Methadone-drug interactions



(*Medications, illicit drugs, & other substances)
Stewart B. Leavitt, MA, PhD; Executive Director, Pain Treatment Topics; January 2006
Reviewed but not revised June 2010 Medical Reviewers: James D. Toombs, MD; Lee Kral, PharmD, BCPS Prior Publication History
3rd Edition: November 2005 Revision/Update, Addiction Treatment Forum Special Report, ATForum.com.
Researcher/Writer: Stewart B. Leavitt, PhD, Editor, Addiction Treatment Forum Medical Reviewers: R. Douglas Bruce, MD, MA; Yale AIDS Program, Yale University School of Medicine; New Haven, CT.; Chin B. Eap, PhD, Biochemistry and Clinical Psychopharmacology, University Department of Adult Psychiatry; Cery Hospital, Prilly-Lausanne, Switzerland; Evan Kharasch, MD, PhD; Professor and Director, Clinical Research Division, Department of Anesthesiology; Washington University, St. Louis, MO; Lee Kral, PharmD, BCPS; Center for Pain Medicine and Regional Anesthesia; University of Iowa Hospitals and Clinics; Iowa City, IA; Elinore McCance-Katz, MD, PhD, Chair, Addiction Psychiatry; Medical College of Virginia, Virginia Commonwealth University, Richmond, VA; J. Thomas Payte, MD; Corporate Medical Director; Colonial Management Group; Orlando, FL. 2nd Edition: January 2004, Addiction Treatment Forum Special Report.
Researcher/Writer: Stewart B. Leavitt, PhD, Editor, Addiction Treatment Forum Medical Reviewers: Chin B. Eap, PhD, Prilly-Lausanne, Switzerland; John J. Faragon, PharmD, RPh, Albany, NY; Gerald Friedland, MD, New Haven, CT; Marc Gourevitch, MD, Bronx, NY; Elinore McCance-Katz, MD, Richmond, VA; J. Thomas Payte, MD, Orlando, FL. 1st Edition: Published as, Leavitt SB. Methadone at work. Addiction Treatment Forum. 1997(Spring);6(2).
Copyright Pain Treatment Topics (SBL Ltd) 2006-2010







Methadone-Drug Interactions, Page 2
Pain-Topics.org Section Contents
Understanding Methadone Metabolism & Drug Interactions „ The Importance of Drug Interactions „ Methadone History „ Metabolic Basics „ Methadone Metabolism „ Methadone-Drug Interactions „ Putting Concepts Into Practice „ Finding Drugs/Substances of Interest in this Document Table Abbreviations, Data Sources, Notes Table 1: Drugs That Are CONTRAINDICATED with Methadone (May Precipitate Opioid Withdrawal) Table 2: Drugs That May Result in Altered Metabolism or Unpredictable Interactions with Methadone Table 3: Drugs That May LOWER SML and/or DECREASE Methadone Effects Table 4: Drugs That May RAISE SML and/or INCREASE Methadone Effects Table 5: Methadone-Drug Interactions: Alphabetical Listing by Generic & Brand Names Table 6: Drug Interactions Resources on the Internet Methadone-Drug Interactions, Page 3
Pain-Topics.org The Importance of Drug Interactions
Each year in the U.S. there are innumerable adverse drug reactions, broadly defined as any unexpected, unintended, undesired, or excessive response to a medicine. Such reactions may require discontinuing or changing medication therapy. Furthermore, greater than 2 million of those are serious reactions resulting in hospitalization and/or permanent disability, and there are more than 100,000 deaths annually attributed to reactions involving prescribed medications (Cohen 1999; Wilkinson Three-fourths of those adverse reactions relate to drug interactions, which occur when the amount or action of a drug in the body is altered – usually increased or decreased – by the presence of another drug or multiple drugs (Bochner 2000; Levy et al. 2000; Piscitelli and Rodvold 2001). Avoiding these can be difficult, since the number of potential interactions among diverse drugs used in clinical practice can be overwhelming; more than 2,000 such interactions have been described in the literature and new cases appear monthly (Levy et al. 2000). As the tables in this document indicate, there are more than100 substances – medications, illicit drugs, OTC products, etc. – that can interact in some fashion to affect a patient's response to methadone. Pharmacotherapy is increasingly complicated by the introduction of new drugs and the use of multidrug regimens – called "polypharmacy" – for acute or chronic disease, which can result in clinically important drug interactions. While multiple drugs often are necessary for treating complex or resistant conditions, side effects of the drugs themselves may induce symptoms rather than any pathological processes (Farrell et al. 2003). This is of vital importance for patients receiving methadone analgesia regimens, since these individuals often have co-morbid physical and/or mental disorders requiring multiple medications. Methadone History
Methadone was discovered in Germany in the late 1930's by Max Bockmühl and Gustav Ehrhart, working for the German chemicals conglomerate IG Farberindustrie. They were exploring synthetic compounds with a structure similar to Dolantin®, which was an opioid analgesic (later marketed as Pethidine®, Demerol®, and others) similar to morphine that was discovered earlier at the same company (Bäumler 1968, Chen 1948; Ehrhart 1956; Eichler and Farah 1957; Erhart and Ruschig 1972; Payte 1991; Preston 2003). Methadone-Drug Interactions, Page 4
