Structure

• Epidemiology /Context• Opioid related mortality morbidity• Treatment with opioid replacement treatment• Detoxification • Risks with opioid replacement treatment

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%

Neoplasms 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 23.1Transport 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 15.1 167 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 Methadone

Drug Related deaths Buprenorphine

Heroin and Morphine

ONS 2014

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

20032004

20052006

20072008

20092009

20102010

20112012

20130%

10%

20%

30%

40%

50%

60%

70%

80%

EnglandNorth West

*Proportion of samples antiHCV positive

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

How long to continue treatment

• Increased length of time in OST associated with improved outcomes

• Short-term treatment associated with poorer outcomes• Study on people on methadone treatment over 30 year

period demonstrated that 40% with stable remission spent between five to eight years in OST

• English government has used findings that heroin users need at least 12 weeks in OST for benefit to underpin policy on treatment

• Some USA authors suggest a 1 year minimum time on OST

ACMD 2014Time limiting opioid substitution therapy

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

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

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.

Dose 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

Pharmacokinetics Methadone• Well absorbed from the gastrointestinal tract with peak plasma

levels occurring 1-5 hours after a single dose. • Wide variations in plasma levels occur during maintenance therapy.• Plasma levels may decrease due to auto-induction of hepatic

microsomal enzymes.• Gradual accumulation in tissues and on discontinuation low

concentrations in the plasma are maintained by slow release from extravascular binding sites accounting for the relatively mild but protracted withdrawal syndrome.

• N-demethylation occurs in the liver and metabolites are excreted in the faeces and urine together with unchanged methadone

• The elimination half-life is long and varies considerably with a range of 15-60 hours having been reported

https://www.medicines.org.uk/emc/medicine/25342

Pharmacokinetics Buprenorphine• Used sublingually as undergoes extensive first-pass metabolism

in the small intestine and the liver.• Peak plasma concentrations are achieved 90 minutes after

sublingual administration • The absorption of buprenorphine is followed by a rapid

distribution phase (distribution half-life of 2 to 5 hours).• CYP3A4 is responsible for the N-dealkylation of buprenorphine. • Elimination of buprenorphine is bi- or tri- exponential, and has a

mean half-life from plasma of 32 hours• Buprenorphine excreted in the faeces by biliary excretion of the

glucuroconjugated metabolites (70%), the rest excreted in the urine.

https://www.medicines.org.uk/emc/medicine/26614

Opioid detoxification General 1 • Clearly defined process supporting safe and effective

discontinuation of opiates while minimising withdrawals. • Varies from 28 days as inpatient to 12 weeks as outpatient• A detoxification alone is rarely successful especially at the first

attempt- Need to have clear access back into treatment • Important factors

– The patient is fully committed to and informed about the process (including risk of relapse)

– The patient is in stable situation or in stable situation following detoxification.

– Plans for continuing support and treatment are in place.

DOH 2007

Opioid detoxification General 2

• Forced detoxification generally results in relapse and associated risks

• Psychosocial intervention critical • Post detox needs drug free services for support

including mutual aid• Slow reduction not detoxification but can allow

lower doses to be attained and act a preparation for detoxification

• Ultra rapid detoxification with sedation not to be used

Methadone Buprenorphine Detox

• Methadone– Following stabilisation reduce at around 5 mg every one or

two weeks.– Usual higher decrements at the start

• Buprenorphine– Reduce by 2 mg every two weeks with final reductions

being around 400 micrograms.– Patients report being able to reduce buprenorphine doses

more quickly than methadone.• Detoxification from either medication similar in terms

of outcomes from detoxification

Symptomatic treatment of withdrawal Lofexidine

• Adrenergic alpha-2-receptor agonist with high affinity for 2A receptor subtypes

• Less anti-hypertensive activity than clonidine- a non-selective alpha-2-receptor agonist.

• Hypotension and bradycardia may occur• Stopping suddenly may result in transient increased BP• Dry mouth and mild drowsiness can occur• Course between 7–10 days

– start at 800 micrograms – rise to maximum of 2.4 mg in divided doses – reducing subsequently

• Consider in those not using methadone or buprenorphine for detoxification, those wanting to detoxify within a short time period and those with mild / uncertain dependence (including young people)

SPC lofexidine 2014

Adjunctive medication

• Diarrhoea – loperamide• Nausea, vomiting metoclopramide

/prochlorperazine • Stomach cramps – mebeverine / hyoscine

butylbromide• Agitation and anxiety, sleeplessness – zopiclone 7.5

mg at bedtime• Muscular pains and headaches –paracetamol,

aspirin and other non-steroidal anti-inflammatory drugs

Setting

• Community detoxification generally to be used• Consider inpatient detoxifications in those

– not benefited from previous community-based detoxification

– With significant co-morbid physical or mental health problems

– require complex polydrug detoxification, (alcohol or benzodiazepines)

– Have significant social problems that will limit the benefit of community-based detoxification.

Relapse prevention with Naltrexone

• Naltrexone is an opioid antagonist used orally in UK• Liver function tests should be conducted before and

during naltrexone treatment (due to risks of hepatoxicity).

• Prior to first dose need negative drug screen• First dose of naltrexone is (25 mg) orally• Continues at 50 mg • Patient information card should be given• Programme of supervision for compliance helpful

Complications with OST

• Older populations with OST• Frequent comorbid physical health problems• Two main concerns

– QTc – Respiratory depression

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

Example of opioid induced respiratory depression

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..

Example of opioid induced respiratory depression 2

Factors for QTc

• Methadone prolongs QTc in a dose dependent manner

• QT prolongation is used as the surrogate marker for TdP

• Certain people at risk for QTc elongation but need trigger for it to occur

• Upper limits – 440 ms in adult males – 470 ms adult females)

Structure

• Epidemiology /Context• Opioid related mortality morbidity• Treatment with opioid replacement treatment• Detoxification • Risks with opioid replacement treatment