problems of Drug Dependence Quebec City Quebec June16-21 2007 (Poster)

8 Elkader AK Sproule BA Brands B Methadone Maintenance Treatment Patients with Comorbid Major Depressive Disorder experience more opioid withdrawal Canadian College of Neuropsychopharmacology Annual meeting Toronto Ontario June 6-9 2008 (Poster)

9 Elkader A Sproule B Brands B Selby P Smoking in methadone maintenance treatment patients Nicotine and methadone relationships 70th Annual scientific meeting of the College on Problems of Drug Dependence San Juan Puerto Rico June 14-19 2008 (Oral)

175

Appendix 1

Patient Informed Consent Form Study 1

176

March 9 2004

Study Name ldquoInfluence of Major Depressive Disorder on the Pharmacokinetic Pharmacodynamic Relationships of Methadonerdquo

Principal Investigator Dr B Sproule Co-investigators Dr B Brands Dr E Dunn Dr P Selby Study Coordinator Alexander Elkader This study will take place at the Centre for Addiction and Mental Health 33

Russell Street site under the supervision of Dr B Sproule This project is part of the

MSc thesis of Alexander Elkader under the supervision of Dr B Sproule There will

be 20 people taking part in this study

You are being asked to participate in this study because you have been in

methadone treatment for at least 6 months and on the same dosage for the past 2 months

We are interested in studying methadone effects and how the body handles methadone

Study participates will be classified into one of four groups for comparison purposes

1 Patient doing well on methadone

2 Patients experiencing withdrawal symptoms while on methadone

3 Patients who are experiencing depressive symptoms and doing well on

methadone

4 Patients who are experiencing depressive symptoms and experiencing

withdrawal symptoms while on methadone

Patient Information and Informed Consent

177

The study procedures are the same regardless of which group you are in Please

take the time to read this information sheet carefully and ask any questions that you may

have before deciding whether you wish to participate in this study

Study Medications

You will not be asked to take any medications other than your regular daily dose

of methadone You should continue to take any medications that you are currently

prescribed

Purpose of the Study

The purpose of this study is to get a better understanding of the relationship

between the effects of methadone and how the amount of methadone in your blood

changes over the course of a day This may be important in explaining why some people

still feel withdrawal symptoms while on methadone In addition we think that people

with depression may experience methadone effects differently This study is designed to

help determine if this is true and how it might relate to methadone blood concentrations

Procedures

This study will involve one assessment session that will take approximately 3

hours one study session that will last 13 hours and one brief (1 hour) session the next

morning

At the assessment session you will be asked a number of questions to determine

your eligibility for the study and to determine to which group you belong You will also

178

be asked to provide a urine sample for toxicological screening This will be used to

determine eligibility for the study only and will not be disclosed to clinic staff This

assessment will include questions about

bull demographics (eg your age education occupation)

bull your past and present drug use

bull current medications

bull your treatment with methadone (we will confirm your current methadone

dosage and duration of time at this dose with your dispensing pharmacy)

bull withdrawal symptoms over the previous 24 hours

bull your previous treatments

bull psychiatric symptoms and history (this will be a fairly long structured

interview) If a diagnosis of current depression is made your treating

physician will be informed

For the study session you will be asked to arrive at CAMH one hour before you

usually take your daily dose of methadone If you have carry privileges you will be asked

to bring your dose for that day with you Please note that you will also be required to

avoid alcohol coffee and all sources of caffeine from 12 hours before the study session

until the testing is completed A urine sample for toxicology screening and a breathalyzer

test will be administered when you arrive Your meals will be provided during the study

session

Over the course of the day you will be asked to provide urine and blood samples

to complete a number of tasks and to answer a number of questions The first set of

testing will be done before you take your methadone dose then the testing will be spaced

179

out over the next 12 hours You will then go home for the night and return the next

morning for the final set of testing before you take your methadone dose again A urine

sample for toxicology screening and a breathalyzer test will be administered again at that

time You will be asked to

bull provide blood samples (2 teaspoonsful each) a total of 13 times (total amount is

130 mls of blood which is less than half of a regular red cross donation) A

catheter will be inserted with the first blood sample (when you arrive) and

removed after the 12-hour blood sample The 24-hour blood sample will be taken

by venipuncture (with a regular needle)

bull provide urine samples a total of 7 times over the course of the study session

bull have your vital signs monitored at the same times as the blood samples are taken

(for example your breathing rate and heart rate)

The following will each be repeated 11 times over the study session You will

bull have your pupil size measured using a special camera

bull complete 2 computer tasks one asks you to replicate box patterns on the screen

and the other has you track a computerized airplane over a moving road (4 mins)

bull complete a series of questions on the computer about how you are feeling (20

mins)

After the final testing session the next morning you will be finished the study and be able

to take your next regular methadone dose

180

Risks and Discomforts

There is little risk associated with this study The main risk would be associated

with the blood draws although this is generally a safe procedure Slight bruising pain or

inflammation is possible

Benefits

There are no direct benefits to you for participating in this study The findings of

this study may be helpful in understanding the relationships between methadone dose

methadone concentrations in the blood and methadone effects This could lead to the

development of more effective dosing strategies for methadone

Compensation

As payment for your participation you will receive $15000 dollars at the end of

the study

Voluntary Participation

Your participation in this study is completely voluntary and you can withdraw

from the study at any time and for any reason If you decide to withdraw from the study

this will not affect your current or any future care at the Centre for Addiction and Mental

Health in any way The investigators may terminate your involvement in the study at any

time This could be due to medical reasons or for not following study procedures

181

Confidentiality

Your identity will be kept strictly confidential to the full extent provided by the

law All information collected during the course of this study will be kept secure and

confidential and will only be made available to the researchers in this study The data

will be identified by your initials and a code number only and not by your name

Published reports and presentations at scientific meetings will refer to only a code

number or grouped data and not a name or initial

If you are not a client of the CAMH methadone maintenance treatment program

you will be required to sign a Form 14 for your dispensing pharmacy so that we can

confirm your methadone dose As well you will be required to sign a Form 14 for your

treating physician if a diagnosis of depression is made Your confidential information

will not be discussed with anyone outside of the study personnel

As part of continuing review of the research your study records may be assessed

on behalf of the Research Ethics Board and if applicable by Health Canada

Therapeutics Products Programme A person from the research ethics team man contact

you (if your contact information is available) to ask you questions about the research

study and your consent to participate The person assessing your file or contacting you

must maintain your confidentiality to the extent permitted by law

182

Informed Consent

I ____________________________ have read (or had read to me) the information sheet

for the study ldquoInfluence of Major Depressive Disorder on the Pharmacokinetic-

Pharmacodynamic Relationship of Methadonerdquo The purpose of this research the

procedures and the risks associated with it have been fully explained to me I have had

the opportunity to ask questions and my questions have been answered to my satisfaction

I understand that I am able to withdraw from this study at any time and for any reason I

understand that my withdrawal from this study would in no way affect any current or

future treatment at the CAMH I voluntarily consent to participate in this research study

I have been given a copy of this informed consent and patient information sheet to

keep for my own records If I have any further questions I understand that I can contact

the Principal Investigator Dr B Sproule at (416) 535-8501 ex 6501 or the Study

Coordinator Alex Elkader at (416) 535-8501 ex 6502 If I have any questions regarding

my rights as a subject in this research I may contact Dr Padraig Darby at (416) 535-8501

ex 6876

Printed Name of Subject Signature of Subject Date Printed Name of Person Signature of Person Date Who Conducted Informed Who Conducted Informed Consent Discussion Consent Discussion

183

Appendix 2

Advertisement Flyer Study 1

184

CAMH is a Pan American Health Organization World Health Organization Collaborating Centre Affiliated with the University of Toronto

Study Volunteers Needed

Are you in Methadone Maintenance Treatment

We are looking for people who have been on methadone for at least 6 months to participate in a study of methadone effects and how the body handles methadone over one 24-hour period

We would like to study people who have been on

methadone who are

- Doing well on methadone andor - Feeling down or depressed andor - Still experiencing withdrawal symptoms

If you are interested please contact Alex for more information at

(416) 535-8501 ex 6502 Financial Compensation Available

CAMH provides other treatment options for mental illness or addiction For more information call CAMH at 416-535-8501

ALL QUERIES ARE STRICTLY CONFIDENTIAL

185

Appendix 3

Brief Telephone Screen Study 1

186

Methadone PK-PD Study ndash Telephone Screen Clinical Research Department Centre for Addiction and Mental Health Brief study explanation We are doing this study so that we can learn more about how methadone in your body relates to it effects Should you meet study requirements you would partake in a 24-hour study You would arrive early in the morning (before you take your methadone dose) and answer some questionnaires do some hand-eye coordination tests and give blood and urine samples You would stay and repeat these tests and give blood and urine samples 11 times over the next 13 hours On this day and your meals will be provided Blood samples would be taken with the aid of an intravenous catheter this means that you would receive only one poke for all the blood samples this day You will come back the next day prior to your methadone dose and repeat all the tests one last time At this point you would be finished the study and paid $15000 dollars for your participation

We are looking for participants who fit into 4 different groups participants with and without current depression and participants who do and do not experience withdrawal symptoms during the course of treatment How long have you been in the methadone program ____________________________ How long have you been on the dose you are on _______________________________ How many times a day do you take your methadone dose ________________________ Do you feel that your methadone dose ldquoholdsrdquo you ie do you feel withdrawal pains towards the end of the day) ______________________ Do you think that you are currently depressed _________________________________ Have you ever been treated for depression ____________________________________ Other Psychiatric disorders ________________________________________________ Do you use recreational drugs We will be doing a urine screen and a positive result for these drugs would mean you cannot participate __________________________________________ Where did you see the study advertisement ___________________________________

187

Appendix 4


188

October 31 2005

Study Name ldquoModification of the Subjective Opioid Withdrawal Scale (SubOWS) for Measuring Opioid Withdrawal in the Context of Opioid Substitution Therapyrdquo

Principal Investigator Dr B Sproule Co-investigators Dr B Brands Dr M Zack Dr R Callaghan Study Coordinator Alexander Elkader This study will take place at the Centre for Addiction and Mental Health 33 Russell Street

site under the supervision of Dr B Sproule This project is part of the PhD thesis of

Alexander Elkader under the supervision of Dr B Sproule and the faculty of Pharmacy

at UofT There will be 90 people taking part in this study


methadonebuprenorphine treatment for at least 6 months and on the same dosage for the

past 1 month We are interested in studying opioid withdrawal symptoms and sensations

in methadonebuprenorphine patients just before they take their daily dose

Study participants will be classified into one of four groups for comparison purposes

1 Complete Holders Treatment is good no withdrawal 2 Partial Holders Satisfied with treatment withdrawal is tolerable 3 Partial Nonholders Not satisfied with treatment withdrawal is not tolerable 4 Complete Nonholders Treatment is bad severe intense withdrawal

The study procedures are the same regardless of which group you are in Please take

the time to read this information sheet carefully and ask any questions that you may have

before deciding whether you wish to participate in this study


Subjectrsquos initials _________

189

Study Medications


of methadone or buprenorphine You should continue to take any medications that you

are currently prescribed


The purpose of this study is to make changes to an available measurement tool of

opioid withdrawal so that it is more appropriate for use in patients in opioid substitution

therapy (methadone or buprenorphine) This may be especially important to help better

understand patients who find that their treatment is not effective This may be because

currently available tools for measuring opioid withdrawal were designed to measure the

features of withdrawal during acute detoxification rather than during opioid substitution

therapy

Procedures

bull The study will involve one study session On the study day you will be asked to

arrive at the Russell St site of CAMH one hour prior to the time you have your

regular dose of opioid substitute (methadone or buprenorphine)

bull To start with you will be asked demographic questions questions about you general

and mental health questions about your past use of drugs and questions about your

past drug treatments

bull You will be asked give a urine sample

bull You will be asked to respond to 9 questionnaires which will take approximately 30 to

45 minutes to complete)


190

bull After this you will receive your regular dose of methadone or buprenorphine You

will be dosed at the CAMH pharmacy or bring your regular dose with you

bull Then you will have a 30 minute break

bull After the break you will be have 5 more questionnaires to answer (which will take

approximately 60 - 90 minutes to complete)

bull Once you have completed these questionnaires you will be finished the study

The questions you will be asked will be about opioid withdrawal drug craving

your mood how your dose makes you feel your personality anxiety pain that you may

be feeling and your quality of life

Benefits


this study may be helpful in understanding why some patients in treatment for opioid use

do not do as well as others

Compensation

As payment for your participation you will receive $3000 dollars at the end of the

study








191

Confidentiality








you will be required to sign a release of personal health information form for your

dispensing pharmacy so that we can confirm your methadone dose and duration at that

dose Your confidential information will not be discussed with anyone outside of the

study personnel








192

Informed Consent


for the study ldquoModification of the Subjective Opioid Withdrawal Scale (SubOWS) for

Measuring Opioid Withdrawal in the Context of Opioid Substitution Therapyrdquo The

purpose of this research the procedures and the risks associated with it have been fully

explained to me I have had the opportunity to ask questions and my questions have been

answered to my satisfaction I understand that I am able to withdraw from this study at

any time and for any reason I understand that my withdrawal from this study would in no

way affect any current or future treatment at the CAMH I voluntarily consent to

participate in this research study I understand that signing this consent form does not

waive my legal rights






ex 6876


193

Appendix 5

Patient Satisfaction Screening Guide used in Study 2

194

Patient Satisfaction With Methadone Maintenance Treatment

Brief Screening Guide

1 How long have you been on your current dose of methadone 2 Do you find that this dose always holds you or do you sometimes experience symptoms

of withdrawal during the day or evening or just before your next scheduled dose If they experience withdrawal 3 Would you say that your withdrawal symptoms are tolerable difficult to tolerate or not

tolerable 4 If you had to classify the level of withdrawal that you experience would you rate it as

mild moderate or severe 5 Do you think that the withdrawal symptoms you experience affect your quality of life