Pain-Topics.org Bockmühl and Ehrhart synthesized a compound that was both analgesic and spasmolytic, which they called "Hoechst 10820" and for which they filed a patent application in September 1941. This agent was found to be at least as powerful as morphine and 10 times more potent than Dolantin; however, its pharmacology was different and little was known about how to best prescribe the new agent. Consequently, Hoechst 10820 was not effectively used as an analgesic during the war years, allegedly because the very high initial doses typically administered at that time produced intolerable side effects (Bäumler 1968, Chen 1948; Ehrhart 1956; Eichler and Farah 1957; Erhart and Ruschig 1972; Payte 1991; Preston 2003). As part of the "spoils of war," the formula for Hoechst 10820 became available to other countries worldwide and was further tested and used for analgesia. It soon became generically known as methadone and trade names in the U.S. include Dolophine® and Methadose®; other brands have been developed outside the U.S. (Bäumler 1968, Chen 1948; Eichler and Farah 1957; Ehrhart 1956; Erhart and Ruschig 1972; Payte 1991; Preston 2003; Velten 1992). Initially, methadone was widely used in clinical medicine as an analgesic and antitussive, for which it was approved in the U.S. in 1947. Early indications for its use included: migraine, dysmenorrhea, labor pain, painful nerve disorders, advanced cancer or tuberculosis, and tetanus, among others. However, at this time, relatively little was known about methadone pharmacology and how best to prescribe it. Due to improper prescribing and/or misuse, there were deaths associated with methadone in the late 1940's and the 1950's, and a number of those fatalities were reported in England and Germany among young children exposed to methadone in cough syrups. Similar deaths in children and adults, or cases of near-fatal respiratory depression, soon occurred in other countries where methadone was widely prescribed. Consequently, due to its perceived toxicity and the potential for methadone to produce physiologic dependence, it fell into disuse as an analgesic by the early 1960's (Harding-Pink 1993; Payte 1991; Preston 2003; Rettig and Yarmalonsky 1995). In the mid-1960's, Vincent P. Dole, MD, and his team at Rockefeller University in New York City began research on a new method for treating heroin addiction. Methadone was chosen for experimentation in treating opioid addicts because it was known to be long-acting, could be taken orally, and had been previously used in analgesia and for withdrawing opioid-addicted persons from heroin. Dole and colleagues found that, once opioid tolerance was established to a methadone dose of 80-120 mg/day, patients were able to function normally, without drug craving (Dole 1988; Joseph and Appel 1993; Joseph et al. 2000; Kreek 1993; McCann et al. 1994; Nadelman and McNeely 1996; During clinical use in the maintenance treatment of opioid addiction spanning more than 40 years, hundreds of studies have examined the pharmacology and efficacy of oral methadone and it has proven to be a well-tolerated medication with minimal adverse reactions when properly prescribed in appropriate doses (Kreek 1973; Novick et al. 1993). However, there are potential methadone-drug interactions – involving other prescribed medications, illicit drugs, OTC products, and other substances – which sometimes can be difficult to predict. Such interactions may be potentially harmful Methadone-Drug Interactions, Page 5
Pain-Topics.org and/or can lead to treatment failures, whether methadone is used as a component of addiction treatment or as an analgesic (Harrington et al. 1999; Levy et al. 2000). Metabolic Basics
Most drugs are foreign to the human body and are metabolized by chemical reactions into molecules that can be more easily eliminated (Flexner and Piscitelli 2000). A primary metabolic pathway involves the actions of proteins, called cytochrome P450 (CYP450) enzymes, that facilitate those chemical reactions. These enzymes evolved as a protective mechanism more than 3 billion years ago to cope with a growing number of naturally occurring environmental chemicals and toxins (Hardman et al. 1996; Richelson 1997). There are more than 28 CYP enzymes encoded by 57 different human genes (Flexner and Piscitelli 2000; Shannon 1997; Wilkinson 2005). Each is designated by a combination of numbers and letters: for example, 3A4 and 2B6 which are important in methadone metabolism. CYP enzymes reside mainly in the liver, but also are present in other organs. Substances that interact with the CYP450 system usually do so in one of three ways: 1) by acting as a substrate, 2) through inhibition, or 3) through induction. „ A substrate is any drug metabolized by one or more CYP enzymes, and more than half of all
medications that undergo metabolism are CYP3A4 substrates (Piscitelli and Rodvold, 2001). „ Some drugs are inhibitors of specific CYP enzymes and thereby slow the metabolism of
drugs that are substrates for those particular enzymes, which may result in excessively high drug levels and related toxic effects (Levy et al. 2000). „ Other drugs are inducers; they boost the activity of specific CYP enzymes resulting in more
rapid metabolism of substrate drugs, which may result in lower than expected levels of the substrate drugs (Flexner and Piscitelli 2000). A drug can at the same time be a substrate for and induce or inhibit one or more CYP enzymes. Co-administered drugs that merely share the same metabolic pathway – that is, are substrates for the same CYP enzymes – may compete with each other. The "winning drug" could garner more enzyme activity, thus diminishing metabolism of the other drug and intensifying its effects (Hardman et al. 1996). Readers may wish to consult current sources listing drugs that are CYP450-enzyme substrates, inducers, or inhibitors; such as at (Flockhart 2003). Methadone Metabolism
Methadone is usually readily absorbed, with about 80% of the administered dose passing into the bloodstream during stabilized, steady-state dosing and the remainder metabolized in the GI tract and liver; although, for reasons described below, bioavailability can range from 35% to 100% (Eap et al. 2002, Moolchan et al. 2001). The three available formulations of oral methadone – solid tablets, dispersible tablets, and liquid concentrate – have been demonstrated as intrinsically equal in terms of their bioavailability and metabolism (Gourevitch et al. 1999); however, patient reactions to each formulation may vary, possibly due to psychosomatic factors in some cases. Methadone-Drug Interactions, Page 6
Pain-Topics.org The most important enzymes in methadone metabolism are CYP3A4 and CYP2B6. Secondarily CYP2D6 appears to have a role, and CYP1A2 may possibly be involved (see Table).
