opioid dependence: highlighting buprenorphine treatment tony tommasello, pharmacist, phd associate...
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Opioid Dependence: Highlighting Buprenorphine
Treatment
Tony Tommasello, Pharmacist, PhDAssociate Professor
UM School of PharmacyOffice of Substance Abuse Studies515 West Lombard Street – 263
ACPE Universal Program Number 025-999-06-054-X01
2
Learning Objectives
At the conclusion of this program participants will be better able to:
1. Describe the forces that are driving the current increase in opioid abuse in the U.S.
2. Explain the need for non-pharmacological interventions for addicted patients
3. List therapeutic outcomes for addiction treatment
4. Distinguish medical withdrawal and medical maintenance
5. Explain the pharmacological basis for medical maintenance
6. Describe differences between methadone, buprenorphine, and naltrexone pharmacotherapy
7. List policy changes relative to opioid addiction treatment in America
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Dynamics of a Heroin Epidemic
Input
Demand reduction
Supply reduction
Negative forces
2.4 million users
0.5 to 1 million addicts
150 to 200,000 new users each year
Broad-based screening
Addiction Severity Index
Treatment on demand
High heroin purity
Increased youth experimentation
Prescription opioid diversion
Positive forces
NarcoticAddiction
Input InputRecovery
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Number of US Narcotic Analgesic-Related ED Visits, 1994-2001
41,687 42,857 44,028
50,58454,516
64,534
75,837
90,232
0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
80,000
90,000
100,000
1994 1995 1996 1997 1998 1999 2000 2001
Vis
its
Source: www.samhsa.gov/oas/2k3/pain/dawnpain.pdf.
5
Teen Abuse of Rx Drugs:National Figures
Percentage of Teens Who Have Ever Used Drugs to Get High
37
20 19
4
0
5
10
15
20
25
30
35
40
Marijuana Pain Meds Inhalants Heroin
Pe
rce
nta
ge
of
Te
en
s
Curran JJ. Prescription for Disaster – The growing problem of prescription drug abuse in Maryland. September 2005.
6
Access to Treatment Is Limited
Of the estimated 810,000 opioid-dependent persons in the United States, only 170,000 maintenancetreatment slots exist
No. of Opioid-Dependent Persons
0
100,000
200,000
300,000
400,000
500,000
600,000
700,000
800,000
900,000
Capacity Need
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Aspects of Addiction
Chronic Incurable but manageable
Primary Not relieved by treating a suspected causative condition
Progressive Gets worse if untreated
Relapsing Prone to recurrence if untreated
Fatal Premature death in untreated individuals
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9
The Memory of Drugs
10
Opioid Addiction: Effects on the Body
Opioids activate receptors in the central nervous system (CNS) and the gastrointestinal (GI) track
CNS stimulation provides pleasurable feelings while GI stimulation produces constipation
Other CNS effects include miosis, respiratory depression, drop in blood pressure
11
Why Treatment?
Dysfunctional lifestyle of opioid addiction makes treatment a desired alternative
Oral methadone and buprenorphine sublingual tablets are approved for both medical withdrawal and medical maintenance
Rewards
Negative Consequences
Utility Theory
12
Addiction Treatment
Optimal treatment combines pharmacological and nonpharmacological therapies for successful management of those addictions for which pharmacotherapy has been approved (opioid, alcohol, nicotine)
13
Primary Treatments Are Nonpharmacological
Individual and/or group cognitive behavioral therapy
Urine monitoring for drugs of abuse (also sweat, saliva, and blood)
Support group participation– Narcotics Anonymous
– Alcoholics Anonymous
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Patient Response to Addiction Treatment Will Vary
Patient characteristics—age, employment experiences, concurrent illnesses, family support
Patient history—past treatment experiences, duration and level of drug use
Patient motivation
Length of time in treatment
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Opioid Addiction Pharmacotherapy Enhances Treatment Outcomes
Medical Withdrawal: Remove the opioid from the body and remain free of future opioid use
Maintenance Therapy: Use a substitute opioid (agonist), “satisfy narcotic hunger,” eliminate craving
Buprenorphine approved for both approaches
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Pharmacology of Opioids
Affinity: The strength with which a drug binds to its receptor
Dissociation: The speed at which a drug uncouples from its receptor
Efficacy: The percent of maximal response that a drug generates when it binds to the receptor
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Full Agonists
Bind to and activate receptor site
As dose is increased, effect is increased until a maximum response is attained
Examples:– Heroin
– Oxycodone
– Methadone
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Antagonists
Bind to the receptor without causing activity
An antagonist can block the receptor from being activated by partial or full agonist
Examples:– Naloxone
– Naltrexone
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Partial Agonists
Bind to receptor and excite the receptor
Activity reaches a plateau at which an increase in dose does not result in increased activity
Examples:– Buprenorphine
(also a kappa antagonist)
– Pentazocine
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Comparative Efficacies
Full Agonist(Methadone)
Partial Agonist(Buprenorphine)
Antagonist(Naloxone)
Log Dose
Op
ioid
Eff
ec
tConceptual Representation of
Opioid Effect Versus Log Dose for Opioid Full Agonists, Partial Agonists, and Antagonists
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Pharmacokinetic Distinctions
Methadone
Slowly absorbed from the gut reaching peak blood level in 45 to 90 minutes
Half-life in maintenance patient is 24 hours
Allows once-daily dosing
Buprenorphine
Sublingual tablets must be held under the tongue for 4 to 8 minutes for absorption
Peak blood level in 60 minutes
Half-life is 32 hours
Allows once-daily or every-other-day dosing
Chiang CN, Hawks RL. Pharmacokinetics of the combination tablet of buprenorphine and naloxone. Drug Alcohol Depend. 2003;70(suppl 2):S39-S47.
