Medication Aspects of Methadone Maintenance Treatment

Assoc. Professor Robert Ali

Discipline of Pharmacology

School of Medical Sciences

University of Adelaide

robert.ali@adelaide.edu.au

Heroin Withdrawal

•      Non-life threatening

•      Commences 6–24+ hours after last use

•      Peaks at around 24–48 hours after use

•      Resolves after 5–7 days.

 

    Increasing recognition of the existence of a protracted phase of withdrawal lasting some weeks or months, characterised by reduced feelings of wellbeing, insomnia, dysthymia, and cravings.

Opioid Withdrawal

        Signs

•      Yawning

•      Lacrimation, mydriasis

•      Diaphoresis

•      Rhinorrhoea, sneezing

•      Tremor

•      Piloerection

•      Diarrhoea and vomiting.

         Symptoms

•      Anorexia and nausea

•      Abdominal pain or cramps

•      Hot and cold flushes

•      Joint and muscle pain or twitching

•      Insomnia

•      Drug cravings

•      Restlessness/anxiety.

Opioid Withdrawal Complications

•      Anxiety and agitation

•      Low tolerance to discomfort and dysphoria

•      Drug-seeking behaviour (requesting or seeking medication to reduce symptom severity)

•      Muscle cramps

•      Abdominal cramps

•      Insomnia.

Predictors of Withdrawal Severity

•       Main predictors

–      Greater regular dose           

–      Rapidity with which drug is withdrawn.

•       Also consider

–      Type of opioid used, dose, pattern and duration of use

–      Prior withdrawal experience, expectancy, settings for withdrawal

–      Physical condition (poor self-care, poor nutritional status, track marks)

–      Intense sadness (dysthymia, depression)

Opioid Withdrawal Management

Withdrawal management aims to:

•      reverse neuroadaptation by managing tolerance and withdrawal

•      promote the uptake of post-withdrawal treatment options.

Opioid Withdrawal Treatment

Involves:

•      reassurance and supportive care

•      information

•      hydration and nutrition

•      opioid pharmacotherapies
(e.g. methadone).

•      medications to reduce severity of somatic complaints (analgesics, antiemetics, benzodiazepines, antispasmodics)

 

Methadone: Clinical Properties

The ‘Gold Standard’ Treatment

•      Synthetic opioid with a long half-life

•      μ agonist with morphine-like properties and actions

•      Action – CNS depressant

•      Effects usually last about 24 hours

•      Daily dosing (same time, daily) maintains constant blood levels and facilitates normal everyday activity

•      Adequate dosage prevents opioid withdrawal
(without intoxication).

 

 

Pharmacodynamics

•      full opioid agonist

–   Main action on mu receptors

•   inhibit adenyl cyclase = ê cAMP

•   é potasium channel opening

•   ê calcium channel opening

–   also inhibit serotonin reuptake

–   also non competitive antagonist NMDA receptor

 

•      Safe medication (acute and chronic dosing)

•      Primary side effects: like other mu agonist opioids (e.g., nausea, constipation), but may be less severe

•      No evidence of significant disruption in cognitive or psychomotor performance with Methadone maintenance

•      No evidence of organ damage with chronic dosing

Methadone:
Advantages of Treatment

•      Suppresses opioid withdrawal

•      Pure – no ‘cutting agents’ present

•      Oral administration (syrup or tablet forms used)

•      Once daily doses enable lifestyle changes

•      Slow reduction and withdrawal can be negotiated with minimal discomfort

•      Counselling and support assists long-term lifestyle changes

•      Legal and affordable – reduced participation in crime

•      Few long-term side-effects.

Methadone:
Disadvantages of Treatment

•      Initial discomfort to be expected during stabilisation phase

•      Opioid dependence is maintained

•      Slow withdrawal (preferably) negotiated and undertaken over a period of months

•      Protracted withdrawal symptoms

•      Can overdose, particularly with polydrug use

•      Daily travel and time commitment

•      Variable duration of action

•      Diversion

To Maximise Treatment Adherence

•      Address psychosocial issues as first priority

–     emotional stability

–    "chaotic" drug use

–    accommodation

–    income

•      Opioid agonist pharmacotherapy can:

–    address psychosocial instability

–    increase opportunities to directly observe the administration of various HIV therapies

Assessment Objectives

•      Clarify nature and severity of problems

•      Establish a therapeutic relationship

•      Formulate problems into a treatment plan

Core Assessment Issues

•      What does the patient want?

•      Is the patient dependent ?

•      What is their level of tolerance ?

•      Is the patient using/dependent on other drugs ?

•      What is their motivation for change ?

•      What social supports exist ?