CYP450 Enzymes Metabolizing Methadone
Important methadone metabolizer (can also be induced by methadone during the early start-up phase of therapy). Relatively recently discovered as an important methadone metabolizer. Secondary role (methadone can inhibit this enzyme in some cases and this enzyme is particularly involved in the metabolism of the active R-methadone enantiomer). Possibly involved (clinical significance still under investigation). Note: Previously CYP2C9 and 2C19 were thought to be involved, but this has not been confirmed (Crettol et al. 2005).
Borg and Kreek 2003; Eap et al. 2002; Gerber 2002; Gerber et al. 2004; Iribarne et al. 1997; Kharasch et al. 2004a; Leavitt et al. 2000; Moolchan et al. 2001; Shinderman et al. 2003; Wu et al. 1993 CYP3A4, the most abundant metabolic enzyme in the body, can vary 30-fold between individuals in terms of its presence and activity in the liver (Eap et al. 2002; Leavitt et al. 2000). This enzyme also is found in the gastrointestinal tract, so methadone metabolism actually can begin before the drug enters the circulatory system (Hardman et al. 1996). The amount of this enzyme in the intestine can vary up to 11-fold, partially accounting for some individual differences in the breakdown and absorption of methadone (Levy et al. 2000). Fairly recently, CYP2B6 has been discovered as playing a prominent role in methadone metabolism (Gerber 2002; Gerber et al. 2004; Kharasch et al. 2004a, Rotger et al. 2005), and especially but not exclusively metabolism of the inactive S-enantiomer (Crettol et al. 2005, in press; Totah et al. 2004). Effects of CYP2B6 were demonstrated in laboratory experiments and also helped account for certain otherwise unexplained methadone-drug interactions during human trials. At present, relatively few agents have been identified as inducers or inhibitors of CYP2B6 (Faucette et al. 2004; Flockhart 2005), and there also can be individual differences in activity of this enzyme (Kharasch et al. 2004a; Rotger et al. 2005). However, as research continues, many agents currently thought to be interacting with methadone primarily via other P450 enzymes also may be identified as CYP2B6 substrates, inducers, or inhibitors. Therefore, in many cases, the most that can be stated with certainty at present is that CYP450 enzymes are involved in a methadone-drug interaction, without always knowing the relative roles of exact enzymes (personal communication, E. Kharasch, Another metabolic protein of some importance is P-glycoprotein (P-gp), which is found in the intestine, along the blood-brain barrier, and in other tissues (Matheny et al. 2001, Wang et al. 2004). This substance functions as a pump, transporting methadone out of cells lining the intestinal wall and back into the lumen. Thus, some of the methadone absorbed by the intestine is pumped back out before it ever enters the circulation. There is up to a 10-fold variation in the amount of intestinal P-gp expressed by individuals (Hall et al. 1999, Leavitt et al. 2000), and some interactions originally considered solely due to intestinal CYP3A4 may involve P-gp as well (Dresser et al. 2000; Eap et al. 2002; Kharasch et al. 2004b). Some evidence suggests that expression of P-gp in the blood-brain Methadone-Drug Interactions, Page 7
Pain-Topics.org barrier, which can vary across individuals, may play a role in the access and effects of methadone in the brain and the potential for adverse effects (Wang et al. 2004). Although, one clinical study found that P-gp may not be a significant factor in this regard (Kharasch et al. 2004b). Drugs or other agents that induce the activity of enzymes involved in methadone metabolism can
accelerate its breakdown, increase its rate of clearance, abbreviate the duration of methadone's effects, lower the serum methadone level (SML), and possibly precipitate opioid-withdrawal syndrome. Conversely, CYP-enzyme inhibitors may slow methadone metabolism, raise the SML,
extend the duration of its effects, and possibly cause methadone-related toxicity such as oversedation and/or respiratory depression (Eap et al. 2002; Leavitt et al. 2000; Methadose PI 2000; Payte et al. 2003; Wolff et al. 2000). Genetic factors also can act on certain enzymes to affect methadone metabolism. For example, CYP2D6 is entirely absent in a significant portion of the population (1 out of 15 persons), resulting in increased sensitivity to methadone's effects; conversely, some persons have high activity of this enzyme and are rapid metabolizers of methadone (Eap et al. 2002). The variability of CYP-enzyme presence and activity means that SMLs can differ significantly even in the absence of interacting substances; some persons can naturally be either extensive (rapid) or poor (slow) metabolizers of methadone. When interactions with other drugs occur on top of this it could further influence problematic methadone under- or overmedication (Eap et al. 2002; Leavitt et al. 2000; Richelson 1997). Methadone-Drug Interactions