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Other Distinctions
Buprenorphine has greater opioid receptor affinity and slower receptor dissociation than methadone
Buprenorphine will displace a full agonist (methadone) and dock at the receptor, thus blocking other full agonists from attaching there
Patients switching from methadone to buprenorphine may experience withdrawal distress and are advised to complete a reduction process before starting buprenorphine
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Buprenorphine/Naloxone Combination and Buprenorphine Alone
Two dosages:– Buprenorphine 2 mg
with naloxone 0.5 mg
– Buprenorphine 8 mg with naloxone 2 mg
Two dosages:– Buprenorphine 2 mg
– Buprenorphine 8 mg
Tablet(s) should be held under the tongue until completely dissolved.
SUBOXONE®
SUBUTEX®
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Medical Withdrawal With Buprenorphine
Opioid-dependent individuals are treated with the goal of achieving a smooth transition to being substance free in a short period of time
Dose-tapering patients should be engaged in counseling and have counseling continued after medical withdrawal is complete
MDs and pharmacists should continue to reinforce to patients the importance of counseling after withdrawal
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Induction Dosing Guidelines: Buprenorphine for Non-Methadone Patients
Give the first dose after discontinuing opioids and some withdrawal symptoms are evident
Precipitated withdrawal is avoided by giving the first dose of buprenorphine after withdrawal symptoms are displayed
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Titrate to Stability
Intoxication
Withdrawal
Insufficient Opioid
Withdrawal
Stabilization
Intoxication
Intoxication
Withdrawal
Excessive Opioid
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Staging and Grading Systems of Opioid Withdrawal (TIP 40)
Stage Grade Physical Signs/Symptoms
Early Withdrawal (8–24 hours after last use)
Grade 1Lacrimation and/or rhinorrheaDiaphoresisYawning, restlessness, insomnia
Grade 2
Dilated pupilsPiloerectionMuscle twitching, myalgia and arthralgiaAbdominal pain
Fully Developed Withdrawal (1–3 days after last use)
Grade 3
Tachycardia, tachypnea HypertensionFeverAnorexia or nauseaExtreme restlessness
Grade 4
Diarrhea and/or vomitingDehydrationHyperglycemiaHypotensionCurled-up (fetal) position
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Signs of Opioid Intoxication and Overdose (TIP 40)
Opioid Intoxication– Conscious
– Sedated, drowsy
– Slurred speech
– “Nodding” or intermittently dozing
– Memory impairment
– Mood normal to euphoric
– Pupillary constriction
Opioid Overdose– Unconscious
– Pinpoint pupils
– Slow, shallow respirations; respirations below 10 per minute
– Pulse rate below 40 per minute
– Overdose triad: apnea, coma, pinpoint pupils (with terminal anoxia: fixed and dilated pupils)
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Medical Withdrawal Dosing: Buprenorphine for Non-Methadone Patients
A maximum dose of 8 mg can be administered on the first day as Subutex® or as Suboxone®
Patients who still have withdrawal distress should be treated symptomatically and have their doses increased to a maximum of 16 mg for Day 2
Stabilize for 2 days before tapering, then taper 2 mg/day every 2 to 3 days
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Model: Prescription Medical Withdrawal
Ralph Amado, M.D.3862 North Hampton LaneRudolph, PA 38216
AA620395XA620395
Roger Bacon1063 Eastlight Dr.Essex, PA 38604
Physician name, address, DEA and waiver number
Patient name and address
Suboxone 2/0.5; Tablets #42 (forty-two)
Drug name and strength
Dosage form and quantity
Day of tx 3* 4 5 6 7 8 9 10 11 12 13
date 5/25 5/26 5/27 5/28 5/29 5/30 5/31 6/1 6/2 6/3 6/4
# tabs 8 7 6 5 4 3 3 2 2 1 1
SIG: for opioid withdrawal
Date issued: 5/24/03
Patient:
* Treatment on days 1 and 2 were done in the physician’s office
Refill x 0 (zero) Physician signature: Ralph Amado
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Medical Withdrawal
“Withdrawal services are essentially acute services with short-term outcomes, whereas heroin dependence is a chronic relapsing condition, and positive long-term outcomes are more often associated with longer participation in treatment.”