Explain

6 How many days a week do you experience withdrawal

Classification Guide

- Establish that patient is on a clinically optimized dose - In cases where group assignment is difficult rely on impact on quality of life and

clinical judgment

Holder None or nearly no withdrawal There is no impact on quality of life

Partial Holder Withdrawal is tolerable mild in severity and infrequent (usually 3 or less daysweek) there is minimal impact on quality of life

Nonholder Withdrawal is not tolerabledifficult to tolerate severity is moderate to severe frequency can vary from semi-frequent to very frequent There is significant impact on the quality of life

195

Appendix 6


196



Are you Currently being treated with Methadone or Buprenorphine

We are looking for people who - Have been on the same dose for at least 1 month - Who have been in treatment for at least the last 6 months - Who are doing well in treatment - Who are still experiencing withdrawal in treatment To participate in a study to better understand why some people do better on these

opioid substitutes than othersIf you are interested please contact Alex for more information at

(416) 535-8501 ex 6502

Financial Compensation Available CAMH provides other treatment options for mental illness or addiction

For more information call CAMH at 416-535-8501


197

Appendix 7


198

Opioid Withdrawal Scale Study ndash Telephone Screen Clinical Research Department Centre for Addiction and Mental Health Brief study explanation

We are conducting a study to understand why some people who take methadone

or buprenorphine for opioid substitution therapy do better than others This study

involves filling out a series of questionnaires and providing a urine sample The currently

available tools for measuring opioid withdrawal may not be sensitive to the aspects of

opioid withdrawal that are more unique to opioid substitution therapy The results of the

series of questionnaires will be used to develop a shorter series of questions with the

purpose of identifying people who are more likely to have withdrawal symptoms while

on opioid substitution therapy This study will take approximately 3-4 hours to

complete At the end of the study you will be paid $3000 for your participation

How old are you________________________________________________________ Are you taking methadone or buprenorphine __________________________________ How long have you been in the program _____________________________________ What is your current dose _________________________________________________ What time do you take your dose ____________________________________________ How long have you been on the dose you are on _______________________________ Do you feel that your methadone dose ldquoholdsrdquo you (ie do you feel withdrawal pains towards the end of the day) _____________________ Do you use recreational drugs We will be doing a urine screen and a positive result for these drugs would mean you cannot participate __________________________________________ Where did you see the study advertisement ___________________________________ Carries ________________________________________________________________

199

Appendix 8


200

October 3 2006

Study Name Smoking in Methadone Maintenance Patients Nicotine and Methadone

Relationships

Principal Investigator Beth Sproule PharmD Co-investigators Bruna Brands PhD Peter Selby MBBS Graduate Student Alex Elkader PhD Student This study will take place at the Centre for Addiction and Mental Health 33 Russell

Street site under the supervision of Dr B Sproule This project is part of the PhD thesis

of Alex Elkader under the supervision of Dr B Sproule There will be 40 people taking

part in this study This study is funded by the Canadian Tobacco Control Research

Initiative (CTCRI)

You are being asked to participate in this study because

1 You have been in methadone treatment for at least 3 months

2 You have been on the same methadone dosage for the past 2 weeks

3 You are a current smoker

Please take the time to read this information sheet carefully and ask any questions that

you may have before deciding whether you wish to participate in this study

Study Medications

During the course of this study you will be asked to smoke your usual brand of cigarettes

chew nicotine gum and chew a placebo version of this nicotine gum on two occasions

each (2 cigarettes 4 pieces on nicotine gum and 4 pieces of placebo gum) A placebo is

an inactive substance that is made to look and taste like the real substance (does not


Pt Initials

201

contain nicotine) You should continue to take any medications that you are currently

prescribed Please consult with the study coordinator prior to taking any other

medications or natural health products for the duration of the study The use of products

designed to help you quit smoking are not permitted throughout the course of this study

including natural products If you are a woman with the ability to have children you will

be required to use an approved method of birth control for the duration of the study

These methods include abstinence oral contraceptives and barrier devices as well

having a partner who has had a vasectomy or is on male contraceptives


There are very high rates of smoking in individuals on methadone maintenance treatment

The purpose of this study is to get information about how smoking and methadone can

influence the effects of each other This may be important in helping design stop smoking

strategies for individuals on methadone maintenance treatment

Procedures

If you agree to participate you will first undergo an assessment to be sure you are

eligible for the study and to collect general information about you This will include

questions about




bull methadone dosage information (we will confirm your current methadone

dosage and duration of time at this dose with your pharmacy)

bull your smoking history

Pt Initials

202

bull your beliefs about how smoking and methadone interact

bull your previous drug treatments

bull psychiatric symptoms and history

Also a urine sample (for a drug screen and pregnancy testing in women) will be

collected

The study itself will involve three (3) study days (5 hours each)

bull For all of the study days you will be asked to arrive at CAMH 45 minutes before

you usually take your daily dose of methadone All study days will be the same

except for the type of nicotine you get

bull On the first study session you will be asked to smoke your regular brand of

cigarette and on the second and last study sessions you will be asked to chew

nicotine gum or placebo gum in a random order This means that you and the

study personnel that you see will not know which of the two gums you have

received

bull If you have carry privileges for your methadone you will be asked to bring your

dose for that day with you Otherwise you will be escorted to the CAMH

pharmacy for administration of your regular dose

bull You will be required to abstain from nicotine (smoking) from 12 hours before the

study session until we ask you to use nicotine (smoke a cigarette or chew

nicotineplacebo gum) Before the study day starts you will be asked to blow into

a smokerlyzer This measures the level of carbon monoxide (CO) in your breath

as an indicator of recent smoking A score of 10 ppm (parts per million) or greater

will disqualify you for that study day and you we will need to reschedule

Pt Initials

203

bull Please note that you will also be required to avoid alcohol coffee and all sources

of caffeine from 12 hours before the study session until the testing is completed

Sources of caffeine include tea and most non-clear sodas If you have any

questions regarding a specific beverage or food please ask study personnel At

the start of each study day you will be asked to blow into a breathalyzer to

confirm no recent alcohol consumption

bull When you arrive for the study day you will also be asked to give a urine sample

for drug testing

Each study session will take approximately 5 hours to complete you will be asked to

complete the same tests on 4 occasions

1 When you arrive prior to your methadone dose and prior to your nicotine

administrations (first smoke or nicotineplacebo gum)

2 After you have your nicotine administration (before you have your methadone)

3 Three hours after your methadone dose before you have a second nicotine

administration (second smoke or nicotineplacebo gum)

4 Three hours after methadone dose after you have a second nicotine

administration

The tests you will be required to complete include the following computerized

assessments

1 Vital Signs measurement We will record your vital signs (such as breathing and

heart rate) at each cycle

2 Measurement of drug effects A number of questions will be asked about how you

are feeling to estimate the drug effects of methadone and nicotine

Pt Initials

204

(time = 5 minutes)

3 Measurement of opioid withdrawal A number of questions will be asked to

assess the level of opioid withdrawal you are feeling (time = 1 minute)

4 Measurement of mood A number of questions will be asked about how you are

feeling to estimate your current mood (time = 5 minutes)

5 Measurement of smoking urges and nicotine withdrawal A number of questions

will be asked about how much you want a cigarette and how much you feel that

you need a cigarette (time = 5 minutes)

In addition at each cycle you will be asked to blow into a smokerlyzer to measure carbon

monoxide levels At the first cycle each day we will ask you about your current level of

desire to quit smoking

At the 1st and the 4th cycles you will give a blood sample by venipuncture The blood

samples will each be 10 ml (2 teaspoons) The blood samples will be tested for

methadone nicotine and cotinine (a breakdown product of nicotine) concentrations As

well on the first study day an extra blood sample will be taken to determine the genetics

of the opioid receptor (specific to you) Often a gene can be responsible for various

functions in your body The opioid receptor is the product of a gene called OPRM1

You receive two copies of each gene (one from each of your parents) We will see what

types of this gene you have as it has been discovered that more than one type does exist

and these types lead to different effects After completing the 4th testing cycle you will

have finished the study day

Pt Initials

205


You will be required to stop smoking starting 12 hours before each study day and during

the study sessions your smoking will be restricted as outlined in the study procedures

This may cause you some discomfort The main physical risk would be associated with

the blood draws although this is a safe procedure slight bruising pain or inflammation is

possible Nicotine gum is usually well tolerated however it can cause the following side

effects headache hiccups upset stomach mouth soreness and throat soreness Because

the nicotine gum is a gum-based product chewing it can cause fillings to loosen and

aggravate other mouth tooth and jaw problems

Benefits

There are no direct benefits to you for participating in this study Findings of this study

may be useful in the development of smoking cessation strategies specifically for


Compensation

In consideration of your participation you will receive $22500 at the end of the study If

you decide to drop out of the study your compensation will be pro-rated


Your participation in this study is completely voluntary and you can withdraw from the

study at any time and for any reason If you decide to withdraw from the study this will

not affect your current or any future care at the Centre for Addiction and Mental Health

Pt Initials

206

in any way The investigators may terminate your involvement in the study at any time

This could be due to medical reasons or for not following study procedures

Confidentiality

Your identity will be kept strictly confidential to the full extent provided by the law All

information collected during the course of this study will be kept secure and confidential

and will only be made available to the researchers in this study The data will be

identified by your initials and a code number only and not by your name Published

reports and presentations at scientific meetings will refer to only a code number or

grouped data and not a name or initial

As part of continuing review of the research your study records may be assessed on

behalf of the Research Ethics Board and if applicable by the Natural Health Products

Directorate A person from the research ethics team may contact you (if your contact

information is available) to ask you questions about the research study and your consent

to participate The person assessing your file or contacting you must maintain your

confidentiality to the extent permitted by law

A genetic measurement will be made from a blood sample you provide We will use this

sample only to see your genetic make up at the opioid receptor gene We will not look at

other genes than the one we have mentioned

Pt Initials

207

Informed Consent


for the study ldquoSmoking in Methadone Maintenance Patients Nicotine and Methadone

Relationshipsrdquo The purpose of this research the procedures and the risks associated

with it have been fully explained to me I have had the opportunity to ask questions and

my questions have been answered to my satisfaction I understand that I am able to

withdraw from this study at any time and for any reason I understand that my withdrawal

from this study would in no way affect any current or future treatment at the CAMH I

voluntarily consent to participate in this research study

I have been given a copy of this informed consent and patient information sheet to keep

for my own records If I have any further questions I understand that I can contact the

Principal Investigator Dr B Sproule at (416) 535-8501 ex 6501 or the Study



ex 6876


Time of Signing

208

Appendix 9


209



Are you a Smoker who is in Methadone Maintenance Treatment

We are looking for people to participate in a study of the influence of nicotine on methadone effects

We would like to study people who are

- On methadone for at least 3 months - On the same dose for at least 2 weeks - Are current Smokers





210

Appendix 10


211

MethadoneNicotine Interaction Study ndash Telephone Screen Clinical Research Department Centre for Addiction and Mental Health Brief study explanation

We are conducting a study to gain a better understanding of how treatment with methadone is influenced by smoking and also how your smoking is influenced by your treatment with methadone This is important as smoking is very common among methadone patients and it has never been examined

The study involves 3 study days each for 4-5 hours You will provide a urine sample

each day and 2 blood samples each day On the first day you will give one extra blood sample for genetic testing As well you will respond to a series of computerized questionnaires about how you are feeling each day The study will involve abstaining from smoking for 12 hours before each study day The first time you come in you will be asked to smoke 2 cigarettes (your regular brand) the next 2 times you come in you will receive nicorette gum or placebo gum in a random order At the end of the study you will receive $22500 for you participation

Age

How Long in MMT

Current Dose of Methadone

How Long on Current Dose

Time Dose Taken

Use Recreational Drugs

Carries

Willing to abstain from smoking for 12 hours before each study session

Where they saw study advertisement

ii

Influencing Factors on Methadone Pharmacology Impact on Patient Satisfaction with Methadone Maintenance Treatment


Doctor of Philosophy Department of Pharmaceutical Sciences

University of Toronto 2009

Abstract

The methadone maintenance treatment population suffers from high rates of comorbid

psychiatric and substance use disorders Despite a more than 40-year treatment history

not all patients are satisfied with methadone treatment and more than half of the patients

complain of significant inter-dose withdrawal at least some of the time The objectives of

this research were to investigate the pharmacological response to methadone under the

influence of comorbid major depressive disorder and smoking and to identify factors

other than physical withdrawal symptoms that can differentiate patients based on their

complaints of dissatisfaction with treatment In Study 1 seven depressed methadone

maintenance patients experienced more opioid withdrawal symptomatology over a 24-

hour methadone-dosing interval than 10 nondepressed methadone patients Depression

severity was significantly correlated with trough opioid withdrawal severity This

suggests that depression or depressive symptoms are related to reported opioid

withdrawal In Study 2 many factors other than physical opioid withdrawal symptoms

were able to differentiate patients who were satisfied with treatment (holders n=25)

partially satisfied with treatment (partial holders n=35) and not satisfied with treatment

(nonholders n=30) Results suggested that these patient satisfaction groups cluster

differently depending on physical opioid withdrawal mood psychological distress and

iii














methadone treatment

iv

Acknowledgements










an honor





are friends forever

v






you guys

vi

Table of Contents

Abstract ii

Acknowledgements iv


List of Tables xii




10 INTRODUCTION 1



121 Purpose 2

122 Objectives 3



131


4



132


5



vii


6












16




22




28









viii


41




1521


43

1522


44


44



45

211 Study Design 45









ix


55

221 Study Design 55








60

231 Study Design 60












x

30 RESULTS 76


76






86




32211 Nonholders 88

32212 Holders 94







108




xi


124


124


129


133





50 REFERENCES 156

60 PUBLICATIONS 173

Appendices 175

xii

List of Tables

Table Title Page








xiii

List of Figures

Figure Title Page










90





95




99



104


105




113


114

xiv












xv









ASN Asparagine

ASP Aspartate



BG Benzedrine Group

C Concentration





ClF Clearance rate




CO Carbon Monoxide








xvi


E Effect




Emax Maximum Effect














N Slope Factor



NH Nonholder








PD Pharmacodyamic


xvii

PH Partial Holder

PK Pharmacokinetic





















xviii

List of Appendices

Appendix Title Page











1














methadone treatment







2











been well studied


121 Purpose



3

122 Objectives














4




Patients (Study 1)











