Structure

• Epidemiology /Context• Deaths from methadone• Metabolism and risks with other drugs• Respiratory depression with opioids• Hepatitis C• Cardiac problems

Numbers of opiate users /OCU by age group Cumbria (2011-2012 estimates)

15-24 25-34 35-64Opiate 223 1,183 1,271

OCU 243 1,433 1,262

Centre for Public Health, Liverpool John Moores University (Hay, 2014)

Rate per 1000 estimate of opiate users by age group (2011-2012 estimates)

15-24 25-34 35-64Cumbria 4.00 16.84 6.00Manchester 2.63 11.58 17.64North West 2.58 13.25 9.91ENGLAND 3.60 13.35 6.48

In Unity, for those prescribed Mean =40 SD =8, normal distribution

Rates per 1000 estimate of drug users 15-64 population (2011-2012 estimates)

OCU Opiate Crack InjectingCumbria 7.48 7.40 1.35 3.59Manchester 12.97 11.65 9.46 4.12North West 9.99 9.07 5.47 2.83ENGLAND 8.40 7.32 4.76 2.49

Cost drug use

UK Focal Point On Drugs Annual Report to the European Monitoring Centre for Drugs and Drug Addiction

Clients (n=4817 ) aged 11–65 years who sought treatment for drug use (Helsinki)

Primary Drug

Alive (n= 4321)

Alive % Dead (n= 496)

Dead % Total (n= 4817)

Total % Dead/ Total %

Alcohol 930 22 74 15 1004 21 7.4

Cannabis 825 19 69 14 894 19 7.7

Prescription medicines 79 2 17 3 96 2 18

Opiates 1290 30 142 29* 1432 30 9.9**

Stimulants 1146 27 188 38 1334 28 14

Others 51 1 6 1 57 1 11

Onyeka,2014** For example 142/1432 *100 = 9.9

* For example 142/496 *100 = 29

Deaths for people who sought who sought treatment for drug use

Causes of death All deaths(n = 496)

All deaths%

25–34 years(n = 189)

25–34 years%

35–44 years(n = 107)

35–44 years %

≥45 years(n = 78)

≥45 years%

Disease 174 35.1 53 28 38 35.5 53 67.9Neoplasms 15 3 1 0.5 3 2.8 11 14.1Mental 49 9.9 19 10.1 9 8.4 4 5.1Circulatory 45 9.1 14 7.4 11 10.3 18 23.1Deaths external 322 64.9 136 72 69 64.5 25 32.1Transport 16 3.2 6 3.2 3 2.8 2 2.6Accidental poisioning/OD 165 33.3 66 34.9 42 39.3 12 15.4Suicide 108 21.8 52 27.5 16 15 8 10.3Assault 14 2.8 6 3.2 3 2.8

Onyeka,2014

Causes of death in people with opioid dependence in NSW 1985–2006

< 25* <25 % 25-34 25-34 %

35-44 35-44 %

>45 >45 %

Accidentalopioid-related 209 59.5 699 50.9 542 40.9 124 20.3Accidental other drug-related 14 4 71 5.2 56 4.2 23 3.8Suicide 53 15.1 211 15.4 167 12.6 53 8.7Liver-related 1 0.3 23 1.7 124 9.4 106 17.3Cardiovascular 2 0.6 38 2.8 82 6.2 84 13.7Cancer 3 0.9 17 1.2 90 6.8 80 13.1HIV 6 1.7 37 2.7 33 2.5 15 2.5Motor vehicle accidents 26 7.4 96 7 42 3.2 16 2.6Violence 11 3.1 37 2.7 31 2.3 6 1Other 26 0 144 10.5 157 11.9 105 17.2

*age of death Degenhardt 2013

SMR in people with opioid dependence in NSW 1985–2006

Causes of death SMR CITotal mortality 6.5 (6.3–6.7)All drug-related 35 (33.4–36.6)Accidental drug-related 39.9 (38.0–41.8)Accidental opioid-related 42.8 (40.7–45.0)Accidental other drug-related 24.1 (20.6–28.1)Unintentional injuries 9.6 (9.0–10.2)Motor vehicle accidents 3.2 (2.7–3.7)Violence 7.6 (6.1–9.5)Suicide 6.2 (5.6–6.7)

SMR in people with opioid dependence in NSW 1985–2006

Causes of death SMR CIAll liver-related 11.4 (10.1–12.9)Chronic liver disease 6.5 (5.3–8.0)Viral hepatitis 46.3 (38.5–55.2)Cardiovascular 2.1 (1.9–2.5)Cancer 1.7 (1.4–1.9)HIV AIDS 4.4 (3.5–5.3)Alcohol-related 5.4 (4.4–6.6)Chronic respiratory disease 3.9 (2.7–5.5)Respiratory infections 7.9 (5.1–11.8)

Trends in deaths

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Drug Related deaths MethadoneAll Drug related Deaths

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Drug Related deaths Buprenorphine

Heroin and Morphine

ONS 2014

Metabolism review

• Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (CYP) enzymes

• Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione.