When co-prescribing medications with methadone, and a suspected drug interaction occurs, the time course of sign/symptom development can be a guide as to whether enzyme induction or inhibition is involved. Overmedication reactions are likely due to CYP inhibition that develops quickly; within a few days after concurrent drug administration. In contrast, CYP induction is slower to emerge, commonly taking about a week to produce significant withdrawal signs/symptoms (Antoniou and Tseng 2002; Faragon and Piliero 2003; Gourevitch and Friedland 2000; Hansten 1995; Wolff et al. 2000). In the presence of strong CYP inducers, merely increasing the methadone dose may be insufficient and an increase plus more frequent daily dosing may be necessary. Potential effects on methadone metabolism also should be considered when discontinuing medications. If a drug that inhibits CYP enzymes is stopped, methadone serum levels may decrease and cause opioid withdrawal that requires increased methadone dose. Conversely, if a CYP inducer is discontinued, metabolizing-enzyme levels will diminish and SMLs may rise to toxic levels unless careful methadone dose reductions are implemented in response to clinical signs of overmedication. Some methadone-drug interactions primarily relate to how certain drug combinations may adversely affect physiological response in the patient (pharmacodynamics) and have little to do with altered pharmacokinetics. For example, the additive effects of methadone combined with other central nervous system (CNS) depressants may cause hypotension, sedation, respiratory depression, or Methadone-Drug Interactions, Page 8
Pain-Topics.org coma (Leavitt 2003; Methadose PI 2000). Also, polysubstance abuse in certain patients may put them at greater risk of adverse additive interactions with other CNS-active drugs (Antonio and Tseng 2002; Harrington et al. 1999; Quinn et al. 1997). Another concern involves the recognition of methadone's potential to affect heart rhythm under certain circumstances (Leavitt and Krantz 2003). Researchers studying patients attending methadone maintenance programs for addiction have reported relatively small but statistically significant QT interval increases; however, the QT measurements generally remained within acceptable limits (Maremmani et al. 2005; Martell et al. 2005). Often, these heart rhythm changes were in patients taking medications or drugs in addition to methadone, or having cardiac risk factors that might normally be of concern (Leavitt and Krantz 2003). In the largest retrospective investigation to date, researchers examined all adverse events associated with methadone officially reported to the FDA during a 33 year period (Pearson and Woosley 2005). Of 5,503 incidents, only 16 noted QT interval prolongation and 43 indicated torsade de pointes (TdP). Most cases involved methadone used in pain management – at doses ranging from 29 to 1,680 mg/day – and it could not be determined that methadone was a direct cause. Five cases (0.09%) were fatal; however, 3 of those involved pre-existing factors known to influence arrhythmia. The conclusions and recommendations of all major investigations to date concur that the risk of TdP is likely to be small, should not deter healthcare providers or patients from using methadone, and it is premature to suggest routine ECGs before or during methadone therapy. However, it would be advisable to take careful medical histories screening for known cardiac risk factors and it would be prudent not to co-prescribe methadone with other drugs known to prolong the QT interval because of the potential for additive effects (Krook et al. 2004; Leavitt and Krantz 2003; Maremmani et al. 2005; Martell et al. 2005; Pearson and Woosley 2005; Piquet et al. 2004). Thus, comedications that might produce acute elevations of serum methadone concentrations or may in themselves contribute to dysrhythmias should be used only after considering the risks versus benefits. In cases of patients on elaborate drug regimens – such as multidrug therapies for HIV/AIDS, hepatitis, and/or severe mental illness – outside consultation with specialists in such pharmacotherapies might be advised. For example, many drugs used for HIV/AIDS therapy interact with each other (Chrisman 2003; Schütz 2002) and their combined effects on methadone can be complex (Antoniou and Tseng 2002; Faragon and Piliero 2003). Putting Concepts Into Practice
Methadone works best when administered in adequate therapeutic doses (Leavitt 2003). However, given the individual variability in methadone absorption and metabolism, it becomes difficult to accurately predict the effects of drug combinations in any one patient (Harrington et al. 1999), or how methadone dosing may need adjustment to compensate for metabolic inducers or inhibitors (Wolff et al. 2000). If a patient is responding unexpectedly or unfavorably to methadone – with signs/symptoms of under- or overmedication – a search for potentially interacting substances Methadone-Drug Interactions, Page 9
Pain-Topics.org (prescribed medications, illicit drugs, OTC products, or other agents) would be appropriate. Taking a comprehensive history from the patient can be important in this search (Kramer 2000). When prescribing comedications the potential for certain drugs and drug combinations to interact with methadone requires careful consideration. Furthermore, polysubstance abuse may place patients at risk for hazardous interactions of methadone with other opioids and drugs such as alcohol, cocaine, barbiturates, and benzodiazepines. Clinical experience, intuition, and common sense can be valuable tools for practitioners in taming drug interactions and the following Table lists some suggestions.
Clinical Suggestions for Minimizing Methadone-Drug Interactions
1. Maintain an accurate, updated profile for each patient that includes all prescribed drugs and OTC
products (including herbal remedies and dietary supplements). 2. Use alternative, non-interacting, drugs whenever possible.