5






(Study 2)




treatment








6
















7















HIV (7)4

Summary Point



8






















9










Summary Points





daily substitute





10














Columbia42

Summary Point


withdrawal




11

















12























13

















Summary Points





14

















binding68 70 71

15

Summary Point

















from 15 to 207 hours51 58-66 78-86



16









Summary Points











17











enantiomers77










18



each enantiomer88

Summary Points



slowly












19






















20





















21

Summary Points




concentration













22


N + CN EC50N + CN








Summary Point


PD relationships









23







Summary Point













with treatment

24








Summary Points












25






















26








Summary Points






27
















Wang (1974)


Judson (1980)



SOWS (SubOWS)












SOWS (ShOWS)










28






















29





















30









Summary Points






pharmacokinetics






31

















with MMT122-125

Summary Points




32






















33










Summary Points



14102 Human Studies










34


















Summary Points



administration

35





















36










methadone22













37



Summary Points



dependence scores


cigarette












38
























39











effects

Summary Points




nicotine

14122 Human Studies



40
















Summary Points






41







CYP3A4)193









Summary Points





42








Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

43

2

43







Specific Hypotheses







44



Treatment (Study 2)

Specific Hypotheses









Specific Hypothesis





45





211 Study Design













46




















47




participation










group






48




















49























50






Day 1 Day 2 Time (hr) 0 05 1 15 2 3 4 5 6 8 10 12 24



Urine Sample X X

Breathalyzer X X







X










51






















52














Canadian

219 Data Analysis






53















withdrawal






54







endpoints












55



Treatment (Study 2)

221 Study Design















study was completed

56








appendix 5











57




analysis






disorders










58



















59

227 Data Analysis














60



231 Study Design














study

61




















62





















63






















64











meal



(-) Nicotine



(-) Nicotine


(+) Nicotine

3 hr 1030 min 1030 min





65






















66















239 Data Analysis





67











ANOVAs





68


















69






















70



















minutes




71





















72


















in two minutes

73














30 minutes






minute

74





















75












76

Section 3 Results




















77









78




Age (years)

387 (105) 366 (118) 419 (81) 0326 396 (106) 368 (113) 0634

Height (cm)

1735 (95) 1724 (93) 1750 (102) 0593 1758 (95) 1678 (71) 0112

Weight (kg)

855 (277) 723 (126) 1044 (332) 0013 900 (308) 820 (212) 0751

Dose (mg)

988 (544) 895 (636) 1121 (385) 0836 892 (514) 1220 (603) 0271

Time on Dose (mo)

91 (99) 121 (120) 48 (27) 0093 93 (105) 86 (93) 0807


370 (402) 500 (480) 185 (135 0115 422 (467) 245 (147) 0426

HAMD 99 (95) 27 (23) 193 (59) lt0001 82 (87) 138 (109) 0229

POMS - DepDej 162 (144) 97 (84) 246 (167) 0035 139 (103) 212 (217) 0307

POMS - TMD 386 (323) 231 (182) 584 (367) 0024 329 (233) 510 (477) 0458


79


















figure 32b

80


14

-31

-60

-40

-20

0

20

40


07

-27

-4

-2

0

2

4

a)

b)

Nondepressed

Nondepressed

Depressed

Depressed


plt004

plt004


81


0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sc

ore




0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sco

re

Holder Nonholder

a)

b)


82





= 050 plt005)



0

10

20

30

40

0 5 10 15 20 25 30

HAMD Score

Su

bO

WS

Sco

re


r=070 plt0004

83




between groups


3

4

5

6

0 6 12 18 24

Time (hr)

Pu

pil D

iam

ter

(mm

)



84








0

5

10

15

20

0 6 12 18 24

Time (hr)

(S)-

Me

tha

do

ne

(n

gm

l)

Holder

Nonholder



85





methadone







86



Treatment (Study 2)



















87





322 Subjective Data







Nonholder p

N 25 35 30

Sex (FM) 1213 1124 1317 0271

Age (yr) 395 (83) 407 (85) 398 (83) 0857

Height (cm) 1706 (102) 1711 (79) 1745 (97) 0209

Weight (kg) 788 (243) 771 (258) 760 (147 0892


Time on Dose (mo) 83 (121) 78 (112) 79 (100) 0984

Dose (mgday) 730 (461) 808 (386) 995 (446) 0062



88


32211 Nonholders









figure 36






89
















90


104 122

220

0

10

20

30

40


Su

bO

WS

Sco

re


591

476429

0

20

40

60

80


AR

CI-

WO

W S

co

re


132

8470

0

5

10

15

20


Sh

OW

S S

co

re


154 168

240

0

10

20

30

40


AR

CI-

SO

W S

co

re


a) b)

c) d)

plt0001 plt0001

p=0001 plt0001


91


50 50

67

0

2

4

6

8

10


Avera

ge P

ain

In

ten

sit

y


193

126120

0

1

2

3

4


Cu

rren

t P

ain


a) b)

p=0013 p=0015

92

OCDUS Total Score

65 64

114

0

5

10

15

20

25


OC

DU

S T

ota

l S

co

re


2824

45

0

2

4

6

8

10


Desir

e a

nd

Co

ntr

ol

Sco

re


69

4038

0

5

10

15


ou

gh

ts a

nd

In

terf

ere

nce S

co

re


a) b)

c)

p=0022

p=0016


p=0023

93

ARCI - LSD

52 54

77

0

4

8

12


LS

D S

co

re


1621

40

0

2

4

6

8


Ph

ys

ica

l S

co

re


36

2418

0

2

4

6


Dy

sp

ho

ria

Sc

ore


6456

36

0

2

4

6

8

10


Ab

us

e P

ote

nti

al S

co

re


a) b)

c) d)

p=0005 p=0002

plt0001 plt0001


94

32212 Holders


and nonholders


















95


153

123

66

0

5

10

15

20

25


Ob

se

ssiv

eC

om

pu

lsiv

e S

co

re


4955

160

4

8

12


An

ge

rH

os

tility

Sc

ore


06

1013

00

05

10

15

20

25


Glo

bal

Severi

ty In

dex S

co

re


a) b)

c)

plt0001

p=0001


plt0001

96


79

172197

0

10

20

30

40


ep

ressio

nD

eje

cti

on

Sco

re


101112

51

0

5

10

15

20

25


An

ger

Ho

sti

lity

Sco

re


b)

d)


72

112

133

0

5

10

15

20


Ten

sio

nA

nx

iety

Sc

ore

a)

p=0001 p=0009

POMS - Confusion

52

80

97

0

4

8

12

16


Co

nfu

sio

n S

co

re

c)

p=0001

p=0002



p=0002


-15 -116 -155

-40

-30

-20

-10

0

10

20

An

ge

rH

osti

lity

Sc

ore

e)

96

p=0002


97






figure 311







540

609633

40

60

80


N-F

ac

tor

Sc

ore

s



p=0006

98



nonholders
















99


536

469

537

30

50

70


O-F

acto

r S

co

res


476

380

442

30

50

70


A-F

acto

r S

co

res


a) b)


p=0008 p=0002

100





















101














3223 Other Measures





102
















103


82111

136

0

5

10

15

20

25


Sen

so

ry P

ain

Sco

re

SFMPQ - Total Pain

108151

190

0

10

20

30

40


To

tal P

ain

Sco

re


5439

26

0

2

4

6

8

10


Aff

ecti

ve P

ain

Sco

re


a) b)

c)


p=0027 p=0001

p=0006

104

ARCI - PCAG

6379

100

0

5

10

15


PC

AG

Sco

re


28 3553

0

2

4

6

8

10


Se

da

tio

n-M

oto

r S

co

re


4657

75

0

4

8

12


Sed

ati

on

-Men

tal S

co

re

a) b)


p=0002 p=0007

p=0004


105


2549

69

0

5

10

15


Ph

ob

ic A

nxie

ty S

co

re


3666

92

0

4

8

12

16


Psych

oti

cis

m S

co

re


90132

169

0

10

20

30


So

mati

zati

on

Sco

re


145 166 178

0

1

2

3


PS

DI

Sco

re

a) b)

c) d)


p=0018 p=0003

p=0003 p=0024


106


267 283311

20

30

40


Po

sit

ive

An

xie

ty S

co

re


150 177213

0

5

10

15

20

25

30


Neg

ati

ve A

nxie

ty S

co

re

STAI Total Anxiety

523461427

30

40

50

60

70


To

tal A

nx

iety

Sc

ore


223 250311

0

10

20

30

40

50


AS

I S

co

re


a) b)

c) d)


p=0001 p=0035

p=0001 p=0052

107

POMS - Fatigue

12494

68

0

5

10

15

20


Fa

tig

ue

Sc

ore

POMS - Arousal

-2914

31

-15

-10

-5

0

5

10

15

Aro

us

al S

co

re


a) b)


p=0003 p=0028


108














N 40

Sex 17F23M

Age (yr) 406 (83)











109


















sexes



110





















clarity

111





smoking day















112













113

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS


Male Female



114

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS


Male Female



115

POMS - Friendliness

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

Fri

en

dlin

ess

Cigarette

Nicotine Gum

Placebo

POMS - Elation

0

5

10

15

M-N- M-N+ M+N- M+N+

Ela

tio

n

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t F

eelin

g in

Min

d

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Incre

ase in

Th

inkin

g S

peed

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t B

od

ily S

en

sati

on

s

Cigarette

Nicotine Gum

Placebo


0

5

10

15

20

M-N- M-N+ M+N- M+N+

An

ger

Ho

sti

lity

Cigarette

Nicotine Gum

Placebo

a)

d)

b)

c)

f) e)


115


116


3038

50 58

0

4

8

12

Cigartte Day

ST

ME

N

M-N-

M-N+

M+N-

M+N+


5162

73 78

0

4

8

12

Cigartte Day

ST

AB

PO

T

M-N-

M-N+

M+N-

M+N+


354521 557 621

0

20

40

60

80

100

Cigartte Day

Ple

as

an

t B

od

ily S

en

sa

tio

ns

M-N-

M-N+

M+N-

M+N+

ARCI - BG

44 4865 73

0

4

8

12

Cigartte Day

BG

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




117

VAS - Irritable

621501 470

364

0

20

40

60

80

100

Cigartte Day

Irri

tab

le

M-N-

M-N+

M+N-

M+N+

VAS - Restless

620532 506

437

0

20

40

60

80

100

Cigartte Day

Re

stl

es

s

M-N-

M-N+

M+N-

M+N+


404306 299 259

0

20

40

60

80

100

Cigartte Day

I F

ee

l D

ep

res

se

d

M-N-

M-N+

M+N-

M+N+


78 70 6751

0

5

10

15

Cigartte Day

An

ge

rH

osti

lity

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




118


307417 416

510

0

20

40

60

80

100

Cigartte Day

Inc

rea

se

in T

hin

kin

g S

pe

ed

M-N-

M-N+

M+N-

M+N+


4868 4193 4368 3675

0

20

40

60

80

100

Cigartte Day

Dif

fic

ult

y C

on

ce

ntr

ati

ng

M-N-

M-N+

M+N-

M+N+


a) b)



119


448354

438341

0

20

40

60

Cigartte Day

AO

PO

M-N-

M-N+

M+N-

M+N+


387328

387325

0

20

40

60

Cigartte Day

RO

WO

NE

M-N-

M-N+

M+N-

M+N+


457360

451357

0

20

40

60

Cigartte Day

ITS

M-N-

M-N+

M+N-

M+N+


457

327449

328

0

20

40

60

Cigartte Day

DT

S

M-N-

M-N+

M+N-

M+N+

QSU - Factor 1

889

684

875

675

50

70

90

110

Cigartte Day

Facto

r 1

M-N-

M-N+

M+N-

M+N+

QSU - Factor 2

542426

536425

20

40

60

80

Cigartte Day

Facto

r 2

M-N-

M-N+

M+N-

M+N+

a) b)

c) d)

e) f)


119





120


313

593

346

582

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


244

592

224

633

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Go

od

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


810

498

835

513

0

20

40

60

80

100

Cigartte Day

I C

rave

a C

iga

rett

e

M-N-

M-N+

M+N-

M+N+

VAS - I Feel High

167

352234

340

0

20

40

60

80

100

Cigartte Day

I F

eel

Hig

h

M-N-

M-N+

M+N-

M+N+


a) b)

c) d)




121



ARCI-MBG 35 (31) 42 (33) 56 (43) 70 (53) 0001


POMS-Vigor 66 (51) 74 (48) 98 (59) 94 (55) lt0001

POMS-Arousal 08 (99) 12 (88) 38 (119) 41 (84) 0002




ARCI-PCAG 80 (38) 79 (40) 55 (36) 51 (37) lt0001






POMS-Fatigue 93 (70) 87 (60) 76 (63) 68 (50) 0026


VAS-Nausea 299 (265) 354 (287) 164 (262) 167 (236) lt0001

VAS-Sick 338 (284) 313 (289) 184 (254) 171 (228) lt0001

VAS-Frustrated 538 (282) 465 (307) 427 (303) 335 (313) 0022


VAS-Headache 255 (314) 271 (307) 257 (339) 202 (296) 0017

VAS-Dizzy 242 (243) 335 (293) 164 (224) 183 (254) 0002

VAS-Drowsy 528 (252) 494 (272) 463 (289) 431 (394) 0043



122















0

200

400

600

800


Me

tha

do

ne

Co

nc (η

gm

L)

Cycle 2

Cycle 4


123


0

20

40

60


Nic

oti

ne

Co

nc

(η

gm

L)

Cycle 2

Cycle 4


0

5

10

15

20

25


Nic

oti

ne

Co

nc

(η

gm

L)



a)

b)


124




Patients (Study 1)



