• The most important phase 2 reaction is glucuronidation

• Glucuronidation produces molecules that are highly hydrophilic and therefore easily excreted.

First Pass Effect

Medcape

First pass effects

• Enzymes for phase 1 metabolism are mainly found in the GI tract (liver, small intestine, and colon).

• High concentration enzymes in GI epithelium, hence this is the initial site for first-pass metabolism of drugs.

• The drug via portal circulation goes to the liver, • Some active drug may miss first-pass metabolism in the GI

tract and liver but subsequent passes through the liver result in further metabolism of the parent drug until it is eliminated

• Nasal mucosa and lung also have these enzymes for first pass. important roles in the first pass metabolism of airborne pollutants and aerosols.

Goodman

Metabolism

Metabolism of opioids

• The basal rate of metabolism is determined by genetic makeup, gender, age, as well as environment including diet, disease state, and concurrent use of medications.

• Most opioids are metabolized by glucuronidation or by the P450 (CYP) system.

• Polymorphism in the human OPRM1 gene (encodes the mu opioid peptide (MOP) receptor) may relate to variation in opioid sensitivity– E.g., opioid analgesia, tolerance, and dependence

Smith 2009

Metabolism of opioids• The CYP2D6 enzyme is entirely responsible for the

metabolism of hydrocodone, codeine, and dihydrocodeine to their active metabolites which in turn undergo phase 2 glucuronidation.

• These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with an array of other drugs which are substrates, inducers, or inhibitors of the CYP2D6 enzyme

• Morphine, oxymorphone, and hydromorphone metabolized by phase 2 glucuronidationand therefore have little potential for metabolically based drug interactions.

Smith 2009

Interactions

• http://bioinformatics.charite.de/supercyp/index.php?site=get_drug_interaction

• Nicotine also important to consider

Methadone

• Methadone plasma concentrations follows a bi-exponential1. rapid phase- transfer of the drug from the central

compartment to the tissue compartment2. slow phase - corresponds to elimination

• The t1/2 of the first phase of methadone varies from 1.9 to 4.2 h

• The t1/2 of the second phase (slow) of drug disappearance from the plasma (-phase, slow, elimination) varies even more, from 8.5 to 47 h Ferrari 2004

Methadone

• High lipid solubility, hence rapidly transferred to tissues, particularly liver, kidneys, lungs and to the brain

• 1–2% remains in the blood compartment• 60–90% bound to plasma proteins, mostly to acid 1-

globulins • The blood concentrations of acid 1-glycoproteins,

increase in stress conditions and in heroin dependent users with a decrease of free and active methadone

• Large Volume of distribution of methadone - short term decreases in blood levels not clinically important

Ferrari 2004

Methadone variability

• Induction of its own metabolism may reduces methadone concentrations

• Different views about extent of this1. 30 days treatment of 40 or 80 mg,

1. Decrease plasma level by three to eight-times2. Excretion of parent drug and metabolites increase from 22.2

to 61.9%.

2. 5–12 months of treatment with 60 or 80 mg 1. Decrease plasma level by 15–25%

• Body clearance of methadone varies from 0.96 to 6.1 ml/min/kg

Ferrari 2004

Opioid pharmacologyMu Delta Kappa

Mu 1 – AnalgesiaMu 2 – Sedation, vomiting, respiratory depression, pruritus, euphoria, anorexia, urinary retention, physical dependence

Analgesia, spinal analgesia

Analgesia, sedation, dyspnea, psychomimetic effects, miosis, respiratory depression, euphoria,dysphoria, dyspneak agonist

Actions of opioidsDrug Mu Delta Kappa

Morphine Agonist Weak agonist

Codeine Weak agonist Weak agonist

Fentanyl Agonist

Methadone Agonist

Buprenorphine Partial agonist Partial agonist

Opioid induced respiratory depression case reports

• 34 case reports describing OIRD in 42 adolescent and adult patients treated for chronic cancer and non-cancer pain from 1980 to 2012.

• The number of cases is relatively small compared to OIRD in acute pain patients (120 cases), but there is a substantial increase in the incidence of cases post-2000 (pre-2000: 0.8 cases/year versus post-2000: 2.3 cases/ year).