Vorrath E (ed) (2001) National Clinical Guidelines and Procedures for the use of Buprenorphine in the Treatment of Heroin Dependence (p.30). Available at http://www.nationaldrugstrategy.gov.au/resources/publications/buprenorphine_guide.pdf
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Medical Withdrawal
Overemphasis on the importance of being drug free
Underestimates the challenges associated with addiction
Nonpharmacological interventions are critical to recovery success
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Sustaining Abstinence
Naltrexone (Trexan) 50 mg/day is used to prevent opioid effects if a patient uses opioids during recovery– Patient must be narcotic free 7 to 10 days before
starting therapy
– Naltrexone “blocks” heroin high and other effects
– Noncompliance and low patient acceptance
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Maintenance Treatment
Patients consume a long-acting prescription opioid medication as a substitute for the illegal short-acting street opioid
“The most dramatic effect of this treatment has been the disappearance of narcotic hunger”
Dole VP, Nyswander M. A medical treatment for diacetylmorphine (heroin) addiction. JAMA. 1965;193:646-650.
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Outcomes of Treatment
Methadone is the standard pharmacotherapy for opioid addiction
Two outcomes for treatment– Reduction of illicit opioid abuse
– Retention in treatment
Medical maintenance is the best treatment option in achieving these outcomes
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Buprenorphine Trials Data (Retention)
Study Retention
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Study Week
% o
f P
ati
en
ts
Levomethadyl Acetate Buprenorphine
High-Dose Methadone Low-Dose Methadone
37
Buprenorphine Trials Data (Opioid Abuse)
Self-Reported Illicit Opioid Use
0
5
10
15
20
25
30
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Study Week
Me
an
Fre
qu
en
cy
(t
ime
s/w
k)
Levomethadyl Acetate Buprenorphine
High-Dose Methadone Low-Dose Methadone
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Buprenorphine Trials Data (Urine Tests)
Opioid-Positive Urine Specimens
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Study Week
% P
os
itiv
e
Levomethadyl Acetate Buprenorphine
High-Dose Methadone Low-Dose Methadone
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Dose Adequacy
0
5
10
15
20
25
30
35
40
0 2 4 6 8 10 12 14 16
Week
VA
S R
ati
ng
s o
f H
old
Strain EC et al. Buprenorphine versus methadone in the treatment of opioid dependence: self-reports, urinalysis, and Addiction Severity Index.J Clin Psychopharmacol. 1995;16:59-67.
Withdrawal Score
0
10
20
30
40
50
60
70
80
90
0 2 4 6 8 10 12 14 16
Week
Sc
ore
Methadone (n=43) Buprenorphine (n=43)
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Fudala PJ et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349:949-958.
Opiate Craving Scores
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4
Weeks
Sc
ore
Buprenorphine-naloxone Buprenorphine alone Placebo
Subjects' Impression of Overall Success
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4
Weeks
Sc
ore
Clinicians' Impression of Overall Success
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4
Weeks
Sc
ore
41
*Data were unavailable for two of the subjects in each group.†P values are for the overall comparison among three groups.
Fudala PJ et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349:949-958.
Adverse Events Reported by at Least 5 Percent of the Subjects in Any Treatment Group During the Double-Blind Trial*
Adverse EventBuprenorphine and Naloxone (n=107)
Buprenorphine Alone(n=103)
Placebo(n=107)
PValue†
No. of subjects (%)
Headache 39 (36.4) 30 (29.1) 24 (22.4) 0.08
Withdrawal syndrome 27 (25.2) 19 (18.4) 40 (37.4) 0.008
Pain 24 (22.4) 19 (18.4) 20 (18.7) 0.74
Insomnia 15 (14.0) 22 (21.4) 17 (15.9) 0.37
Nausea 16 (15.0) 14 (13.6) 12 (11.2) 0.73
Sweating 15 (14.0) 13 (12.6) 11 (10.3) 0.70
Abdominal pain 12 (11.2) 12 (11.7) 7 (6.5) 0.37
Rhinitis 5 (4.7) 10 (9.7) 14 (13.1) 0.09
Diarrhea 4 (3.7) 5 (4.9) 16 (15.0) 0.005
Infection 6 (5.6) 12 (11.7) 7 (6.5) 0.24
Chills 8 (7.5) 8 (7.8) 8 (7.5) 1.0
Constipation 13 (12.1) 8 (7.8) 3 (2.8) 0.03
Back pain 4 (3.7) 8 (7.8) 12 (11.2) 0.12
Vasodilation or flushing 10 (9.3) 4 (3.9) 7 (6.5) 0.28
Vomiting 8 (7.5) 8 (7.8) 5 (4.7) 0.66
Weakness 7 (6.5) 5 (4.9) 7 (6.5) 0.87
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Model PrescriptionMaintenance Treatment
Ralph Amado, M.D.3862 North Hampton LaneRudolph, PA 38216
AA620395XA620395
Roger Bacon1063 Eastlight Dr.Essex, PA 38604
Physician name, address, DEA and waiver number
Patient name and address
Suboxone 8/2 Tablets #60 (sixty)
Drug name and strength
Dosage form and quantity
SIG: for opioid maintenance take two tablets daily dissolved under the tongue.