125





correlated



















126






















more intuitive

127
























128






















129



(Study 2)


















the other groups

130
















outcomes122-125







131









dissatisfaction













132























133










assessments












134











Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

4 3

2



135
























136























137




of nicotine gum

















suppression

138
























139
























140






















141























142




















patients



143



study findings




















144
























145













146



a)

b)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 1



147



c)

d)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 3



Study 2

148

Methadone

Effects

Physical

Psychological



Patient

Satisfaction

Patient Factors



149






Case

















150

Discussion







Applied Lessons















151
























152














46 Recommendations








153






















154
























155





47 Final Comment






realities

156

50 REFERENCES

















157


















158


















159
















160

















161

















162


















163

















164

















165
















166

















167

















168


















169

















170
















171

















172





173

60 PUBLICATIONS

Refereed Papers








Abstracts





174






175

Appendix 1


176

March 9 2004













methadone




177




Study Medications



prescribed








Procedures



morning



178




















session




179


















mins)



180





Benefits





Compensation


the study







181

Confidentiality


















182

Informed Consent














ex 6876


183

Appendix 2


184






methadone who are






185

Appendix 3


186



187

Appendix 4


188

October 31 2005

















189

Study Medications











therapy

Procedures











190










Benefits




Compensation


study








191

Confidentiality











study personnel








192

Informed Consent
















ex 6876


193

Appendix 5


194







Explain




clinical judgment




195

Appendix 6


196






(416) 535-8501 ex 6502




197

Appendix 7


198












199

Appendix 8


200

October 3 2006


Relationships





Initiative (CTCRI)







Study Medications






Pt Initials

201














Procedures



questions about







Pt Initials

202





collected









received










Pt Initials

203








for drug testing









administration


assessments





Pt Initials

204

(time = 5 minutes)





















Pt Initials

205










Benefits




Compensation







Pt Initials

206



Confidentiality
















Pt Initials

207

Informed Consent














ex 6876


Time of Signing

208

Appendix 9


209











210

Appendix 10


211





Age

How Long in MMT



Time Dose Taken


Carries



iii














methadone treatment

iv

Acknowledgements










an honor





are friends forever

v






you guys

vi

Table of Contents

Abstract ii

Acknowledgements iv


List of Tables xii




10 INTRODUCTION 1



121 Purpose 2

122 Objectives 3



131


4



132


5



vii


6












16




22




28









viii


41




1521


43

1522


44


44



45

211 Study Design 45









ix


55

221 Study Design 55








60

231 Study Design 60












x

30 RESULTS 76


76






86




32211 Nonholders 88

32212 Holders 94







108




xi


124


124


129


133





50 REFERENCES 156

60 PUBLICATIONS 173

Appendices 175

xii

List of Tables

Table Title Page








xiii

List of Figures

Figure Title Page










90





95




99



104


105




113


114

xiv












xv









ASN Asparagine

ASP Aspartate



BG Benzedrine Group

C Concentration





ClF Clearance rate




CO Carbon Monoxide








xvi


E Effect




Emax Maximum Effect














N Slope Factor



NH Nonholder








PD Pharmacodyamic


xvii

PH Partial Holder

PK Pharmacokinetic





















xviii

List of Appendices

Appendix Title Page











1














methadone treatment







2











been well studied


121 Purpose



3

122 Objectives














4




Patients (Study 1)











5






(Study 2)




treatment








6
















7















HIV (7)4

Summary Point



8






















9










Summary Points





daily substitute





10














Columbia42

Summary Point


withdrawal




11

















12























13

















Summary Points





14

















binding68 70 71

15

Summary Point

















from 15 to 207 hours51 58-66 78-86



16









Summary Points











17











enantiomers77










18



each enantiomer88

Summary Points



slowly












19






















20





















21

Summary Points




concentration













22


N + CN EC50N + CN








Summary Point


PD relationships









23







Summary Point













with treatment

24








Summary Points












25






















26








Summary Points






27
















Wang (1974)


Judson (1980)



SOWS (SubOWS)












SOWS (ShOWS)










28






















29





















30









Summary Points






pharmacokinetics






31

















with MMT122-125

Summary Points




32






















33










Summary Points



14102 Human Studies










34


















Summary Points



administration

35





















36










methadone22













37



Summary Points



dependence scores


cigarette












38
























39











effects

Summary Points




nicotine

14122 Human Studies



40
















Summary Points






41







CYP3A4)193









Summary Points





42








Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

43

2

43







Specific Hypotheses







44



Treatment (Study 2)

Specific Hypotheses









Specific Hypothesis





45





211 Study Design













46




















47




participation










group






48




















49























50






Day 1 Day 2 Time (hr) 0 05 1 15 2 3 4 5 6 8 10 12 24



Urine Sample X X

Breathalyzer X X







X










51






















52














Canadian

219 Data Analysis






53















withdrawal






54







endpoints












55



Treatment (Study 2)

221 Study Design















study was completed

56








appendix 5











57




analysis






disorders










58



















59

227 Data Analysis














60



231 Study Design














study

61




















62





















63






















64











meal



(-) Nicotine



(-) Nicotine


(+) Nicotine

3 hr 1030 min 1030 min





65






















66















239 Data Analysis





67











ANOVAs





68


















69






















70



















minutes




71





















72


















in two minutes

73














30 minutes






minute

74





















75












76

Section 3 Results




















77









78




Age (years)

387 (105) 366 (118) 419 (81) 0326 396 (106) 368 (113) 0634

Height (cm)

1735 (95) 1724 (93) 1750 (102) 0593 1758 (95) 1678 (71) 0112

Weight (kg)

855 (277) 723 (126) 1044 (332) 0013 900 (308) 820 (212) 0751

Dose (mg)

988 (544) 895 (636) 1121 (385) 0836 892 (514) 1220 (603) 0271

Time on Dose (mo)

91 (99) 121 (120) 48 (27) 0093 93 (105) 86 (93) 0807


370 (402) 500 (480) 185 (135 0115 422 (467) 245 (147) 0426

HAMD 99 (95) 27 (23) 193 (59) lt0001 82 (87) 138 (109) 0229

POMS - DepDej 162 (144) 97 (84) 246 (167) 0035 139 (103) 212 (217) 0307

POMS - TMD 386 (323) 231 (182) 584 (367) 0024 329 (233) 510 (477) 0458


79


















figure 32b

80


14

-31

-60

-40

-20

0

20

40


07

-27

-4

-2

0

2

4

a)

b)

Nondepressed

Nondepressed

Depressed

Depressed


plt004

plt004


81


0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sc

ore




0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sco

re

Holder Nonholder

a)

b)


82





= 050 plt005)



0

10

20

30

40

0 5 10 15 20 25 30

HAMD Score

Su

bO

WS

Sco

re


r=070 plt0004

83




between groups


3

4

5

6

0 6 12 18 24

Time (hr)

Pu

pil D

iam

ter

(mm

)



84








0

5

10

15

20

0 6 12 18 24

Time (hr)

(S)-

Me

tha

do

ne

(n

gm

l)

Holder

Nonholder



85





methadone







86



Treatment (Study 2)



















87





322 Subjective Data







Nonholder p

N 25 35 30

Sex (FM) 1213 1124 1317 0271

Age (yr) 395 (83) 407 (85) 398 (83) 0857

Height (cm) 1706 (102) 1711 (79) 1745 (97) 0209

Weight (kg) 788 (243) 771 (258) 760 (147 0892


Time on Dose (mo) 83 (121) 78 (112) 79 (100) 0984

Dose (mgday) 730 (461) 808 (386) 995 (446) 0062



88


32211 Nonholders









figure 36






89
















90


104 122

220

0

10

20

30

40


Su

bO

WS

Sco

re


591

476429

0

20

40

60

80


AR

CI-

WO

W S

co

re


132

8470

0

5

10

15

20


Sh

OW

S S

co

re


154 168

240

0

10

20

30

40


AR

CI-

SO

W S

co

re


a) b)

c) d)

plt0001 plt0001

p=0001 plt0001


91


50 50

67

0

2

4

6

8

10


Avera

ge P

ain

In

ten

sit

y


193

126120

0

1

2

3

4


Cu

rren

t P

ain


a) b)

p=0013 p=0015

92

OCDUS Total Score

65 64

114

0

5

10

15

20

25


OC

DU

S T

ota

l S

co

re


2824

45

0

2

4

6

8

10


Desir

e a

nd

Co

ntr

ol

Sco

re


69

4038

0

5

10

15


ou

gh

ts a

nd

In

terf

ere

nce S

co

re


a) b)

c)

p=0022

p=0016


p=0023

93

ARCI - LSD

52 54

77

0

4

8

12


LS

D S

co

re


1621

40

0

2

4

6

8


Ph

ys

ica

l S

co

re


36

2418

0

2

4

6


Dy

sp

ho

ria

Sc

ore


6456

36

0

2

4

6

8

10


Ab

us

e P

ote

nti

al S

co

re


a) b)

c) d)

p=0005 p=0002

plt0001 plt0001


94

32212 Holders


and nonholders


















95


153

123

66

0

5

10

15

20

25


Ob

se

ssiv

eC

om

pu

lsiv

e S

co

re


4955

160

4

8

12


An

ge

rH

os

tility

Sc

ore


06

1013

00

05

10

15

20

25


Glo

bal

Severi

ty In

dex S

co

re


a) b)

c)

plt0001

p=0001


plt0001

96


79

172197

0

10

20

30

40


ep

ressio

nD

eje

cti

on

Sco

re


101112

51

0

5

10

15

20

25


An

ger

Ho

sti

lity

Sco

re


b)

d)


72

112

133

0

5

10

15

20


Ten

sio

nA

nx

iety

Sc

ore

a)

p=0001 p=0009

POMS - Confusion

52

80

97

0

4

8

12

16


Co

nfu

sio

n S

co

re

c)

p=0001

p=0002



p=0002


-15 -116 -155

-40

-30

-20

-10

0

10

20

An

ge

rH

osti

lity

Sc

ore

e)

96

p=0002


97






figure 311







540

609633

40

60

80


N-F

ac

tor

Sc

ore

s



p=0006

98



nonholders
















99


536

469

537

30

50

70


O-F

acto

r S

co

res


476

380

442

30

50

70


A-F

acto

r S

co

res


a) b)


p=0008 p=0002

100





















101














3223 Other Measures





102
















103


82111

136

0

5

10

15

20

25


Sen

so

ry P

ain

Sco

re

SFMPQ - Total Pain

108151

190

0

10

20

30

40


To

tal P

ain

Sco

re


5439

26

0

2

4

6

8

10


Aff

ecti

ve P

ain

Sco

re


a) b)

c)


p=0027 p=0001

p=0006

104

ARCI - PCAG

6379

100

0

5

10

15


PC

AG

Sco

re


28 3553

0

2

4

6

8

10


Se

da

tio

n-M

oto

r S

co

re


4657

75

0

4

8

12


Sed

ati

on

-Men

tal S

co

re

a) b)


p=0002 p=0007

p=0004


105


2549

69

0

5

10

15


Ph

ob

ic A

nxie

ty S

co

re


3666

92

0

4

8

12

16


Psych

oti

cis

m S

co

re


90132

169

0

10

20

30


So

mati

zati

on

Sco

re


145 166 178

0

1

2

3


PS

DI

Sco

re

a) b)

c) d)


p=0018 p=0003

p=0003 p=0024


106


267 283311

20

30

40


Po

sit

ive

An

xie

ty S

co

re


150 177213

0

5

10

15

20

25

30


Neg

ati

ve A

nxie

ty S

co

re

STAI Total Anxiety

523461427

30

40

50

60

70


To

tal A

nx

iety

Sc

ore


223 250311

0

10

20

30

40

50


AS

I S

co

re


a) b)

c) d)


p=0001 p=0035

p=0001 p=0052

107

POMS - Fatigue

12494

68

0

5

10

15

20


Fa

tig

ue

Sc

ore

POMS - Arousal

-2914

31

-15

-10

-5

0

5

10

15

Aro

us

al S

co

re


a) b)


p=0003 p=0028


108














N 40

Sex 17F23M

Age (yr) 406 (83)











109


















sexes



110





















clarity

111





smoking day















112













113

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS


Male Female



114

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS


Male Female



115

POMS - Friendliness

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

Fri

en

dlin

ess

Cigarette

Nicotine Gum

Placebo

POMS - Elation

0

5

10

15

M-N- M-N+ M+N- M+N+

Ela

tio

n

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t F

eelin

g in

Min

d

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Incre

ase in

Th

inkin

g S

peed

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t B

od

ily S

en

sati

on

s

Cigarette

Nicotine Gum

Placebo


0

5

10

15

20

M-N- M-N+ M+N- M+N+

An

ger

Ho

sti

lity

Cigarette

Nicotine Gum

Placebo

a)

d)

b)

c)

f) e)


115


116


3038

50 58

0

4

8

12

Cigartte Day

ST

ME

N

M-N-

M-N+

M+N-

M+N+


5162

73 78

0

4

8

12

Cigartte Day

ST

AB

PO

T

M-N-

M-N+

M+N-

M+N+


354521 557 621

0

20

40

60

80

100

Cigartte Day

Ple

as

an

t B

od

ily S

en

sa

tio

ns

M-N-

M-N+

M+N-

M+N+

ARCI - BG

44 4865 73

0

4

8

12

Cigartte Day

BG

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




117

VAS - Irritable

621501 470

364

0

20

40

60

80

100

Cigartte Day

Irri

tab

le

M-N-

M-N+

M+N-

M+N+

VAS - Restless

620532 506

437

0

20

40

60

80

100

Cigartte Day

Re

stl

es

s

M-N-

M-N+

M+N-

M+N+


404306 299 259

0

20

40

60

80

100

Cigartte Day

I F

ee

l D

ep

res

se

d

M-N-

M-N+

M+N-

M+N+


78 70 6751

0

5

10

15

Cigartte Day

An

ge

rH

osti

lity

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




118


307417 416

510

0

20

40

60

80

100

Cigartte Day

Inc

rea

se

in T

hin

kin

g S

pe

ed

M-N-

M-N+

M+N-

M+N+


4868 4193 4368 3675

0

20

40

60

80

100

Cigartte Day

Dif

fic

ult

y C

on

ce

ntr

ati

ng

M-N-

M-N+

M+N-

M+N+


a) b)