Dahan 2013

Dahan 2013

15 cases 1980- 2000 27 cases 2000 - 2013

Indication cancer pain 67% pre-2000, 41% post- 2000

Reason long term opioid used

• The indication for opioid use was cancer pain in 67% of the cases pre-2000, but dropped to 41% post- 2000

• Post-2000 the indication for opioid prescriptions for non-cancer pain was 59%, most commonly for treatment of musculoskeletal pain (33%) followed by neuropathic pain and complex regional pain syndrome (11%)

Age/ Sex

Drug Length Complication OtherDrugs

Cause

42 yr. F

Methadone

6 years

Sedation/respiratorydepression responsive tonaloxone

Ciprofloxacin

Inhibition ofCYP1A2 and 3A4activity, increasingmethadone bloodlevels

60 yr. M

Methadone

15 days

Respiratory depressionresponsive to naloxone

Fluconazole

Inhibition ofCYP3A4 and2Y9, increasingmethadone bloodlevels

Dahan 2013

Age/Sex

Drug Length Complication OtherDrugs

Cause

46 yr. M

Fentanyl TD patchmorphine,oxazepam

45 days

8 days following start of fluconazole patient died during sleep. Forensicanalysis showed high plasma conc. of fentanyl and fluconazole

Fluconazole

Inhibition ofCYP3A4 system,increasing fentanylblood levels

34 yr. M

Buprenorphine TDpatch

12 h Respiratory depressionupon start ofchemotherapy withifosfamide resolved by removal of the patch

Ifosfamide, analkylating agent

Possible competitiveinteraction viacommon metabolicpathway (CYP3A4

Age/Sex

Drug Length Complication OtherDrugs

Cause

81 yr M

Fentanyl TD patch

Long-term

36 h after receivingthe first dose ofclarithromycine hedeveloped naloxoneresponsiverespiratorydepression.

Clarithromycin

Inhibition of theCYP3A4 system,increasing fentanyl’splasma levels

46 yr M

Methadone 4 months

Smoking cessation (after 33 pack years) initiated naloxone-responsiverespiratory depression

Smokingcessation

Polycyclic aromatichydrocarbons intobacco smokeinduce CYP1A2. Smokingcessation may have reduced methadone’smetabolism.

Age/ Sex

Drug Length Complication OtherDrugs

Cause

70 yr. M

Methadone

Event 1 week after long term opioid use

Respiratory depressionresponsive to naloxone

Sertraline

Inhibition ofthe CYP system,increasingmethadone bloodlevels.

61 yr F Methadone

Long-term

Naloxone-responsiverespiratory depression 11days after carbamazepinewithdrawal

CarbamazepineGabapentin

Induction ofCYP3A4 activity. Itswithdrawal slowsdown methadone’smetabolism causingan increase in plasmalevels

Hepatitis C

• In England, 160,000 adults are estimated to be chronically infected with hepatitis C

• This is about 0.4% of the adult population.• Injecting drug use continues to be the most

important risk factor for HCV infection• In England, 16% of PWID reported direct

sharing of needles in 2013 (29% in 2003).

PHE 2014

Deaths from ESLD or HCC in those with HCV mentioned on their death certificate in England: 1996-2013**

Risk factor information in laboratory reports* of hepatitis C fromEngland: 1996-2013

Number of deaths from ESLD* or HCC in those with HCV mentioned on their death certificate by PHE Centre 2008-2013** (per 100,000 population)

Unlinked Anonymous Monitoring Survey of Hepatitis C* in PWID

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80%

EnglandNorth West

*Proportion of samples antiHCV positive

Factors for QTc

• Methadone prolongs QTc in a dose dependent manner

• QT prolongation is used as the surrogate marker for TdP

• If methadone is a risk factor why does not everyone suffer from QTc elongation on methadone?

• “Forme fruste” theory• Certain people at risk for QTc elongation but need

trigger for it to occur

Risk factors of QTc• Metabolic disorders/ Misc• hypokalemia,

hypomagnesemia, hypocalcemia

• Starvation• Anorexia nervosa• Hypothyroidism• HIV infection• Hypothermia• Connective tissue disorders

with anti-Ro/SSA antibodies• Male, age

• Cardiac disease• Bradyarrhythmias: sinus

node dysfunction, AV block-second or third degree

• Advanced cardiac disease• Myocardial ischemia or

infarction, esp. with prominent T wave inversions

Mujtaba, 2013

Drug Causes of QTc• Antiarrhythmic drugs e.g.: quinidine, procainamide,

sotalol• Antimicrobial drugs: erythromycin, azithromycin,

levofloxacin• Antihistamines: terfenadine• HIV Protease inhibitors: ritonavir, nelfinavir, atazanavir• Psychotropic drugs: thioridazine, haloperidol,

olanzapine• Motility drugs: cisapride, domperidone

http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm, www.qtdrugs.org.

