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Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence. Geneva: World Health Organization; 2009.

Cover of Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence

Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence.

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Annex 5Drug interactions involving methadone and buprenorphine

Drug interactions occur because medications have synergistic or antagonistic effects (so-called pharmacodynamic interactions), or because the presence of one medication affects the absorption, distribution, circulation, metabolism or elimination of another medication (so-called pharmacokinetic interactions).

A5.1. Pharmacodynamic interactions


Any drugs that cause sedation may cause additive sedation with methadone and buprenorphine, increasing the risk of sedative overdose. Such drugs include benzodiazepines, alcohol, other sedative psychotropic medications (e.g. phenothiazines and other antipsychotics), tricyclic and other sedating antidepressants, alpha adrenergic agonists (e.g. clonidine and lofexidine) and sedative antihistamines. Most overdose deaths associated with methadone and buprenorphine are in combination with one or more of these sedatives.

Opioid withdrawal

Opiate antagonists, such as naltrexone, result in opioid withdrawal for patients on methadone and buprenorphine. Naltrexone cannot be used for the management of alcohol dependence in this population. A combination of agonists and partial agonists can also result in opioid withdrawal. Methadone should generally not be combined with the partial agonists buprenorphine, pentazocine, nalbuphine or butorphanol. Patients on buprenorphine who are also taking opioid agonists for pain may experience incomplete pain relief.

QT prolongation

A group of medications affect the time it takes cardiac ventricular muscle to depolarize and subsequently repolarize – the QT interval in an electrocardiogram. A prolongation of the QT interval predisposes people to serious cardiac arrhythmias, such as torsades de pointes and other ventricular tachyarrhythmias, which may be fatal if untreated. Methadone is one such medication. Combinations of methadone with other medications that prolong the QT interval should be used with caution, as they may further increase the risk of QT prolongation-associated cardiac arrhythmias. These medications are mainly class I or III antiarrhythmic agents, calcium channel blocking agents, some antipsychotic agents and some antidepressants (see Table A5.1 for a more complete list). Drugs that result in electrolyte disorders (e.g. hypokalaemia and hypomagnesaemia) also result in an increased risk of QT prolongation-related arrhythmias (i.e. diuretics, laxatives, corticosteroid hormones with mineralocorticoid activity). Buprenorphine does not appear to produce clinically significant prolongation of the QT interval.

Table A5.1. Drugs that increase the risk of torsades de pointes or QT interval prolongation.

Table A5.1

Drugs that increase the risk of torsades de pointes or QT interval prolongation.

A5.2. Pharmacokinetic interactions

Methadone and buprenorphine are metabolized principally by the cytochrome P450 enzyme pathways. A range of drugs and medication either induce or inhibit cytochrome P450 enzymes. The process of induction is relatively slow as it depends on the synthesis of new enzyme proteins, and occurs over days, whereas inhibition can occur rapidly, depending on the concentration of the inhibiting substance.

Methadone is largely metabolized from active to largely inactive metabolites through CYP3A4 and to a lesser extent CYP1A2, CYP2D6, CYP2B6, CYP2C8 and also possibly CYP2C9 and CYP2C19 [275, 276, 277, 278, 279, 280, 281, 282, 283]. CYP enzyme inducers can result in lower plasma methadone levels and inhibitors can result in higher levels. Because of the potential for sedative overdose, patients on methadone should be observed particularly closely when commencing cytochrome P450 inhibitors, and consideration should be given to simultaneous methadone reduction. After introducing a potentially interacting new medicine, it is important to make careful clinical observations and adjust the dose of methadone if necessary.

Buprenorphine is metabolized in the liver, principally by the CYP3A4 isoenzyme [282]. The active metabolite, nor-buprenorphine is metabolized via a separate pathway. Drugs that inhibit CYP3A4 (e.g. ketoconazole, erythromycin, some protease inhibitors) may result in increases in buprenorphine concentration and the need to reduce the buprenorphine dose. Drugs that induce CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine) may result in reduced buprenorphine concentrations. Research on drug interactions involving buprenorphine is limited.

A more comprehensive list of drugs that interact on the cytochrome P450 system are listed in Table A5.2 [282].

Table A5.2. Interactions between antiretroviral agents and methadone.

Table A5.2

Interactions between antiretroviral agents and methadone.

CYP450 inducers


Chronic consumption of alcohol has been reported to increase the metabolism of methadone, whereas acute consumption has been reported to increase the area under the curve (AUC)1 of methadone, resulting in increased potential for adverse effects.


Phenytoin, carbamazepine and phenobarbital are all significant inducers of CYP3A4 and have all resulted in withdrawal symptoms in patients on methadone.


Sertraline, fluoxetine and fluvoxamine are inducers of CYP3A4. Methadone may potentiate the effects of tricyclic antidepressants.


Rifampicin (rifampin) has resulted in clinically significant reductions in methadone levels.


Many antiretroviral medications interact with methadone and buprenorphine, see Table A5.2 and Table A5.3.

Table A5.3. Interactions between antiretroviral agents and buprenorphine.

Table A5.3

Interactions between antiretroviral agents and buprenorphine.

Other agents

St John's wort (Hypericum) is also a CYP3A4 inducer.

CYP450 inhibitors


Azole agents including ketoconazole, fluconazole and itraconazole, are potent inhibitors of CYP3A4 and have increased the effects of both methadone and buprenorphine. Prophylactic dose reductions should be considered.


Many antiretroviral medications interact with methadone and buprenorphine, see Table A5.2 and Table A5.3.

Macrolide antibiotics

Most macrolides (erythromycin, clarithromycin, dirithromycin, roxithromycin) inhibit CYP3A4. Only azithromycin does not inhibit CYP3A4.

Other agents

Grapefruit juice is also a significant inhibitor of cytochrome P450 enzymes.



Area under the curve is a measure of the bioavailability of a drug or medicine. It is the area under the plasma concentration-time curve for that drug in a particular patient. Increase in this indicates more of the drug has reached the systemic circulation and this is nearly always accompanied by a rise in plasma concentration.

Copyright © 2009, World Health Organization.

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: tni.ohw@sredrokoob). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: tni.ohw@snoissimrep).

Bookshelf ID: NBK143177


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