119


448354

438341

0

20

40

60

Cigartte Day

AO

PO

M-N-

M-N+

M+N-

M+N+


387328

387325

0

20

40

60

Cigartte Day

RO

WO

NE

M-N-

M-N+

M+N-

M+N+


457360

451357

0

20

40

60

Cigartte Day

ITS

M-N-

M-N+

M+N-

M+N+


457

327449

328

0

20

40

60

Cigartte Day

DT

S

M-N-

M-N+

M+N-

M+N+

QSU - Factor 1

889

684

875

675

50

70

90

110

Cigartte Day

Facto

r 1

M-N-

M-N+

M+N-

M+N+

QSU - Factor 2

542426

536425

20

40

60

80

Cigartte Day

Facto

r 2

M-N-

M-N+

M+N-

M+N+

a) b)

c) d)

e) f)


119





120


313

593

346

582

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


244

592

224

633

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Go

od

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


810

498

835

513

0

20

40

60

80

100

Cigartte Day

I C

rave

a C

iga

rett

e

M-N-

M-N+

M+N-

M+N+

VAS - I Feel High

167

352234

340

0

20

40

60

80

100

Cigartte Day

I F

eel

Hig

h

M-N-

M-N+

M+N-

M+N+


a) b)

c) d)




121



ARCI-MBG 35 (31) 42 (33) 56 (43) 70 (53) 0001


POMS-Vigor 66 (51) 74 (48) 98 (59) 94 (55) lt0001

POMS-Arousal 08 (99) 12 (88) 38 (119) 41 (84) 0002




ARCI-PCAG 80 (38) 79 (40) 55 (36) 51 (37) lt0001






POMS-Fatigue 93 (70) 87 (60) 76 (63) 68 (50) 0026


VAS-Nausea 299 (265) 354 (287) 164 (262) 167 (236) lt0001

VAS-Sick 338 (284) 313 (289) 184 (254) 171 (228) lt0001

VAS-Frustrated 538 (282) 465 (307) 427 (303) 335 (313) 0022


VAS-Headache 255 (314) 271 (307) 257 (339) 202 (296) 0017

VAS-Dizzy 242 (243) 335 (293) 164 (224) 183 (254) 0002

VAS-Drowsy 528 (252) 494 (272) 463 (289) 431 (394) 0043



122















0

200

400

600

800


Me

tha

do

ne

Co

nc (η

gm

L)

Cycle 2

Cycle 4


123


0

20

40

60


Nic

oti

ne

Co

nc

(η

gm

L)

Cycle 2

Cycle 4


0

5

10

15

20

25


Nic

oti

ne

Co

nc

(η

gm

L)



a)

b)


124




Patients (Study 1)



















125





correlated



















126






















more intuitive

127
























128






















129



(Study 2)


















the other groups

130
















outcomes122-125







131









dissatisfaction













132























133










assessments












134











Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

4 3

2



135
























136























137




of nicotine gum

















suppression

138
























139
























140






















141























142




















patients



143



study findings




















144
























145













146



a)

b)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 1



147



c)

d)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 3



Study 2

148

Methadone

Effects

Physical

Psychological



Patient

Satisfaction

Patient Factors



149






Case

















150

Discussion







Applied Lessons















151
























152














46 Recommendations








153






















154
























155





47 Final Comment






realities

156

50 REFERENCES

















157


















158


















159
















160

















161

















162


















163

















164

















165
















166

















167

















168


















169

















170
















171

















172





173

60 PUBLICATIONS

Refereed Papers








Abstracts





174






175

Appendix 1


176

March 9 2004













methadone




177




Study Medications



prescribed








Procedures



morning



178




















session




179


















mins)



180





Benefits





Compensation


the study







181

Confidentiality


















182

Informed Consent














ex 6876


183

Appendix 2


184






methadone who are






185

Appendix 3


186



187

Appendix 4


188

October 31 2005

















189

Study Medications











therapy

Procedures











190










Benefits




Compensation


study








191

Confidentiality











study personnel








192

Informed Consent
















ex 6876


193

Appendix 5


194







Explain




clinical judgment




195

Appendix 6


196






(416) 535-8501 ex 6502




197

Appendix 7


198












199

Appendix 8


200

October 3 2006


Relationships





Initiative (CTCRI)







Study Medications






Pt Initials

201














Procedures



questions about







Pt Initials

202





collected









received










Pt Initials

203








for drug testing









administration


assessments





Pt Initials

204

(time = 5 minutes)





















Pt Initials

205










Benefits




Compensation







Pt Initials

206



Confidentiality
















Pt Initials

207

Informed Consent














ex 6876


Time of Signing

208

Appendix 9


209











210

Appendix 10


211





Age

How Long in MMT



Time Dose Taken


Carries



iv

Acknowledgements










an honor





are friends forever

v






you guys

vi

Table of Contents

Abstract ii

Acknowledgements iv


List of Tables xii




10 INTRODUCTION 1



121 Purpose 2

122 Objectives 3



131


4



132


5



vii


6












16




22




28









viii


41




1521


43

1522


44


44



45

211 Study Design 45









ix


55

221 Study Design 55








60

231 Study Design 60












x

30 RESULTS 76


76






86




32211 Nonholders 88

32212 Holders 94







108




xi


124


124


129


133





50 REFERENCES 156

60 PUBLICATIONS 173

Appendices 175

xii

List of Tables

Table Title Page








xiii

List of Figures

Figure Title Page










90





95




99



104


105




113


114

xiv












xv









ASN Asparagine

ASP Aspartate



BG Benzedrine Group

C Concentration





ClF Clearance rate




CO Carbon Monoxide








xvi


E Effect




Emax Maximum Effect














N Slope Factor



NH Nonholder








PD Pharmacodyamic


xvii

PH Partial Holder

PK Pharmacokinetic





















xviii

List of Appendices

Appendix Title Page











1














methadone treatment







2











been well studied


121 Purpose



3

122 Objectives














4




Patients (Study 1)











5






(Study 2)




treatment








6
















7















HIV (7)4

Summary Point



8






















9










Summary Points





daily substitute





10














Columbia42

Summary Point


withdrawal




11

















12























13

















Summary Points





14

















binding68 70 71

15

Summary Point

















from 15 to 207 hours51 58-66 78-86



16









Summary Points











17











enantiomers77










18



each enantiomer88

Summary Points



slowly












19






















20





















21

Summary Points




concentration













22


N + CN EC50N + CN








Summary Point


PD relationships









23







Summary Point













with treatment

24








Summary Points












25






















26








Summary Points






27
















Wang (1974)


Judson (1980)



SOWS (SubOWS)












SOWS (ShOWS)










28






















29





















30









Summary Points






pharmacokinetics






31

















with MMT122-125

Summary Points




32






















33










Summary Points



14102 Human Studies










34


















Summary Points



administration

35





















36










methadone22













37



Summary Points



dependence scores


cigarette












38
























39











effects

Summary Points




nicotine

14122 Human Studies



40
















Summary Points






41







CYP3A4)193









Summary Points





42








Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

43

2

43







Specific Hypotheses







44



Treatment (Study 2)

Specific Hypotheses









Specific Hypothesis





45





211 Study Design













46




















47




participation










group






48




















49























50






Day 1 Day 2 Time (hr) 0 05 1 15 2 3 4 5 6 8 10 12 24



Urine Sample X X

Breathalyzer X X







X










51






















52














Canadian

219 Data Analysis






53















withdrawal






54







endpoints












55



Treatment (Study 2)

221 Study Design















study was completed

56








appendix 5











57




analysis






disorders










58



















59

227 Data Analysis














60



231 Study Design














study

61




















62





















63






















64











meal



(-) Nicotine



(-) Nicotine


(+) Nicotine

3 hr 1030 min 1030 min





65






















66















239 Data Analysis





67











ANOVAs





68


















69






















70



















minutes




71





















72


















in two minutes

73














30 minutes






minute

74





















75












76

Section 3 Results




















77









78




Age (years)

387 (105) 366 (118) 419 (81) 0326 396 (106) 368 (113) 0634

Height (cm)

1735 (95) 1724 (93) 1750 (102) 0593 1758 (95) 1678 (71) 0112

Weight (kg)

855 (277) 723 (126) 1044 (332) 0013 900 (308) 820 (212) 0751

Dose (mg)

988 (544) 895 (636) 1121 (385) 0836 892 (514) 1220 (603) 0271

Time on Dose (mo)

91 (99) 121 (120) 48 (27) 0093 93 (105) 86 (93) 0807


370 (402) 500 (480) 185 (135 0115 422 (467) 245 (147) 0426

HAMD 99 (95) 27 (23) 193 (59) lt0001 82 (87) 138 (109) 0229

POMS - DepDej 162 (144) 97 (84) 246 (167) 0035 139 (103) 212 (217) 0307

POMS - TMD 386 (323) 231 (182) 584 (367) 0024 329 (233) 510 (477) 0458


79


















figure 32b

80


14

-31

-60

-40

-20

0

20

40


07

-27

-4

-2

0

2

4

a)

b)

Nondepressed

Nondepressed

Depressed

Depressed


plt004

plt004


81


0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sc

ore




0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sco

re

Holder Nonholder

a)

b)


82





= 050 plt005)



0

10

20

30

40

0 5 10 15 20 25 30

HAMD Score

Su

bO

WS

Sco

re


r=070 plt0004

83




between groups


3

4

5

6

0 6 12 18 24

Time (hr)

Pu

pil D

iam

ter

(mm

)



84








0

5

10

15

20

0 6 12 18 24

Time (hr)

(S)-

Me

tha

do

ne

(n

gm

l)

Holder

Nonholder



85





methadone







86



Treatment (Study 2)



















87





322 Subjective Data







Nonholder p

N 25 35 30

Sex (FM) 1213 1124 1317 0271

Age (yr) 395 (83) 407 (85) 398 (83) 0857

Height (cm) 1706 (102) 1711 (79) 1745 (97) 0209

Weight (kg) 788 (243) 771 (258) 760 (147 0892


Time on Dose (mo) 83 (121) 78 (112) 79 (100) 0984

Dose (mgday) 730 (461) 808 (386) 995 (446) 0062



88


32211 Nonholders









figure 36






89
















90


104 122

220

0

10

20

30

40


Su

bO

WS

Sco

re


591

476429

0

20

40

60

80


AR

CI-

WO

W S

co

re


132

8470

0

5

10

15

20


Sh

OW

S S

co

re


154 168

240

0

10

20

30

40


AR

CI-

SO

W S

co

re


a) b)

c) d)

plt0001 plt0001

p=0001 plt0001


91


50 50

67

0

2

4

6

8

10


Avera

ge P

ain

In

ten

sit

y


193

126120

0

1

2

3

4


Cu

rren

t P

ain


a) b)

p=0013 p=0015

92

OCDUS Total Score

65 64

114

0

5

10

15

20

25


OC

DU

S T

ota

l S

co

re


2824

45

0

2

4

6

8

10


Desir

e a

nd

Co

ntr

ol

Sco

re


69

4038

0

5

10

15


ou

gh

ts a

nd

In

terf

ere

nce S

co

re


a) b)

c)

p=0022

p=0016


p=0023

93

ARCI - LSD

52 54

77

0

4

8

12


LS

D S

co

re


1621

40

0

2

4

6

8


Ph

ys

ica

l S

co

re


36

2418

0

2

4

6


Dy

sp

ho

ria

Sc

ore


6456

36

0

2

4

6

8

10


Ab

us

e P

ote

nti

al S

co

re


a) b)

c) d)

p=0005 p=0002

plt0001 plt0001


94

32212 Holders


and nonholders


















95


153

123

66

0

5

10

15

20

25


Ob

se

ssiv

eC

om

pu

lsiv

e S

co

re


4955

160

4

8

12


An

ge

rH

os

tility

Sc

ore


06

1013

00

05

10

15

20

25


Glo

bal

Severi

ty In

dex S

co

re


a) b)

c)

plt0001

p=0001


plt0001

96


79

172197

0

10

20

30

40


ep

ressio

nD

eje

cti

on

Sco

re


101112

51

0

5

10

15

20

25


An

ger

Ho

sti

lity

Sco

re


b)

d)


72

112

133

0

5

10

15

20


Ten

sio

nA

nx

iety

Sc

ore

a)

p=0001 p=0009

POMS - Confusion

52

80

97

0

4

8

12

16


Co

nfu

sio

n S

co

re

c)

p=0001

p=0002



p=0002


-15 -116 -155

-40

-30

-20

-10

0

10

20

An

ge

rH

osti

lity

Sc

ore

e)

96

p=0002


97






figure 311







540

609633

40

60

80


N-F

ac

tor

Sc

ore

s



p=0006

98



nonholders
















99


536

469

537

30

50

70


O-F

acto

r S

co

res


476

380

442

30

50

70


A-F

acto

r S

co

res


a) b)


p=0008 p=0002

100





















101














3223 Other Measures





102
















103


82111

136

0

5

10

15

20

25


Sen

so

ry P

ain

Sco

re

SFMPQ - Total Pain

108151

190

0

10

20

30

40


To

tal P

ain

Sco

re


5439

26

0

2

4

6

8

10


Aff

ecti

ve P

ain

Sco

re


a) b)

c)


p=0027 p=0001

p=0006

104

ARCI - PCAG

6379

100

0

5

10

15


PC

AG

Sco

re


28 3553

0

2

4

6

8

10


Se

da

tio

n-M

oto

r S

co

re


4657

75

0

4

8

12


Sed

ati

on

-Men

tal S

co

re

a) b)


p=0002 p=0007

p=0004


105


2549

69

0

5

10

15


Ph

ob

ic A

nxie

ty S

co

re


3666

92

0

4

8

12

16


Psych

oti

cis

m S

co

re


90132

169

0

10

20

30


So

mati

zati

on

Sco

re


145 166 178

0

1

2

3


PS

DI

Sco

re

a) b)

c) d)


p=0018 p=0003

p=0003 p=0024


106


267 283311

20

30

40


Po

sit

ive

An

xie

ty S

co

re


150 177213

0

5

10

15

20

25

30


Neg

ati

ve A

nxie

ty S

co

re

STAI Total Anxiety

523461427

30

40

50

60

70


To

tal A

nx

iety

Sc

ore


223 250311

0

10

20

30

40

50


AS

I S

co

re


a) b)

c) d)


p=0001 p=0035

p=0001 p=0052

107

POMS - Fatigue

12494

68

0

5

10

15

20


Fa

tig

ue

Sc

ore

POMS - Arousal

-2914

31

-15

-10

-5

0

5

10

15

Aro

us

al S

co

re


a) b)


p=0003 p=0028


108














N 40

Sex 17F23M

Age (yr) 406 (83)