•      Are there other co-existing medical and psychiatric conditions?

Drug Use History

•      Primary drug

–    Average daily use (quantity/duration)

–    Time last used

–    Route of administration

–    Age commenced, periods of abstinence

–    Severity of dependence

–    Previous treatment(s)

•      Other drugs

–    Current and previous

–    dependence

 

Medical and Psychiatric

•      BBV

•      Pregnancy

•      Other major medical conditions

–   Liver

–   Cardiac

•      Major psychiatric conditions

–   Depression, suicide, psychosis

•      Opioid related overdose

Psychosocial

•      Relationship with family

•      Relationship with partner

•      Education and Employment

•      Criminal justice

•      Living circumstances

•      Sources of income

Examination

•      Mental state

–   Mood

–   Affect

–   Cognition

•      Injection sites

•      Signs of intoxication/withdrawal

•      Stigmata of liver disease

•      Nutritional state

Induction Stabilization Phase

•      Dose adequacy and drug interactions

–    signs intoxication/withdrawal

–    frequency of drug use

–    frequency of sharing

•      Case coordination and management

–    psychological

–    social

–    medical

–    health/welfare system interaction

Induction Stabilization Phase

•      Risk Assessment

–   Drug use practices

•   polydrug

•   OD

•   sharing

–   Sexual practices

SAFE INITIAL DOSE

•      20 - 30mg methadone is generally safe

•      Deaths have occurred with higher starting doses or poly-drug use

•      Opioid-dependent polydrug users may be safer to start as inpatients

 

Methadone:
Initial Effects and Side-effects

 

 

Opioid Withdrawal Scales

•      guide treatment

•      monitor progress
(subjective and objective signs)

•      do not diagnose withdrawal but describe severity

•      guide ongoing assessment.

If the withdrawal pattern is unusual, or the patient is not responding, suspect other conditions.

COWS 5-12 mild  13-24 moderate  25-36 moderately severe  more than 36 severe withdrawal

Methadone: Inappropriate Dosing

Dose too low – Withdrawal

•  ‘Flu-like’ symptoms

•  Runny nose, sneezing

•  Abdominal cramps, diarrhoea

•  Tremor, muscle spasm, ache and cramping

•  Yawning, ‘teary’ eyes

•  Hot and cold sweats

•  Irritability, anxiety, aggression

•  Aching bones

•  Craving.

Dose too high – Intoxicated

•  Drowsy, ‘nodding off’

•  Nausea vomiting

•  Shallow breathing

•  ‘Pinned’ (pinpoint) pupils

•  Drop in body temperature

•  Slow pulse, low BP,
palpitations

•  Dizziness.

STABILISATION

RATE OF DOSE INCREASE

•      Increase 0-10mg methadone per 1-3 days during the first week according to physical assessment and SOWS score

•      Maximum increase of 20-25mg over 1st week

•      Subsequent dose increases should not exceed 10mg per week

 

STABILISATION

RATE OF DOSE INCREASE

•      gradual increase essential due to long half-life

•      Best outcomes from maintenance doses   > 60mg

•      Lethal dose 20mg for children, as low as 50 mg for opioid-naïve adults

 

 

STABILISATION

FREQUENCY OF APPOINTMENTS

•      First 5 -7 days - see every 1-2 days

•      Write prescription till next appointment only

•      Always see the patient before increasing the dose

•      Continue the assessment process, build the therapeutic relationship

 

Other Treatment Issues

•      Promote Compassionate Opioid Analgesia

–   Health care worker education especially at hospital

–   Role of maintenance treatment in analgesia     

 

•      Encourage Good Vein Care

–   To maintain venous access

•   important later in the clinical course of HIV infection

Ongoing Management Issues

•      Monitoring HIV progression

–   Co-infection

–   cognitive state

•      Mental health

–   depression

–   suicide ideation

•      Pain management

•      Drug substitution

 

Ongoing Management Issues

•      Risk exposure

–   dose

–   compliance with program rules

•      Cost of medication

•      Staff attitudes

EFFECTIVE PROGRAMS

•      Longer duration (2-4 years).

•      Higher doses - > 60mg methadone.

•      Accessible prescriber and dispenser.

•      Ancillary services.

•      Quality of therapeutic relationship.

Drug Interactions-metabolism

•      Methadone

–   metabolism Cytochrome P450 mediated

•   CYP3A4 main

•   also CYP2D6, CYP1A2, CYP2C9 and CYP2C19

–   genetic variability

–   CYP3A4 breaks down 50% of drugs

•   Methadone mixed inhibitor

–   may increase other drug levels  eg Nifidepine etc.

 

Opioids: Other Drug Interactions