Usually, there are differences in the interactive properties of at least some members of any drug class. For example, the macrolide antibiotic erythromycin is a strong CYP3A4 inhibitor, likely to possibly interact with methadone, whereas the macrolide azithromycin does not appear to have this effect. 3. If a potentially interacting drug is used with methadone, it is better to adjust the methadone dose
based on patient response rather than in advance based on an expected interaction. The magnitude of drug interactions varies dramatically from patient to patient, and it is unlikely that the selected methadone dosage adjustment would exactly offset the actual effect of the second drug. 4. Signs/symptoms of either opioid withdrawal or overmedication (e.g., sedation), and their severity,
can help gauge serum methadone level (SML) adequacy in the presence of an interacting drug. Adjustments of methadone or concomitant drug(s) may be appropriate to overcome such adverse reactions. 5. If there are concerns about adverse effects of increased methadone concentrations, patients
should be advised in advance of physical signs/symptoms of overmedication that might occur and what to do. It may be desirable to temporarily monitor SMLs in certain cases. 6. Whenever possible, avoid concurrent administration of drugs with overlapping adverse-effect
profiles. Otherwise, signs/symptoms of major variations in methadone concentration may be confused with side effects of concomitantly administered drugs, and vice versa. 7. Consider preexisting disease states.
For example, conditions associated with impaired renal or hepatic function may significantly alter drug metabolism and excretion. Patients with preexisting cardiovascular conditions – particularly those with congestive heart failure or left ventricular systolic dysfunction – may be more sensitive to potential arrhythmogenic effects of certain drugs (including methadone). 8. In some cases, adverse drug reactions can be resolved by prescribing a medication with or without
food, by altering dosing schedules, or by splitting doses into smaller increments. 9. Unreported or seemingly inconsequential factors may play a role in drug interactions.
For example, grapefruit juice can hinder metabolism and increase methadone serum levels. 10. Patients may not adhere to prescribed medication regimens, which could affect adverse reactions,
and the more complicated the regimen the less likely that the patient will adhere to it. This can be important in methadone-maintained patients prescribed multiple medications. Adapted from: Chung 2002; Cohen, 1999; Kramer 2000; Levy et al., 2000; Piscattelli and Rodvold, 2001 Methadone-Drug Interactions, Page 10
Pain-Topics.org The traditional advice when adding drugs to a therapeutic regimen is to start low, go slow, and monitor closely. This may be especially prudent with methadone analgesia, since many commonly prescribed drugs are associated with dose- and concentration-dependent toxicities, and individual response may vary by several orders of magnitude. Potential adverse reactions also can be minimized by using the smallest effective doses for drugs added to methadone therapy. In many cases, doses of adjunctive medications lower than those recommended by the manufacturer may be sufficient for desired therapeutic effect (Cohen, 1999). It has long been recognized that patient education is essential for successful outcomes with methadone and this should be initiated early in treatment. Better informed patients can partner more effectively with clinic staff regarding their pharmacotherapy. However, as with all other aspects of pain management, this relies on mutual trust and effective communication. Several important points need to be emphasized with patients regarding potential interactions of methadone with other substances and to help them avoid all drug interactions, as noted in the Table below.
Helping Patients Avoid Drug Interactions
„ Patients maintained on methadone should be cautioned to consult healthcare professionals before taking any OTC products, herbal remedies, or dietary supplements. „ Patients should provide to their healthcare providers and pharmacist an updated list of all medical „ Patients should understand their prescriptions and the dosage, and be able to cross-check what was prescribed with what they receive from the pharmacist. „ For each prescribed medication, patients should be verbally instructed on what the drug is used for, how to take it, and how to reduce the risk of side effects or drug interactions. It cannot be assumed that patients will read or understand product labels or written information provided with medications or other healthcare products. „ Compliance with prescribed medication regimens should be emphasized. Patients need to understand the importance of taking all medications exactly when, how, and in the quantities specified. „ Patients should be educated on the hazards of taking excess medication or sharing medicines with anyone else. They should be reminded about safe storage of medications and proper disposal of unused portions. „ Patients should be counseled on the importance of quickly reporting any sudden or unexpected signs/symptoms of either methadone withdrawal or overmedication, as this could indicate a potentially hazardous interaction with another drug or substance. „ Special consideration and instruction will be required for patients with physical conditions that may cause or exacerbate drug interactions, such as: liver or kidney disorders, pulmonary or heart ailments, pregnancy, etc. „ Patients taking multiple medications should be assisted in keeping a journal or chart listing the name, purpose, and dose schedule for each drug. „ Patients should be instructed in advance on what to do in the event of an emergency if their supply
of methadone and/or other medications runs out and they do not have access to their usual source of supply. Ideally, such instructions also would be provided in writing. Adapted from: FDA/CDER 2000; NCPIE 2003. Methadone-Drug Interactions, Page 11
Pain-Topics.org Theoretically, any drug or substance metabolized by the same CYP enzymes as methadone, or affecting their expression by inhibition or induction, might interact with methadone; although, many of these interactions would not be clinically important. Just because certain drugs can interact does not mean that they will, or to what extent. The methadone-drug interaction Tables below list only drugs and substances specifically
mentioned in the scientific literature that either: A) should definitely be avoided with methadone, B) may influence unexpected results or are themselves altered by their combination with methadone, or C) raise or lower SMLs and increase or decrease methadone's effects, respectively. Due to space limitations, earlier editions of this document most extensively cited literature-review articles in reporting sources of information. This current document retains those references but is greatly expanded to also include citations of the primary studies and articles. There have been a limited number of clinical studies investigating methadone interactions with specific drugs; therefore, some interactions are predicted based on lower levels of evidence, such as case reports, laboratory experiments, or pharmacologic principles. The various levels of evidence are denoted in the Tables by different colors and typefaces as follows:
„ Interaction demonstrated via published clinical studies and/or by the
well-established and specific pharmacology of methadone metabolism.