109


















sexes



110





















clarity

111





smoking day















112













113

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS


Male Female



114

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS


Male Female



115

POMS - Friendliness

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

Fri

en

dlin

ess

Cigarette

Nicotine Gum

Placebo

POMS - Elation

0

5

10

15

M-N- M-N+ M+N- M+N+

Ela

tio

n

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t F

eelin

g in

Min

d

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Incre

ase in

Th

inkin

g S

peed

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t B

od

ily S

en

sati

on

s

Cigarette

Nicotine Gum

Placebo


0

5

10

15

20

M-N- M-N+ M+N- M+N+

An

ger

Ho

sti

lity

Cigarette

Nicotine Gum

Placebo

a)

d)

b)

c)

f) e)


115


116


3038

50 58

0

4

8

12

Cigartte Day

ST

ME

N

M-N-

M-N+

M+N-

M+N+


5162

73 78

0

4

8

12

Cigartte Day

ST

AB

PO

T

M-N-

M-N+

M+N-

M+N+


354521 557 621

0

20

40

60

80

100

Cigartte Day

Ple

as

an

t B

od

ily S

en

sa

tio

ns

M-N-

M-N+

M+N-

M+N+

ARCI - BG

44 4865 73

0

4

8

12

Cigartte Day

BG

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




117

VAS - Irritable

621501 470

364

0

20

40

60

80

100

Cigartte Day

Irri

tab

le

M-N-

M-N+

M+N-

M+N+

VAS - Restless

620532 506

437

0

20

40

60

80

100

Cigartte Day

Re

stl

es

s

M-N-

M-N+

M+N-

M+N+


404306 299 259

0

20

40

60

80

100

Cigartte Day

I F

ee

l D

ep

res

se

d

M-N-

M-N+

M+N-

M+N+


78 70 6751

0

5

10

15

Cigartte Day

An

ge

rH

osti

lity

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




118


307417 416

510

0

20

40

60

80

100

Cigartte Day

Inc

rea

se

in T

hin

kin

g S

pe

ed

M-N-

M-N+

M+N-

M+N+


4868 4193 4368 3675

0

20

40

60

80

100

Cigartte Day

Dif

fic

ult

y C

on

ce

ntr

ati

ng

M-N-

M-N+

M+N-

M+N+


a) b)



119


448354

438341

0

20

40

60

Cigartte Day

AO

PO

M-N-

M-N+

M+N-

M+N+


387328

387325

0

20

40

60

Cigartte Day

RO

WO

NE

M-N-

M-N+

M+N-

M+N+


457360

451357

0

20

40

60

Cigartte Day

ITS

M-N-

M-N+

M+N-

M+N+


457

327449

328

0

20

40

60

Cigartte Day

DT

S

M-N-

M-N+

M+N-

M+N+

QSU - Factor 1

889

684

875

675

50

70

90

110

Cigartte Day

Facto

r 1

M-N-

M-N+

M+N-

M+N+

QSU - Factor 2

542426

536425

20

40

60

80

Cigartte Day

Facto

r 2

M-N-

M-N+

M+N-

M+N+

a) b)

c) d)

e) f)


119





120


313

593

346

582

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


244

592

224

633

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Go

od

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


810

498

835

513

0

20

40

60

80

100

Cigartte Day

I C

rave

a C

iga

rett

e

M-N-

M-N+

M+N-

M+N+

VAS - I Feel High

167

352234

340

0

20

40

60

80

100

Cigartte Day

I F

eel

Hig

h

M-N-

M-N+

M+N-

M+N+


a) b)

c) d)




121



ARCI-MBG 35 (31) 42 (33) 56 (43) 70 (53) 0001


POMS-Vigor 66 (51) 74 (48) 98 (59) 94 (55) lt0001

POMS-Arousal 08 (99) 12 (88) 38 (119) 41 (84) 0002




ARCI-PCAG 80 (38) 79 (40) 55 (36) 51 (37) lt0001






POMS-Fatigue 93 (70) 87 (60) 76 (63) 68 (50) 0026


VAS-Nausea 299 (265) 354 (287) 164 (262) 167 (236) lt0001

VAS-Sick 338 (284) 313 (289) 184 (254) 171 (228) lt0001

VAS-Frustrated 538 (282) 465 (307) 427 (303) 335 (313) 0022


VAS-Headache 255 (314) 271 (307) 257 (339) 202 (296) 0017

VAS-Dizzy 242 (243) 335 (293) 164 (224) 183 (254) 0002

VAS-Drowsy 528 (252) 494 (272) 463 (289) 431 (394) 0043



122















0

200

400

600

800


Me

tha

do

ne

Co

nc (η

gm

L)

Cycle 2

Cycle 4


123


0

20

40

60


Nic

oti

ne

Co

nc

(η

gm

L)

Cycle 2

Cycle 4


0

5

10

15

20

25


Nic

oti

ne

Co

nc

(η

gm

L)



a)

b)


124




Patients (Study 1)



















125





correlated



















126






















more intuitive

127
























128






















129



(Study 2)


















the other groups

130
















outcomes122-125







131









dissatisfaction













132























133










assessments












134











Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

4 3

2



135
























136























137




of nicotine gum

















suppression

138
























139
























140






















141























142




















patients



143



study findings




















144
























145













146



a)

b)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 1



147



c)

d)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 3



Study 2

148

Methadone

Effects

Physical

Psychological



Patient

Satisfaction

Patient Factors



149






Case

















150

Discussion







Applied Lessons















151
























152














46 Recommendations








153






















154
























155





47 Final Comment






realities

156

50 REFERENCES

















157


















158


















159
















160

















161

















162


















163

















164

















165
















166

















167

















168


















169

















170
















171

















172





173

60 PUBLICATIONS

Refereed Papers








Abstracts





174






175

Appendix 1


176

March 9 2004













methadone




177




Study Medications



prescribed








Procedures



morning



178




















session




179


















mins)



180





Benefits





Compensation


the study







181

Confidentiality


















182

Informed Consent














ex 6876


183

Appendix 2


184






methadone who are






185

Appendix 3


186



187

Appendix 4


188

October 31 2005

















189

Study Medications











therapy

Procedures











190










Benefits




Compensation


study








191

Confidentiality











study personnel








192

Informed Consent
















ex 6876


193

Appendix 5


194







Explain




clinical judgment




195

Appendix 6


196






(416) 535-8501 ex 6502




197

Appendix 7


198












199

Appendix 8


200

October 3 2006


Relationships





Initiative (CTCRI)







Study Medications






Pt Initials

201














Procedures



questions about







Pt Initials

202





collected









received










Pt Initials

203








for drug testing









administration


assessments





Pt Initials

204

(time = 5 minutes)





















Pt Initials

205










Benefits




Compensation







Pt Initials

206



Confidentiality
















Pt Initials

207

Informed Consent














ex 6876


Time of Signing

208

Appendix 9


209











210

Appendix 10


211





Age

How Long in MMT



Time Dose Taken


Carries



v






you guys

vi

Table of Contents

Abstract ii

Acknowledgements iv


List of Tables xii




10 INTRODUCTION 1



121 Purpose 2

122 Objectives 3



131


4



132


5



vii


6












16




22




28









viii


41




1521


43

1522


44


44



45

211 Study Design 45









ix


55

221 Study Design 55








60

231 Study Design 60












x

30 RESULTS 76


76






86




32211 Nonholders 88

32212 Holders 94







108




xi


124


124


129


133





50 REFERENCES 156

60 PUBLICATIONS 173

Appendices 175

xii

List of Tables

Table Title Page








xiii

List of Figures

Figure Title Page










90





95




99



104


105




113


114

xiv












xv









ASN Asparagine

ASP Aspartate



BG Benzedrine Group

C Concentration





ClF Clearance rate




CO Carbon Monoxide








xvi


E Effect




Emax Maximum Effect














N Slope Factor



NH Nonholder








PD Pharmacodyamic


xvii

PH Partial Holder

PK Pharmacokinetic





















xviii

List of Appendices

Appendix Title Page











1














methadone treatment







2











been well studied


121 Purpose



3

122 Objectives














4




Patients (Study 1)











5






(Study 2)




treatment








6
















7















HIV (7)4

Summary Point



8






















9










Summary Points





daily substitute





10














Columbia42

Summary Point


withdrawal




11

















12























13

















Summary Points





14

















binding68 70 71

15

Summary Point

















from 15 to 207 hours51 58-66 78-86



16









Summary Points











17











enantiomers77










18



each enantiomer88

Summary Points



slowly












19






















20





















21

Summary Points




concentration













22


N + CN EC50N + CN








Summary Point


PD relationships









23







Summary Point













with treatment

24








Summary Points












25






















26








Summary Points






27
















Wang (1974)


Judson (1980)



SOWS (SubOWS)












SOWS (ShOWS)










28






















29





















30









Summary Points






pharmacokinetics






31

















with MMT122-125

Summary Points




32






















33










Summary Points



14102 Human Studies










34


















Summary Points



administration

35





















36










methadone22













37



Summary Points



dependence scores


cigarette












38
























39











effects

Summary Points




nicotine

14122 Human Studies



40
















Summary Points






41







CYP3A4)193









Summary Points





42








Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

43

2

43







Specific Hypotheses







44



Treatment (Study 2)

Specific Hypotheses









Specific Hypothesis





45





211 Study Design













46




















47




participation










group






48




















49























50






Day 1 Day 2 Time (hr) 0 05 1 15 2 3 4 5 6 8 10 12 24



Urine Sample X X

Breathalyzer X X







X










51






















52














Canadian

219 Data Analysis






53















withdrawal






54







endpoints












55



Treatment (Study 2)

221 Study Design















study was completed

56








appendix 5











57




analysis






disorders










58



















59

227 Data Analysis














60



231 Study Design














study

61




















62





















63






















64











meal



(-) Nicotine



(-) Nicotine


(+) Nicotine

3 hr 1030 min 1030 min





65






















66















239 Data Analysis





67











ANOVAs





68


















69






















70



















minutes




71





















72


















in two minutes

73














30 minutes






minute

74





















75












76

Section 3 Results




















77









78




Age (years)

387 (105) 366 (118) 419 (81) 0326 396 (106) 368 (113) 0634

Height (cm)

1735 (95) 1724 (93) 1750 (102) 0593 1758 (95) 1678 (71) 0112

Weight (kg)

855 (277) 723 (126) 1044 (332) 0013 900 (308) 820 (212) 0751

Dose (mg)

988 (544) 895 (636) 1121 (385) 0836 892 (514) 1220 (603) 0271

Time on Dose (mo)

91 (99) 121 (120) 48 (27) 0093 93 (105) 86 (93) 0807


370 (402) 500 (480) 185 (135 0115 422 (467) 245 (147) 0426

HAMD 99 (95) 27 (23) 193 (59) lt0001 82 (87) 138 (109) 0229

POMS - DepDej 162 (144) 97 (84) 246 (167) 0035 139 (103) 212 (217) 0307

POMS - TMD 386 (323) 231 (182) 584 (367) 0024 329 (233) 510 (477) 0458


79


















figure 32b

80


14

-31

-60

-40

-20

0

20

40


07

-27

-4

-2

0

2

4

a)

b)

Nondepressed

Nondepressed

Depressed

Depressed


plt004

plt004


81


0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sc

ore




0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sco

re

Holder Nonholder

a)

b)


82





= 050 plt005)



0

10

20

30

40

0 5 10 15 20 25 30

HAMD Score

Su

bO

WS

Sco

re


r=070 plt0004

83




between groups


3

4

5

6

0 6 12 18 24

Time (hr)

Pu

pil D

iam

ter

(mm

)



84








0

5

10

15

20

0 6 12 18 24

Time (hr)

(S)-

Me

tha

do

ne

(n

gm

l)

Holder

Nonholder



85





methadone







86



Treatment (Study 2)



















87





322 Subjective Data







Nonholder p

N 25 35 30

Sex (FM) 1213 1124 1317 0271

Age (yr) 395 (83) 407 (85) 398 (83) 0857

Height (cm) 1706 (102) 1711 (79) 1745 (97) 0209

Weight (kg) 788 (243) 771 (258) 760 (147 0892


Time on Dose (mo) 83 (121) 78 (112) 79 (100) 0984

Dose (mgday) 730 (461) 808 (386) 995 (446) 0062



88


32211 Nonholders









figure 36






89
















90


104 122

220

0

10

20

30

40


Su

bO

WS

Sco

re


591

476429

0

20

40

60

80


AR

CI-

WO

W S

co

re


132

8470

0

5

10

15

20


Sh

OW

S S

co

re


154 168

240

0

10

20

30

40


AR

CI-

SO

W S

co

re


a) b)

c) d)

plt0001 plt0001

p=0001 plt0001


91


50 50

67

0

2

4

6

8

10


Avera

ge P

ain

In

ten

sit

y


193

126120

0

1

2

3

4


Cu

rren

t P

ain


a) b)

p=0013 p=0015

92

OCDUS Total Score

65 64

114

0

5

10

15

20

25


OC

DU

S T

ota

l S

co

re


2824

45

0

2

4

6

8

10


Desir

e a

nd

Co

ntr

ol

Sco

re


69

4038

0

5

10

15


ou

gh

ts a

nd

In

terf

ere

nce S

co

re


a) b)

c)

p=0022

p=0016


p=0023

93

ARCI - LSD

52 54

77

0

4

8

12


LS

D S

co

re


1621

40

0

2

4

6

8


Ph

ys

ica

l S

co

re


36

2418

0

2

4

6


Dy

sp

ho

ria

Sc

ore


6456

36

0

2

4

6

8

10


Ab

us

e P

ote

nti

al S

co

re


a) b)

c) d)

p=0005 p=0002

plt0001 plt0001


94

32212 Holders


and nonholders


















95


153

123

66

0

5

10

15

20

25


Ob

se

ssiv

eC

om

pu

lsiv

e S

co

re


4955

160

4

8

12


An

ge

rH

os

tility

Sc

ore


06

1013

00

05

10

15

20

25


Glo

bal

Severi

ty In

dex S

co

re


a) b)

c)

plt0001

p=0001


plt0001

96


79

172197

0

10

20

30

40


ep

ressio

nD

eje

cti

on

Sco

re


101112

51

0

5

10

15

20

25


An

ger

Ho

sti

lity

Sco

re


b)

d)


