Methadone: a review of drug-drug and pathophysiological interactions

Abstract

Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to α₁ -acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone’s fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.

Keywords::

• Methadone
• drug-interactions
• pathophysiological factors
• α₁-acid glycoprotein
• CYP P450

Declarations of interests

Bhushan M Kapur: None related to methadone or buprenorphine in the last 5 years.

Grants/research support: CHIR, CFFAR.

Janine R. Hutson is supported by a Canadian Institutes for Health Research Vanier Canada Graduate Scholarship. This author reports no declarations of interest.

Tamanna Chibber: This author reports no declarations of interest.

Adriana Luk: This author reports no declarations of interest.

Peter Selby: None related to methadone or buprenorphine in the last 5 years. Financial disclosure

Grants/research support:

Health Canada, Smoke Free Ontario, MHP, CTCRI, CIHR

Alberta Health Services (formerly Alberta Cancer Board)

Vancouver Coastal Authority

Speakers bureau/honoraria:

Schering Canada, Johnson & Johnson Consumer Health Care Canada

Pfizer Inc. Canada, Pfizer Global

Sanofi-Synthelabo Canada, GSK Canada, Genpharm and Prempharm Canada

Consulting fees:

Schering Canada, Johnson & Johnson Consumer Health Care Canada

Pfizer Inc. Canada, Pfizer Global

Sanofi-Synthelabo Canada, GSK Canada

Genpharm and Prempharm Canada, NABI Pharmaceuticals

V-CC Systems Inc. & EHealth Behaviour Change Software Co.

AstroZeneca Canada Inc.

Research funding:

Other: Schering Canada (Buprenorphine training 2000)

Spousal:

Dr. Rita Selby:

Sanofi-Aventis, Boehringer Ingelheim, Bayer (Paid consultant)