„ Based on published clinical case series reports and/or laboratory investigations in animals or tissues (in vitro). „ Proposed in the literature, but predicted from general pharmacologic principles and/or sporadic anecdotal cases. To simplify the presentation, only substances reported or proposed as interacting in a substantive way with methadone are included in the Tables. In some cases, the interaction potential of certain
drugs may have been examined but no clinically significant interaction was found; therefore, these drugs are not listed in this document. Furthermore, enzymes involved in methadone-drug interactions are often broadly indicated here as part of the CYP450 family, without specifying the exact enzymes. As noted above, this is an ongoing area of investigation and many agents currently thought to be interacting with methadone via specific P450 enzymes may be otherwise identified as time passes. Therefore, the most that often can be stated with certainty is that CYP450 enzymes are involved in a methadone-drug interaction. Clinically, this is still helpful in understanding the possible interaction and suggesting when therapeutic adjustments of methadone and/or the interacting agent(s) might be appropriate. Methadone-Drug Interactions, Page 12
Pain-Topics.org Finding Drugs/Substances of Interest in this Document
While viewing this Adobe Reader® PDF document, use the "Search" function to easily and quickly locate a drug/substance within the document. Click on the "Search" button icon (graphic at left) on the menu bar. This function also is
available under the "Edit" menu, or by pressing the "Control [Ctrl]" plus the "F" keys simultaneously on the In the panel that appears along the right side of the document (graphic at right), enter the name of the drug
or substance of interest or concern and click on the search button. All instances of the named drug/substance in the document will be listed and these can be selected individually for viewing. Methadone-Drug Interactions, Page 13
Pain-Topics.org Table Legend
Abbreviations: NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase
inhibitor; PI = protease inhibitor; SML = serum methadone level; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant. ♥ Denotes drugs that have been associated in the literature with cardiac rhythm disturbances (prolonged QTc interval and/or torsade de pointes [TdP]) and should be used cautiously with methadone. For regularly updated information on TdP riey 2003). Also see, Leavitt and Krantz 2003. Reference Sources: The original document (2004) principally cited current review articles specifically mentioning
methadone-drug interactions. This revision/update (2005) now also includes references to primary studies, if available, demonstrating the methadone-drug interaction. Note: Drug brand names are registered trademarks of their respective manufacturers. Additional brands may be on the
market and the tables may not be all-inclusive of drugs/brands that might be contraindicated or interact with methadone. Clinical experiences with drugs may differ, as there are often individual patient variations in methadone metabolism and reactions to any drug or combination of therapies. Levels of Evidence (The following colors/typefaces are used in the tables to designate the certainty of interactions):
„ Interaction demonstrated via published clinical studies and/or by the specific pharmacology of methadone.
„ Based on published case series reports and/or laboratory investigations in animals or tissues (in vitro).
„ Proposed in the literature, but predicted from general pharmacologic principles and/or sporadic anecdotal cases.
Generic Name
Buprenex, Subutex,
Opioid analgesics with
Can displace methadone on µ-opioid receptors
analgesics
Suboxone, Stadol,
some opioid-
to cause acute withdrawal (DeMaria 2003;
Dalgan, Nubain,
antagonist activity.
Kalvik et al. 1996).
butorphanol, dezocine,
nalbuphine, pentazocine
monoamine oxidase (MAO) Nardil, Parnate, others Antidepressants. Contraindicated with methadone due to potential inhibitors adverse reactions (Methadose® PI 2000). opioid antagonists
Depade, ReVia, Revex,
Blockade or reversal of
Interaction displaces methadone on µ-opioid
naltrexone, nalmefene,
opioid effects or
receptors, causing severe acute withdrawal
naloxone
treatment of
(DeMaria 2003; Kalvik et al. 1996, Strang 1999).
alcoholism.
tramadol Ultram, Ultracet Synthetic analgesic. Potentially may cause withdrawal in persons already taking opioids (Ultram PI 1998); anecdotal cases have been reported. Methadone-Drug Interactions, Page 14
Pain-Topics.org Generic Name
benzodiazepines Xanax, Tranxene, Sedatives. Potential interaction due to common CYP450 metabolic pathway alprazolam, clorazepate, ProSom, Dalmane, with methadone (Harrington et al. 1999). May cause additive CNS estazolam, flurazepam, Versed, Halcion, depression (Strang 1999); potentially fatal (Ernst et al. 2002). midazolam, triazolam, Note: Diazepam has been more thoroughly studied and zopiclone increases methadone effects (see Table 4). Marijuana, hash, hemp, Psychotropic agent. Interaction proposed due to common CYP450 metabolic pathway with methadone (Harrington et al. 1999). chloral hydrate Noctec, Somnote, Sedative hypnotic. Case report of additive effects with methadone causing fatal adverse event (Thurau et al. 2003). chlormethiazole Enhanced sedative effects due to additive CNS depression noted (clomethiazole) neurin, Heminevrin anticonvulsant. anecdotally (Physeptone 2000). cyclizine (meclizine) Antivert, Bonine, Antivertigo, If abused, increased sedative effects due to additive CNS depression Emoquil Marezine, antiemetic. noted anecdotally (Physeptone 2000). didanosine (ddl,
Buffered tablet: decrease in ddl concentration (Rainey et
buffered tablet)
al. 2000). Enteric coated (EC) capsule: effect not seen
(Friedland et al. 2002).