72

112

133

0

5

10

15

20


Ten

sio

nA

nx

iety

Sc

ore

a)

p=0001 p=0009

POMS - Confusion

52

80

97

0

4

8

12

16


Co

nfu

sio

n S

co

re

c)

p=0001

p=0002



p=0002


-15 -116 -155

-40

-30

-20

-10

0

10

20

An

ge

rH

osti

lity

Sc

ore

e)

96

p=0002


97






figure 311







540

609633

40

60

80


N-F

ac

tor

Sc

ore

s



p=0006

98



nonholders
















99


536

469

537

30

50

70


O-F

acto

r S

co

res


476

380

442

30

50

70


A-F

acto

r S

co

res


a) b)


p=0008 p=0002

100





















101














3223 Other Measures





102
















103


82111

136

0

5

10

15

20

25


Sen

so

ry P

ain

Sco

re

SFMPQ - Total Pain

108151

190

0

10

20

30

40


To

tal P

ain

Sco

re


5439

26

0

2

4

6

8

10


Aff

ecti

ve P

ain

Sco

re


a) b)

c)


p=0027 p=0001

p=0006

104

ARCI - PCAG

6379

100

0

5

10

15


PC

AG

Sco

re


28 3553

0

2

4

6

8

10


Se

da

tio

n-M

oto

r S

co

re


4657

75

0

4

8

12


Sed

ati

on

-Men

tal S

co

re

a) b)


p=0002 p=0007

p=0004


105


2549

69

0

5

10

15


Ph

ob

ic A

nxie

ty S

co

re


3666

92

0

4

8

12

16


Psych

oti

cis

m S

co

re


90132

169

0

10

20

30


So

mati

zati

on

Sco

re


145 166 178

0

1

2

3


PS

DI

Sco

re

a) b)

c) d)


p=0018 p=0003

p=0003 p=0024


106


267 283311

20

30

40


Po

sit

ive

An

xie

ty S

co

re


150 177213

0

5

10

15

20

25

30


Neg

ati

ve A

nxie

ty S

co

re

STAI Total Anxiety

523461427

30

40

50

60

70


To

tal A

nx

iety

Sc

ore


223 250311

0

10

20

30

40

50


AS

I S

co

re


a) b)

c) d)


p=0001 p=0035

p=0001 p=0052

107

POMS - Fatigue

12494

68

0

5

10

15

20


Fa

tig

ue

Sc

ore

POMS - Arousal

-2914

31

-15

-10

-5

0

5

10

15

Aro

us

al S

co

re


a) b)


p=0003 p=0028


108














N 40

Sex 17F23M

Age (yr) 406 (83)











109


















sexes



110





















clarity

111





smoking day















112













113

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS


Male Female



114

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS


Male Female



115

POMS - Friendliness

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

Fri

en

dlin

ess

Cigarette

Nicotine Gum

Placebo

POMS - Elation

0

5

10

15

M-N- M-N+ M+N- M+N+

Ela

tio

n

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t F

eelin

g in

Min

d

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Incre

ase in

Th

inkin

g S

peed

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t B

od

ily S

en

sati

on

s

Cigarette

Nicotine Gum

Placebo


0

5

10

15

20

M-N- M-N+ M+N- M+N+

An

ger

Ho

sti

lity

Cigarette

Nicotine Gum

Placebo

a)

d)

b)

c)

f) e)


115


116


3038

50 58

0

4

8

12

Cigartte Day

ST

ME

N

M-N-

M-N+

M+N-

M+N+


5162

73 78

0

4

8

12

Cigartte Day

ST

AB

PO

T

M-N-

M-N+

M+N-

M+N+


354521 557 621

0

20

40

60

80

100

Cigartte Day

Ple

as

an

t B

od

ily S

en

sa

tio

ns

M-N-

M-N+

M+N-

M+N+

ARCI - BG

44 4865 73

0

4

8

12

Cigartte Day

BG

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




117

VAS - Irritable

621501 470

364

0

20

40

60

80

100

Cigartte Day

Irri

tab

le

M-N-

M-N+

M+N-

M+N+

VAS - Restless

620532 506

437

0

20

40

60

80

100

Cigartte Day

Re

stl

es

s

M-N-

M-N+

M+N-

M+N+


404306 299 259

0

20

40

60

80

100

Cigartte Day

I F

ee

l D

ep

res

se

d

M-N-

M-N+

M+N-

M+N+


78 70 6751

0

5

10

15

Cigartte Day

An

ge

rH

osti

lity

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




118


307417 416

510

0

20

40

60

80

100

Cigartte Day

Inc

rea

se

in T

hin

kin

g S

pe

ed

M-N-

M-N+

M+N-

M+N+


4868 4193 4368 3675

0

20

40

60

80

100

Cigartte Day

Dif

fic

ult

y C

on

ce

ntr

ati

ng

M-N-

M-N+

M+N-

M+N+


a) b)



119


448354

438341

0

20

40

60

Cigartte Day

AO

PO

M-N-

M-N+

M+N-

M+N+


387328

387325

0

20

40

60

Cigartte Day

RO

WO

NE

M-N-

M-N+

M+N-

M+N+


457360

451357

0

20

40

60

Cigartte Day

ITS

M-N-

M-N+

M+N-

M+N+


457

327449

328

0

20

40

60

Cigartte Day

DT

S

M-N-

M-N+

M+N-

M+N+

QSU - Factor 1

889

684

875

675

50

70

90

110

Cigartte Day

Facto

r 1

M-N-

M-N+

M+N-

M+N+

QSU - Factor 2

542426

536425

20

40

60

80

Cigartte Day

Facto

r 2

M-N-

M-N+

M+N-

M+N+

a) b)

c) d)

e) f)


119





120


313

593

346

582

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


244

592

224

633

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Go

od

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


810

498

835

513

0

20

40

60

80

100

Cigartte Day

I C

rave

a C

iga

rett

e

M-N-

M-N+

M+N-

M+N+

VAS - I Feel High

167

352234

340

0

20

40

60

80

100

Cigartte Day

I F

eel

Hig

h

M-N-

M-N+

M+N-

M+N+


a) b)

c) d)




121



ARCI-MBG 35 (31) 42 (33) 56 (43) 70 (53) 0001


POMS-Vigor 66 (51) 74 (48) 98 (59) 94 (55) lt0001

POMS-Arousal 08 (99) 12 (88) 38 (119) 41 (84) 0002




ARCI-PCAG 80 (38) 79 (40) 55 (36) 51 (37) lt0001






POMS-Fatigue 93 (70) 87 (60) 76 (63) 68 (50) 0026


VAS-Nausea 299 (265) 354 (287) 164 (262) 167 (236) lt0001

VAS-Sick 338 (284) 313 (289) 184 (254) 171 (228) lt0001

VAS-Frustrated 538 (282) 465 (307) 427 (303) 335 (313) 0022


VAS-Headache 255 (314) 271 (307) 257 (339) 202 (296) 0017

VAS-Dizzy 242 (243) 335 (293) 164 (224) 183 (254) 0002

VAS-Drowsy 528 (252) 494 (272) 463 (289) 431 (394) 0043



122















0

200

400

600

800


Me

tha

do

ne

Co

nc (η

gm

L)

Cycle 2

Cycle 4


123


0

20

40

60


Nic

oti

ne

Co

nc

(η

gm

L)

Cycle 2

Cycle 4


0

5

10

15

20

25


Nic

oti

ne

Co

nc

(η

gm

L)



a)

b)


124




Patients (Study 1)



















125





correlated



















126






















more intuitive

127
























128






















129



(Study 2)


















the other groups

130
















outcomes122-125







131









dissatisfaction













132























133










assessments












134











Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

4 3

2



135
























136























137




of nicotine gum

















suppression

138
























139
























140






















141























142




















patients



143



study findings




















144
























145













146



a)

b)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 1



147



c)

d)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 3



Study 2

148

Methadone

Effects

Physical

Psychological



Patient

Satisfaction

Patient Factors



149






Case

















150

Discussion







Applied Lessons















151
























152














46 Recommendations








153






















154
























155





47 Final Comment






realities

156

50 REFERENCES

















157


















158


















159
















160

















161

















162


















163

















164

















165
















166

















167

















168


















169

















170
















171

















172





173

60 PUBLICATIONS

Refereed Papers








Abstracts





174






175

Appendix 1


176

March 9 2004













methadone




177




Study Medications



prescribed








Procedures



morning



178




















session




179


















mins)



180





Benefits





Compensation


the study







181

Confidentiality


















182

Informed Consent














ex 6876


183

Appendix 2


184






methadone who are






185

Appendix 3


186



187

Appendix 4


188

October 31 2005

















189

Study Medications











therapy

Procedures











190










Benefits




Compensation


study








191

Confidentiality











study personnel








192

Informed Consent
















ex 6876


193

Appendix 5


194







Explain




clinical judgment




195

Appendix 6


196






(416) 535-8501 ex 6502




197

Appendix 7


198












199

Appendix 8


200

October 3 2006


Relationships





Initiative (CTCRI)







Study Medications






Pt Initials

201














Procedures



questions about







Pt Initials

202





collected









received










Pt Initials

203








for drug testing









administration


assessments





Pt Initials

204

(time = 5 minutes)





















Pt Initials

205










Benefits




Compensation







Pt Initials

206



Confidentiality
















Pt Initials

207

Informed Consent














ex 6876


Time of Signing

208

Appendix 9


209











210

Appendix 10


211





Age

How Long in MMT



Time Dose Taken


Carries



vi

Table of Contents

Abstract ii

Acknowledgements iv


List of Tables xii




10 INTRODUCTION 1



121 Purpose 2

122 Objectives 3



131


4



132


5



vii


6












16




22




28









viii


41




1521


43

1522


44


44



45

211 Study Design 45









ix


55

221 Study Design 55








60

231 Study Design 60












x

30 RESULTS 76


76






86




32211 Nonholders 88

32212 Holders 94







108




xi


124


124


129


133





50 REFERENCES 156

60 PUBLICATIONS 173

Appendices 175

xii

List of Tables

Table Title Page








xiii

List of Figures

Figure Title Page










90





95




99



104


105




113


114

xiv












xv









ASN Asparagine

ASP Aspartate



BG Benzedrine Group

C Concentration





ClF Clearance rate




CO Carbon Monoxide








xvi


E Effect




Emax Maximum Effect














N Slope Factor



NH Nonholder








PD Pharmacodyamic


xvii

PH Partial Holder

PK Pharmacokinetic





















xviii

List of Appendices

Appendix Title Page











1














methadone treatment







2











been well studied


121 Purpose



3

122 Objectives














4




Patients (Study 1)











5






(Study 2)




treatment








6
















7















HIV (7)4

Summary Point



8






















9










Summary Points





daily substitute





10














Columbia42

Summary Point


withdrawal




11

















12























13

















Summary Points





14

















binding68 70 71

15

Summary Point

















from 15 to 207 hours51 58-66 78-86



16









Summary Points











17











enantiomers77










18



each enantiomer88

Summary Points



slowly












19






















20





















21

Summary Points




concentration













22


N + CN EC50N + CN








Summary Point


PD relationships









23







Summary Point













with treatment

24








Summary Points












25






















26








Summary Points






27
















Wang (1974)


Judson (1980)



SOWS (SubOWS)












SOWS (ShOWS)










28






















29





















30









Summary Points






pharmacokinetics






31

















with MMT122-125

Summary Points




32






















33










Summary Points



14102 Human Studies










34


















Summary Points



administration

35





















36










methadone22













37



Summary Points



dependence scores


cigarette












38
























39











effects

Summary Points




nicotine

14122 Human Studies



40
















Summary Points






41







CYP3A4)193









Summary Points





42








Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

43

2

43







Specific Hypotheses







44



Treatment (Study 2)

Specific Hypotheses









Specific Hypothesis





45





211 Study Design













46




















47




participation










group






48




















49























50






Day 1 Day 2 Time (hr) 0 05 1 15 2 3 4 5 6 8 10 12 24



Urine Sample X X

Breathalyzer X X







X










51






















52














Canadian

219 Data Analysis






53















withdrawal






54







endpoints












55



Treatment (Study 2)

221 Study Design















study was completed

56








appendix 5











57




analysis






disorders










58



















59

227 Data Analysis














60



231 Study Design














study

61




















62





















63






















64











meal



(-) Nicotine



(-) Nicotine


(+) Nicotine

3 hr 1030 min 1030 min





65






















66















239 Data Analysis





67











ANOVAs





68


















69






















70



















minutes




71





















72


















in two minutes

73














30 minutes






minute

74





















75












76

Section 3 Results




















77









78




Age (years)

387 (105) 366 (118) 419 (81) 0326 396 (106) 368 (113) 0634

Height (cm)

1735 (95) 1724 (93) 1750 (102) 0593 1758 (95) 1678 (71) 0112

Weight (kg)

855 (277) 723 (126) 1044 (332) 0013 900 (308) 820 (212) 0751

Dose (mg)

988 (544) 895 (636) 1121 (385) 0836 892 (514) 1220 (603) 0271

Time on Dose (mo)

