DRUG INTERACTIONS WITH

METHADONE

DR. JACKLINE OCHIENG’

CONSULTANT PSYCHIATRIST
MATHARI NATIONAL TEACHING AND REFERRAL
HOSPITAL
MAT CLINIC
OUTLINE
 Introduction
 Methadone Metabolism
 Types of drug interactions
 Interference with metabolism (Methadone Inducers and
Inhibitors)
 Additive effects with other CNS depressants leading to
overdose
 Additive toxic effects to the heart
 Strategies to prevent or minimize drug interactions
INTRODUCTION

 Most drugs are foreign to the body

 Are broken down (metabolized) by chemical reactions into
chemicals that can be easily eliminated.
 Most common enzymes involved are group of proteins called
cytochrome P450
 Some drugs inhibit these enzymes resulting in high drug
levels, while others induce them resulting in low drug levels.
METHADONE METABOLISM

 Usually rapidly absorbed

 Metabolized by Cytochrome P450 enzymes in the liver
 Excreted in urine

 Methadone - mixed inhibitor may increase

other drug levels, e.g., Nifedipine
DRUG INTERACTIONS

Types of interactions
 Interference with metabolism
 Additive effects with others CNS depressants leading to
overdose
 Additive toxic effects to the heart
INTERFERENCE WITH METABOLISM:
INDUCERS
 Inducers may reduce methadone levels
 These include:
 Anticonvulsants: Carbamazepine, phenytoin, barbiturates

 ARVs: efavirenz, nevirapine, lopinavir+ritonavir (kaletra),

abacavir

 Anti TBs: rifampicin, rifabutin, isoniazid

 Others: tobacco, dexamethasone, AL/Coartem

INTERFERENCE WITH METABOLISM:
INHIBITORS
•Inhibitors may Increase Methadone Levels:
•These include:
 Itraconazole
 Ketoconazole  Cannabinoids
Metronidazole  Clarithromycin
 Erythromycin
Indinavir  Norfloxacin
 Ciprofloxacin
 Miconazole  Omeprazole (slight)
 Quinine
 Grapefruit Juice  Saquinavir
Fluconazole
 DRUG INTERACTIONS WITH METHADONE
May result in:
Dose too low –Withdrawal Dose too high – Intoxication/Overdose
 ―Flu-like‖ symptoms  Drowsy, ―nodding off ‖
 Runny nose, sneezing  Nausea, vomiting
 Shallow breathing
 Abdominal cramps, diarrhoea
 ―Pinned‖ (pinpoint) pupils
 Tremor, muscle spasm, aches, and
cramping  Drop in body temperature
 Slow pulse, low BP,
 Yawning, ―teary‖ eyes
palpitations
 Hot and cold sweats  Dizziness
 Irritability, anxiety, aggression
 Aching bones
 Craving
DRUG INTERACTIONS WITH
METHADONE
Appropriate Methadone dose adjustment is required after
introduction of other drugs:

 Gradually increase to maintenance dose.

 Effective dose usually 60-100mg
 May change in some patients: some may require higher or
lower doses than this due to various factors.
 Dose may require adjustment even after achieving a
stabilization dose.
ADDITIVE EFFECTS WITH OTHER CNS
DEPRESSANTS
 Concomitant use of these drugs can lead to over dose and
death through respiratory depression

 Have an additive effect

 Benzodiazepines
 Alcohol
 Other Opioids
ADDITIVE EFFECTS WITH OTHER
DRUGS
Respiratory Toxicity Hypotension Coma
Depression / Risk of
death
CNS * * *
Depressants
MAOIs * * *
TCAs * *
Beta *
blockers
BZDs *
ADDITIVE TOXIC EFFECTS TO THE
HEART
 Methadone in has been shown to increase QT interval
(abnormal heart beats/ arrhythmias) though rarely
 More common with high doses of methadone > 200mg
 Ideally patients should have an ECG at induction and even
after stabilization
 Worsened by concomitant administration of medication that
may cause the same such as erythromycin, amitriptyline,
ciprofloxacin , fluoxetine, some antifungals such as
fluconazole
OTHER DRUG INTERACTIONS WITH
METHADONE
Alcohol effects:
 Alcohol-related factors are a major cause of death
among patients in MAT.
 Overdose deaths or over sedation can occur when
alcohol is used with opioid treatment medication.
 Alcohol use can aggravate liver damage from hepatitis
C.
 Alcohol use stimulates the metabolic activity of the
P450 enzymes, increasing methadone metabolism.
OTHER DRUG INTERACTIONS WITH
METHADONE
Benzodiazepine effects:
 People with opioid dependence are more likely to
abuse benzodiazepines.
 Benzodiazepines increase the effects of methadone—
―boosting.‖
 Benzodiazepines produce synergistic sedative effects
and respiratory depressant when combined with
opioids.
 Document instances of benzodiazepine use.
 Consider referral to services for treatment of
benzodiazepine use.
OTHER DRUG INTERACTIONS WITH
METHADONE
Cocaine and Stimulant effects:
Adverse effects of these substances include:
 Cardiovascular effects
 Respiratory effects
 Problems with mood swings and compliance with
group or individual therapy
 Decreasing methadone concentration in blood.
OTHER DRUG INTERACTIONS WITH
METHADONE
Nicotine effects:

 Related Illnesses (respiratory, cardiac)

 Inhibitory effect, hence potentiates the effect of

methadone

 Withdrawal effects of smoking (nicotine) are similar to

opioids and may confuse clinician to increasing
methadone dose
STRATEGIES TO PREVENT OR MINIMIZE
DRUG INTERACTIONS
Patient education with emphasis on:
 Communicating with patients to determine how they are
feeling
 Stressing that abuse of drugs/medications that are CNS
depressants may be fatal
 Pointing out that other medications can interact adversely
with methadone
 Need to inform their medical practitioner that they are on
Methadone
 Avoid over the counter purchase of medications
STRATEGIES TO PREVENT OR MINIMIZE
DRUG INTERACTIONS
Identify symptoms of toxicity and cardiac side effects
 Explaining that cardiovascular risk factors may be
aggravated by methadone (arrhythmias)
 Increasing patient understanding of the symptoms of
arrhythmia, such as palpitations, dizziness, light-
headedness, syncope, or seizures
 Encouraging patients to seek immediate medical
attention if symptoms of arrhythmia occur
 Maintaining and not exceeding dosage schedules or
amounts
CASE STUDY
 A MAT client on 100mg of methadone presents at the Psychiatric
unit at 8p.m with tremors, seeing snakes crawling in the room and
he was jumping on top of tables. The clinician prescribed P.O
Diazepam 10mg tds x3/7, 5mg tds x3/7, 5mg bd 3/7, 5mg od
x3/7.
 The next day at 10a.m, he presents at the MAT clinic for his
methadone dose and the Pharmacist notices that he is drowsy. He
is referred to the clinician.

 Discuss the emerging issues and diagnosis

 Discuss his management
 What are the possible complications ?
CASE STUDY
 Alcohol withdrawal – Alcohol dependence
 Detox on Benzodiazepines – additive effects on CNS
depression
 Management: Detox? Methadone dosing? Inpatient vs
Outpatient detox?
 Potential overdose?