dextromethorphan Robitussin, Vicks, Cough medicine. Possible increase in levels/effects of dextromethorphan proposed Delsym, Touro DM (Levy et al. 2000). interferon-alfa + Rebetron (possibly Antihepatitis C Side effects can mimic opioid withdrawal symptoms and ribavirin also pegylated treatment. methadone dose is often increased (Schafer 2001; Sylvestre interferon, e.g., methylphenidate Ritalin, Ritalin SR, Stimulant used for CYP2D6 inhibition (Flockhart 2005) might slightly increase treating AD/HD. methadone effects. Anecdotal reports only (Leavitt 2005). nifedipine Procardia, Cardiac medication Possible increase in nifedipine proposed (Levy et al. 2000; Strang (Ca++ blocker). Alfenta, Vicodin,
Analgesics.
Common CYP450 pathways with methadone; however,
Sublimaze, Demerol,
interaction probably occurs due to possible additive
codone, fentanyl,
Duramorph, MS
opioid effects. Long-acting excitatory metabolites of
Contin, OxyContin,
meperidine and propoxyphene can reach toxic levels
phine, oxycodone,
(Harrington et al. 1999).
promethazine Insomn-eze, Mepergan, Antihistamine. Increased methadone effect mentioned only anecdotally, possibly Phenergan, others due to CYP2D6 inhibition (Brown and Griffiths 2000) or synergistic sedation (Phenergan PI 2000). Effects with other phenothiazines (Thorazine, Stelazine) not reported. stavudine (d4T)
Decrease in d4T concentration; no effect on methadone
(Rainey et al. 2000). Clinical significance in d4T decrease
unclear; no dosage adjustments necessary.

Elavil, Norpramin, Tricyclic Combination with methadone increases TCA toxicity Tofranil, Pamelor, antidepressants (DeMaria 2003; Maany et al. 1989; Quinn et al. 1997; Trimipramine, Richelson 1997). Mixed reports of methadone increase or Sinequan, Vivactil, decrease (Eap et al. 2002; Moolchan et al. 2001; Strang and other brands 1999; Venkatakrishnan et al. 1998). Caution might be advised when using the drugs in combination with methadone due to possible proarrhythmic effects. Methadone-Drug Interactions, Page 15
Pain-Topics.org Table 2 CONTINUED: Drugs That Result in Altered Metabolism / Unpredictable Interactions
zidovudine (AZT)
Retrovir, AZT
AZT concentration increased significantly with
combinations (e.g.,
methadone; more frequent AZT side effects are possible,
Combivir, Trizivir)
but no effect on methadone (McCance-Katz et al. 1998,
2001; Rainey et al. 2002; Retrovir PI 2001; Schwartz et al.
1992; Trepnell et al. 1998).

Generic Name(s)
abacavir (ABC)
NRTI antiretroviral.
Methadone level mildly decreased; also
reduces ABC peak concentration (Bart et al.
2001; Gourevitch 2001; Sellers et al. 1999;
Ziagen PI 2002).

amprenavir Agenerase
CYP3A4 enzyme induction may decrease
methadone levels (Agenerase PI 1999; Bart et
al. 2001; Chrisman 2003; Eap et al. 2002), but
no adjustment in methadone dose required
(Henrix et al. 2000, 2004). Amprenavir levels
also may be reduced but the clinical
significance is unclear.

barbiturates Amytal, Butisol, Fioricet, Barbiturate sedatives CYP450 enzyme induction (Kreek 1986). Fiorinal, Lotusate, and/or hypnotics. Phenobarbital, the most studied, can cause
barbitone butabarbital, Luminal, Mebaral, sharp decrease in methadone (Alvares and
Kappas 1972; Faucette et al. 2004; Gourevitch
barbital, pentobarbital,
barbital, Seconal, Tal-
2001; Liu and Wang 1984; Plummer et al. 1988)
secobarbital, others butal, Tuinal, and others A methadone dose increase may be required.
carbamazepine Atretol,
Tegretol
Anticonvulsant for
Strong CYP3A4 and CYP2B6 enzyme
epilepsy and
induction may cause withdrawal (Bochner
trigeminal
2000; Faucette et al. 2004; Kuhn et al. 1989).
neuralgia.