91 (99) 121 (120) 48 (27) 0093 93 (105) 86 (93) 0807


370 (402) 500 (480) 185 (135 0115 422 (467) 245 (147) 0426

HAMD 99 (95) 27 (23) 193 (59) lt0001 82 (87) 138 (109) 0229

POMS - DepDej 162 (144) 97 (84) 246 (167) 0035 139 (103) 212 (217) 0307

POMS - TMD 386 (323) 231 (182) 584 (367) 0024 329 (233) 510 (477) 0458


79


















figure 32b

80


14

-31

-60

-40

-20

0

20

40


07

-27

-4

-2

0

2

4

a)

b)

Nondepressed

Nondepressed

Depressed

Depressed


plt004

plt004


81


0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sc

ore




0

5

10

15

20

25

0 6 12 18 24

Time (hr)

Su

bO

WS

Sco

re

Holder Nonholder

a)

b)


82





= 050 plt005)



0

10

20

30

40

0 5 10 15 20 25 30

HAMD Score

Su

bO

WS

Sco

re


r=070 plt0004

83




between groups


3

4

5

6

0 6 12 18 24

Time (hr)

Pu

pil D

iam

ter

(mm

)



84








0

5

10

15

20

0 6 12 18 24

Time (hr)

(S)-

Me

tha

do

ne

(n

gm

l)

Holder

Nonholder



85





methadone







86



Treatment (Study 2)



















87





322 Subjective Data







Nonholder p

N 25 35 30

Sex (FM) 1213 1124 1317 0271

Age (yr) 395 (83) 407 (85) 398 (83) 0857

Height (cm) 1706 (102) 1711 (79) 1745 (97) 0209

Weight (kg) 788 (243) 771 (258) 760 (147 0892


Time on Dose (mo) 83 (121) 78 (112) 79 (100) 0984

Dose (mgday) 730 (461) 808 (386) 995 (446) 0062



88


32211 Nonholders









figure 36






89
















90


104 122

220

0

10

20

30

40


Su

bO

WS

Sco

re


591

476429

0

20

40

60

80


AR

CI-

WO

W S

co

re


132

8470

0

5

10

15

20


Sh

OW

S S

co

re


154 168

240

0

10

20

30

40


AR

CI-

SO

W S

co

re


a) b)

c) d)

plt0001 plt0001

p=0001 plt0001


91


50 50

67

0

2

4

6

8

10


Avera

ge P

ain

In

ten

sit

y


193

126120

0

1

2

3

4


Cu

rren

t P

ain


a) b)

p=0013 p=0015

92

OCDUS Total Score

65 64

114

0

5

10

15

20

25


OC

DU

S T

ota

l S

co

re


2824

45

0

2

4

6

8

10


Desir

e a

nd

Co

ntr

ol

Sco

re


69

4038

0

5

10

15


ou

gh

ts a

nd

In

terf

ere

nce S

co

re


a) b)

c)

p=0022

p=0016


p=0023

93

ARCI - LSD

52 54

77

0

4

8

12


LS

D S

co

re


1621

40

0

2

4

6

8


Ph

ys

ica

l S

co

re


36

2418

0

2

4

6


Dy

sp

ho

ria

Sc

ore


6456

36

0

2

4

6

8

10


Ab

us

e P

ote

nti

al S

co

re


a) b)

c) d)

p=0005 p=0002

plt0001 plt0001


94

32212 Holders


and nonholders


















95


153

123

66

0

5

10

15

20

25


Ob

se

ssiv

eC

om

pu

lsiv

e S

co

re


4955

160

4

8

12


An

ge

rH

os

tility

Sc

ore


06

1013

00

05

10

15

20

25


Glo

bal

Severi

ty In

dex S

co

re


a) b)

c)

plt0001

p=0001


plt0001

96


79

172197

0

10

20

30

40


ep

ressio

nD

eje

cti

on

Sco

re


101112

51

0

5

10

15

20

25


An

ger

Ho

sti

lity

Sco

re


b)

d)


72

112

133

0

5

10

15

20


Ten

sio

nA

nx

iety

Sc

ore

a)

p=0001 p=0009

POMS - Confusion

52

80

97

0

4

8

12

16


Co

nfu

sio

n S

co

re

c)

p=0001

p=0002



p=0002


-15 -116 -155

-40

-30

-20

-10

0

10

20

An

ge

rH

osti

lity

Sc

ore

e)

96

p=0002


97






figure 311







540

609633

40

60

80


N-F

ac

tor

Sc

ore

s



p=0006

98



nonholders
















99


536

469

537

30

50

70


O-F

acto

r S

co

res


476

380

442

30

50

70


A-F

acto

r S

co

res


a) b)


p=0008 p=0002

100





















101














3223 Other Measures





102
















103


82111

136

0

5

10

15

20

25


Sen

so

ry P

ain

Sco

re

SFMPQ - Total Pain

108151

190

0

10

20

30

40


To

tal P

ain

Sco

re


5439

26

0

2

4

6

8

10


Aff

ecti

ve P

ain

Sco

re


a) b)

c)


p=0027 p=0001

p=0006

104

ARCI - PCAG

6379

100

0

5

10

15


PC

AG

Sco

re


28 3553

0

2

4

6

8

10


Se

da

tio

n-M

oto

r S

co

re


4657

75

0

4

8

12


Sed

ati

on

-Men

tal S

co

re

a) b)


p=0002 p=0007

p=0004


105


2549

69

0

5

10

15


Ph

ob

ic A

nxie

ty S

co

re


3666

92

0

4

8

12

16


Psych

oti

cis

m S

co

re


90132

169

0

10

20

30


So

mati

zati

on

Sco

re


145 166 178

0

1

2

3


PS

DI

Sco

re

a) b)

c) d)


p=0018 p=0003

p=0003 p=0024


106


267 283311

20

30

40


Po

sit

ive

An

xie

ty S

co

re


150 177213

0

5

10

15

20

25

30


Neg

ati

ve A

nxie

ty S

co

re

STAI Total Anxiety

523461427

30

40

50

60

70


To

tal A

nx

iety

Sc

ore


223 250311

0

10

20

30

40

50


AS

I S

co

re


a) b)

c) d)


p=0001 p=0035

p=0001 p=0052

107

POMS - Fatigue

12494

68

0

5

10

15

20


Fa

tig

ue

Sc

ore

POMS - Arousal

-2914

31

-15

-10

-5

0

5

10

15

Aro

us

al S

co

re


a) b)


p=0003 p=0028


108














N 40

Sex 17F23M

Age (yr) 406 (83)











109


















sexes



110





















clarity

111





smoking day















112













113

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS

0

8

16

24

32

40

M-N- M-N+ M+N- M+N+

Su

bO

WS


Male Female



114

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

MN

WS


Male Female



115

POMS - Friendliness

0

5

10

15

20

25

M-N- M-N+ M+N- M+N+

Fri

en

dlin

ess

Cigarette

Nicotine Gum

Placebo

POMS - Elation

0

5

10

15

M-N- M-N+ M+N- M+N+

Ela

tio

n

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t F

eelin

g in

Min

d

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Incre

ase in

Th

inkin

g S

peed

Cigarette

Nicotine Gum

Placebo


0

20

40

60

80

100

M-N- M-N+ M+N- M+N+

Ple

asan

t B

od

ily S

en

sati

on

s

Cigarette

Nicotine Gum

Placebo


0

5

10

15

20

M-N- M-N+ M+N- M+N+

An

ger

Ho

sti

lity

Cigarette

Nicotine Gum

Placebo

a)

d)

b)

c)

f) e)


115


116


3038

50 58

0

4

8

12

Cigartte Day

ST

ME

N

M-N-

M-N+

M+N-

M+N+


5162

73 78

0

4

8

12

Cigartte Day

ST

AB

PO

T

M-N-

M-N+

M+N-

M+N+


354521 557 621

0

20

40

60

80

100

Cigartte Day

Ple

as

an

t B

od

ily S

en

sa

tio

ns

M-N-

M-N+

M+N-

M+N+

ARCI - BG

44 4865 73

0

4

8

12

Cigartte Day

BG

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




117

VAS - Irritable

621501 470

364

0

20

40

60

80

100

Cigartte Day

Irri

tab

le

M-N-

M-N+

M+N-

M+N+

VAS - Restless

620532 506

437

0

20

40

60

80

100

Cigartte Day

Re

stl

es

s

M-N-

M-N+

M+N-

M+N+


404306 299 259

0

20

40

60

80

100

Cigartte Day

I F

ee

l D

ep

res

se

d

M-N-

M-N+

M+N-

M+N+


78 70 6751

0

5

10

15

Cigartte Day

An

ge

rH

osti

lity

M-N-

M-N+

M+N-

M+N+


a)

d)

b)

c)




118


307417 416

510

0

20

40

60

80

100

Cigartte Day

Inc

rea

se

in T

hin

kin

g S

pe

ed

M-N-

M-N+

M+N-

M+N+


4868 4193 4368 3675

0

20

40

60

80

100

Cigartte Day

Dif

fic

ult

y C

on

ce

ntr

ati

ng

M-N-

M-N+

M+N-

M+N+


a) b)



119


448354

438341

0

20

40

60

Cigartte Day

AO

PO

M-N-

M-N+

M+N-

M+N+


387328

387325

0

20

40

60

Cigartte Day

RO

WO

NE

M-N-

M-N+

M+N-

M+N+


457360

451357

0

20

40

60

Cigartte Day

ITS

M-N-

M-N+

M+N-

M+N+


457

327449

328

0

20

40

60

Cigartte Day

DT

S

M-N-

M-N+

M+N-

M+N+

QSU - Factor 1

889

684

875

675

50

70

90

110

Cigartte Day

Facto

r 1

M-N-

M-N+

M+N-

M+N+

QSU - Factor 2

542426

536425

20

40

60

80

Cigartte Day

Facto

r 2

M-N-

M-N+

M+N-

M+N+

a) b)

c) d)

e) f)


119





120


313

593

346

582

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


244

592

224

633

0

20

40

60

80

100

Cigartte Day

I F

ee

l a

Go

od

Nic

oti

ne E

ffec

t

M-N-

M-N+

M+N-

M+N+


810

498

835

513

0

20

40

60

80

100

Cigartte Day

I C

rave

a C

iga

rett

e

M-N-

M-N+

M+N-

M+N+

VAS - I Feel High

167

352234

340

0

20

40

60

80

100

Cigartte Day

I F

eel

Hig

h

M-N-

M-N+

M+N-

M+N+


a) b)

c) d)




121



ARCI-MBG 35 (31) 42 (33) 56 (43) 70 (53) 0001


POMS-Vigor 66 (51) 74 (48) 98 (59) 94 (55) lt0001

POMS-Arousal 08 (99) 12 (88) 38 (119) 41 (84) 0002




ARCI-PCAG 80 (38) 79 (40) 55 (36) 51 (37) lt0001






POMS-Fatigue 93 (70) 87 (60) 76 (63) 68 (50) 0026


VAS-Nausea 299 (265) 354 (287) 164 (262) 167 (236) lt0001

VAS-Sick 338 (284) 313 (289) 184 (254) 171 (228) lt0001

VAS-Frustrated 538 (282) 465 (307) 427 (303) 335 (313) 0022


VAS-Headache 255 (314) 271 (307) 257 (339) 202 (296) 0017

VAS-Dizzy 242 (243) 335 (293) 164 (224) 183 (254) 0002

VAS-Drowsy 528 (252) 494 (272) 463 (289) 431 (394) 0043



122















0

200

400

600

800


Me

tha

do

ne

Co

nc (η

gm

L)

Cycle 2

Cycle 4


123


0

20

40

60


Nic

oti

ne

Co

nc

(η

gm

L)

Cycle 2

Cycle 4


0

5

10

15

20

25


Nic

oti

ne

Co

nc

(η

gm

L)



a)

b)


124




Patients (Study 1)



















125





correlated



















126






















more intuitive

127
























128






















129



(Study 2)


















the other groups

130
















outcomes122-125







131









dissatisfaction













132























133










assessments












134











Methadone (+)

Nicotine (+)

Methadone (+)

Nicotine (-)


Methadone (-)

Nicotine (-)



Nicotine Withdrawal


1

4 3

2



135
























136























137




of nicotine gum

















suppression

138
























139
























140






















141























142




















patients



143



study findings




















144
























145













146



a)

b)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 1



147



c)

d)

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Methadone

Effects

Opioid

Withdrawal

Patient

Satisfaction

Study 3



Study 2

148

Methadone

Effects

Physical

Psychological



Patient

Satisfaction

Patient Factors



149






Case

















150

Discussion







Applied Lessons















151
























152














46 Recommendations








153






















154
























155





47 Final Comment






realities

156

50 REFERENCES

















157


















158


















159
















160

















161

















162


















163

















164

















165
















166

















167

















168


















169

















170
















171

















172





173

60 PUBLICATIONS

Refereed Papers








Abstracts





174






175

Appendix 1


176

March 9 2004













methadone




177




Study Medications



prescribed








Procedures



morning



178




















session




179


















mins)



180





Benefits





Compensation


the study







181

Confidentiality


















182

Informed Consent














ex 6876


183

Appendix 2


184






methadone who are






185

Appendix 3


186



187

Appendix 4


188

October 31 2005

















189

Study Medications











therapy

Procedures











190










Benefits




Compensation


study








191

Confidentiality











study personnel








192

Informed Consent
















ex 6876


193

Appendix 5


194







Explain




clinical judgment




195

Appendix 6


196






(416) 535-8501 ex 6502




197

Appendix 7


198












199

Appendix 8


200

October 3 2006


Relationships





Initiative (CTCRI)







Study Medications






Pt Initials

201














Procedures



questions about







Pt Initials

202





collected









received










Pt Initials

203








for drug testing









administration


assessments





Pt Initials

204

(time = 5 minutes)





















Pt Initials

205










Benefits




Compensation







Pt Initials

206



Confidentiality
















Pt Initials

207

Informed Consent














ex 6876


Time of Signing

208

Appendix 9


209











210

Appendix 10


211





Age

How Long in MMT



Time Dose Taken


Carries



impact on patient satisfaction with methadone maintenance treatment by alexan

Documents