Myocardial action potential Phases

Gupta 2007

Na entryK efflux

Slow Ca entry K exit cause 2

K re-enters Na exits

QTc prolongation

• Myocardial repolarization via efflux of potassium ions.

• Mediated by two subtypes of the delayed rectifier K+ current, Ikr (rapid) and Iks (slow)

• Drugs prolonging QTc block Ikr thereby delaying phase 3

• Longer action potential results in QT prolongation. – It may also distort T waves or produce prominent U

waves

Gupta 2007

Mechanism of action

• Inhibitor of Ikr• Increased QT dispersion (marker of

heterogenous cardiac repolarization) has been observed in association with methadone

• Methadone has bradycardia effect– Due to anticholinesterase & calcium channel

antagonist properties – Adds to risks TdP

Mujtaba, 2013

Comparison of opioids effects on Ikr

Drug IC50 for HERG Blockade (uM)

Maximum Plasma Conc. (Cmax) (uM)

Ratio: IC50/Cmax

Methadone 9.8 3.6 2.7Fentanyl 1.8 0.030 60Buprenorphine 7.5 0.036 208Morphine >1000 2.5 >400Codeine >300 0.66 >455

Katchman 2002

Electrical impulse

http://courses.kcumb.edu/physio/ecg%20primer/ecgaxis.htm

http://en.wikiversity.org/wiki/User:Bron766/ECG/Axis

Normal ECG

http://www.ecglibrary.com/ecghome.html

Torsade de pointes

Patients with opioid dependence in Taiwan

• Taiwan launched MMT in 2006 in response to the HIV/AIDS surge endemic in eastern Asia

• 33,603 patients registered throughout 2006 to 2008• Average age = 37.7 years, men (84.8%),• HIV infection rate was 14.1%• The average treatment duration was 171.5 days, and the

average follow-up duration 358.4 days.• Mean (SD) methadone dosage was 46.5 (20.9) mg/day.• No take-home dosage was permitted throughout the

treatment

Adjusted hazard ratios for all-cause deaths for MMT patients 2006 -08.

Age Adjusteed hazard rate

CI for adjusted hazard rate

P for trend

≤30 1 1

30-45 0.96 (0.74-1.25) 0.767

45-60 0.75 (0.56-1.01) 0.057

>60 0.68 (0.50-0.92) 0.016

Adjusted for age, sex, marital status, education, HIV status

Hazard function of low to high methadone dosage subgroups

Ding-Lieh Liao 2013

Comparison 1 RCT, Outcome 6 Opioid abstinence at >3-4 weeks (urine based).

Faggiano 2003

MMT vs No MMTMorphine positive urine or hair analysis.

Mattick 2009

High-dose buprenorphine versus placebo, Morphine-positive urines

Treatment opioid dependence• The needs of all drug misusers should be assessed across the four

domains of drug and alcohol misuse, health, social functioning and criminal involvement.

• Risks to dependent children should be assessed for all drug-using parents.

• All drug misusers entering structured treatment should have a care or treatment plan which is regularly reviewed.

• A named individual should manage and deliver aspects of the patient’s care or treatment plan

• Drug testing can be a useful tool in assessment and in monitoring• Drug misuse treatment involves a range of interventions, not just

prescribing.

DOH 2007

Pharmacological components

• Methadone or buprenorphine are are effective medicines for maintenance (opioids)

• Dose induction with buprenorphine may be carried out more rapidly with less risk of overdose

• Care with children • Supervised consumption should be available• Methadone, buprenorphine, lofexidine are effective

in detoxification regimens

DoH 2009 Drug misuse and dependence. UK guidelines on clinical management

Opioid substitution treatment (OST) effectiveness

• The evidence is good that OST– OST reduces the risk of death among heroin users

participating in treatment – Suppresses illicit use of heroin– Prevents people dropping out of treatment

reduces crime – OST reduces involvement in crime among heroin users participating in treatment

– OST reduces the risk of BBV transmission, including in prisons

Medications In Recovery Re-orientating Drug Dependence Treatment NTA 2012

Opioid substitution treatment (OST) effectiveness

• Evidence is less good that OST– Suppresses other drug use– Promotes abstinence from all drugs– Improves physical and mental health –the

evidence suggests rapid and substantial improvements on treatment entry, which may or may not be maintained or further improved

– Improves social reintegration of marginalised heroin users

Medications In Recovery Re-orientating Drug Dependence Treatment NTA 2012