Date issued: 5/24/03
Patient:
Refill x 5 (five) Physician signature: Ralph Amado
43
Clinical Trials Dosing
Sublingual buprenorphine daily doses of 8 to16 mg has been shown to be equally effective to oral methadone daily doses of 80 to 120 mg
Buprenorphine maintenance is ideal for people abusing illegal opiates and for those who want to switch from methadone to buprenorphine
Protocols for treatment can be found in the manual Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction: a Treatment Improvement Protocol (TIP) 40. Available at: www.samhsa.gov/centers/csat/csat.html
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Drug Interactions
Benzodiazepines—respiratory depression and cardiovascular collapse are possible when high doses are taken of both drugs. Patients must be closely monitored
Other depressants produce additive effects on the CNS and may create interactive effects for patients operating motor vehicles or heavy machinery
Buprenorphine given to tolerant physically dependent opiate addicts may produce withdrawal symptoms
Buprenorphine is metabolized by the cytochrome p450 3A4 pathway. Drugs metabolized by the same pathway could result in higher than normal levels of either drug. Patients who are on both buprenorphine and one of these drugs need to be monitored closely
45
DATA (Drug Addiction Treatment Act)New Policy—New Practice
The Children’s Health Act
of 2000
46
Provisions of DATA
An amendment to the Controlled Substances Act
Allows certain physicians to prescribe and dispense for up to 30 patients Schedule III, IV, and V narcotic drugs that have been approved by the Food and Drug Administration for use in maintenance or detoxification treatment
An authorized physician, one year after his or her initial notification, may petition to increase up to 100 the number of patients s/he will treat*
* Changed by public law 109-56 on 8-2-2005
47
Authorized Buprenorphine Prescribers in the United States
http://buprenorphine.samhsa.gov/
Physician locator selection provides map. Click on your state for physician listing
48
List of Drugs Approved by FDA for Use Under DATA
Only buprenorphine formulated for sublingual use has been approved
Approved on October 8, 2002
Two formulations, Subutex® and Suboxone® are available
No other medications are approved for use under DATA
49
Expanded Access to Care
One public health goal is to make opioid addiction treatment available on demand
Methadone treatment clinics are operating at full capacity
The Drug Addiction Treatment Act, if widely implemented, will offer numerous points of entry into opioid addiction treatment
50
Pharmacists’ Roles
Case finding through screening
Dispense buprenorphine sublingual tablets in accordance with the law
Patient education on proper sublingual use
Counsel patients regarding drug interactions
Advise counseling interventions and help patients locate appropriate therapists
Manage refill regularity
51
Code of Federal Regulation Title 42 Part 2
Protects the confidentiality of alcohol and drug abuse patients and their medical records
Is different from HIPAA
Restricts disclosure of patient information and any patient identifying information
Requires consent for ANY information to be disclosed
52
Practice Implications
Pharmacists need to practice diligence when counseling patients
Pharmacists need to train their staff on the importance of not disclosing information on a patient receiving treatment
Pharmacists must limit the information they provide to others
53
Initial Reports Are Favorable*
Pharmacists involved in early trials with buprenorphine sublingual pharmacotherapy generally found the experience to be clinically rewarding
Few expressed concerns about dangers associated with this treatment ofopioid addiction
* Raisch DW et al. J Am Pharm Assoc. 2005;45:23-32.
54
Summary
Buprenorphine–effective pharmacotherapy for opioid addiction
Knowledgeable pharmacists can effectively counsel patients undergoing treatment with this medication
Pharmacists will be increasingly expected to dispense buprenorphine prescriptions and provide associated services
Opioid Dependence: Highlighting Buprenorphine
Treatment
Tony Tommasello, Pharmacist, PhDAssociate Professor
UM School of PharmacyOffice of Substance Abuse Studies515 West Lombard Street – 263