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The content of this application is for information purposes only. It is not intended to amount to advice on which you should rely.

The content is based on a review of published literature available to the producers at the time of development. Although reasonable efforts are made to ensure content is up to date and accurate, no representations, warranties or guarantees, whether expressed or implied, are made that the content on our site is accurate, complete or up to date.

Reference should be made at all times to the licence holder’s product information and to relevant clinical guidelines before co-prescribing any medications. If the product information and other clinical resources do not provide sufficient information, you should consult the licence holder of the relevant products for further information; this application should not be used as a substitute for such information.

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V2.0 (December 2015). Content finalised November 2015

What are pharmacokinetic and pharmacodynamic interactions?

Pharmacokinetics can be described as how an individual metabolises a drug while pharmacodynamic effects are what the drug does to the individual. Pharmacokinetic interactions generally involve the inhibition or induction of hepatic cytochrome P450 (CYP) enzymes, drug effects on glucuronidation, medication effects on the function of the drug transporter, P-glycoprotein, and effects on drug absorption. Pharmacodynamic interactions may involve additive effects of two drugs with similar actions; for example central nervous system (CNS) depression.

What are the effects of drug–drug interactions?

Drugs that are substrates for the same enzymes may cause changes in the rate of metabolism of either or both drugs and may subsequently affect plasma drug concentrations.

Drugs that inhibit CYP enzyme activity may cause increases in plasma drug concentrations with associated risks of toxicity and, in some instances, overdose.

Some drugs increase the synthesis of CYP enzymes and therefore, drugs may be metabolised more rapidly, reducing efficacy. In the case of opioids, this potentially means symptoms of withdrawal.

Drug−drug interactions may also become apparent in response to physiological changes. Pregnancy, for example, increases plasma volume as well as hepatic and renal blood flow, which can result in the need for elevated opioid doses (McCance-Katz, 2011).

What are the CYP450 enzymes?

The CYP enzymes, found in the liver and the luminal epithelium of the small intestine, oxidise endogenous and exogenous compounds, preparing them for further metabolism and elimination. There are over 40 CYP enzymes in the human body with six responsible for 90% of human drug metabolism: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. CYP3A4 is particularly important, metabolising around 50% of drugs. Methadone interacts with a wide number of CYP enzymes and is metabolised by CYP3A4, CYP2B6, CYP2C9, CYP2C19 and CYP2D6. Buprenorphine has a narrower metabolism profile and is predominantly metabolised by CYP3A4.

QTC prolongation and torsades de pointes

Increases in the cardiac QT interval have been documented in patients receiving treatment for opioid dependence. In vitro studies have shown that methadone, but not buprenorphine, blocks the cardiac potassium currents at clinically relevant concentrations, providing a plausible mechanism for the adverse cardiac effects observed in some methadone patients (Katchman et al, 2002).

Torsades de pointes (TdP) has been associated with the use of methadone and may be potentiated in vulnerable patients by the concurrent use of CYP3A4-interacting medications (Walker et al, 2003). An analysis by the US Food and Drug Administration Adverse Event Reporting System of all reports of drug-induced TdP during 2004–2007 found that methadone was associated with the second highest number of reported cases, after amiodarone (Polluzi et al, 2009). This has led to a black box warning on methadone in the USA. The US FDA has also required that an advisory be given to clinicians prescribing buprenorphine transdermal patches for treatment of pain because buprenorphine was found to be associated with a significant increase in QT interval at dosages of 40 mcg/hr; therefore there is some potential for buprenorphine to lengthen cardiac QT interval, but this appears to be less likely than for methadone (Wedam et al, 2007). To date, TdP has not been reported in buprenorphine-maintained patients.

QT interval prolongation and TdP have been the subject of several recent reviews (George et al, 2008, Stringer et al, 2009, Martin et al, 2011). These summarise the available data and provide guidance for the clinician in the prevention of QT interval prolongation in methadone users.

Methodology

Literature searching is carried out annually for any drug interactions with methadone and buprenorphine using Pubmed. Any drugs identified as having interactions are then researched further through a review of the summary of product characteristics/product license and any other relevant information available online. This information is then compiled for inclusion in the next update.

The list of drugs included in the DDI website and app should therefore represent all drugs available for which drug interaction information with either methadone or buprenorphine has been published in the peer-reviewed literature, excepting for any unintentional omissions.