Effect not seen with valproate (Depakote; Saxon et al. 1989). Crack, coke, others Illicit stimulant. Accelerates methadone elimination (Moolchan et al. 2001). dexamethasone Decadron, Hexadrol Corticosteroid. CYP3A4 and CYP2B6 enzyme inducer (Eap et al. 2002; Faucette et al. 2004); cases reported in pain patients (Plummer et al. 1988). efavirenz Sustiva NNRTI
Due to CYP3A4 and/or CYP2B6 induction
(Barry et al. 1999; Boffito et al. 2002; Clarke et
al. 2000, 2001a; Eap et al. 2002, Gerber et al.
2004; Marzolini et al. 2000; McCance-Katz et al.
2002; Pinzanni et al. 2000; Rotger et al. 2005;
Tashima et al. 1999). Methadone withdrawal is
common and a significant methadone dose
increase is usually required.

ethanol (chronic use) Wine, beer, whiskey, etc. Euphoric, sedative. CYP450 enzyme induction (Borowsky and Lieber 1978; Kreek 1976, 1984; Quinn et al. 1997). fusidic acid Steroidal antibacterial. CYP450 enzyme induction (Eap et al. 2002; Van Beusekom and Iguchi 2001); reports of opioid withdrawal symptoms after 4-weeks of therapy (Reimann et al. 1999). Smack, scat, others Illicit opioid. Decreases free fraction of methadone (Moolchan et al. 2001). Methadone-Drug Interactions, Page 16
Pain-Topics.org Table 3 CONTINUED: Drugs That May Lower SML and/or Decrease Methadone Effects
lopinavir + ritonavir
Kaletra PI
Combination lowers SML (Clarke et al. 2002),
although there is some evidence to the
contrary (Stevens et al. 2003). Withdrawal
symptoms might occur requiring methadone
dose increase; however, side effects of Kaletra
may mimic GI side effects of opioid
withdrawal. Most
but not all research
suggests this effect is not seen with ritonavir
alone or ritonavir/saquinavir combination
(Beauverie et al. 1998; Chrisman 2003; Geletko
and Erickson 2000; Gerber et al. 2001; Hsu et
al. 1998; Kharasch and Hoffer 2004; McCance-
Katz et al. 2003; Munsiff et al. 2001; Shelton et
al. 2001, 2004)
although ritonavir induces CYP
2B6 (Faucette et al. 2004).

nelfinavir Viracept PI
CYP3A4 and P-gp induction (Beauverie et al.
1998; Eap et al. 2002), but clinical methadone
withdrawal is rare (Brown et al. 2001; Hsyu et
al. 2000; Maroldo et al. 2000; McCance-Katz et
al. 2004); however, manufacturer suggests
methadone may need to be increased
(Viracept PI 2000). Interaction may (Chrisman
2003) or may not (McCance-Katz et al. 2004)
occur to decrease nelfinavir, which also is a
potent inhibitor of CYP2B6 (Antoniou and
Tseng 2002).

nevirapine Viramune
CYP3A4 and/or 2B6 enzyme induction reduces
methadone level and precipitates opioid
withdrawal. Methadone dose increase
necessary in some patients (Altice et al. 1999;
Clarke et al. 2001; Eap et al. 2002; Gerber et
al.; Heelon et al. 1999; Otero et al. 1999;
Pinzanni et al. 2000; Rotger et al. 2005;
Staszewski et al. 1998).

phenytoin Dilantin Control
seizures.
Sharp decrease in methadone due to CYP3A4
and
CYP2B6 enzyme induction (Eap et al.
2002;
Faucette et al. 2004; Finelli 1976; Kreek
1986; Tong et al. 1981).

primidone Myidone, Mysoline Anticonvulsant. Proposed in the literature (Vlessides 2005) due to CYP450 enzyme induction (Michalets 1998) including CYP2B6 (Brown & Griffiths 2000) but not clinically verified. rifampin (rifampicin) and
Rifadin, Rimactane
Treatment of
Induces CYP450 enzymes; cases of severe
Rifamate
pulmonary
withdrawal reported (Bending and Skacel
1977; Borg and Kreek 1995; Eap et al. 2002;
Faucette et al. 2004; Holmes 1990; Kreek 1986;
Kreek et al. 1976). Effect not seen with
rifabutin (Mycobutin: Brown et al. 1996;
Gourevitch 2001; Levy et al. 2000).

spironolactone Aldactone K+-sparing diuretic. Possible CYP450 induction (Eap et al. 2002). Effect observed in patients receiving methadone for cancer pain (Plummer et al.). St. John's wort Ingredient in various OTC Herb used as Induces CYP3A4 and P-gp; 47% decrease in (Hypericum perforatum) antidepressant. methadone noted in one study (Eich-Höchli et al. 2003; Scot and Elmer 2002). Various brands Habitual smoking. Some mixed reports, but most indicate reduced effectiveness of methadone, possibly due to CYP1A2 induction (Eap et al. 2002; Moolchan et al. 2001; Tacke et al. 2001). urinary acidifiers (e.g., Vitamin C (extremely large Dietary supplement; Proposed, methadone excreted by kidneys more rapidly ascorbic acid) doses); K-Phos keeps calcium soluble. at lower pH (Nillson et al. 1982; Strang 1999). Methadone-Drug Interactions, Page 17
Pain-Topics.org Warning: Acute increases in serum methadone concentration may produce significant signs/symptoms of methadone overmedication,
possibly resulting in overdose. Recent data suggest that in susceptible individuals acutely elevated methadone levels – alone or, more
commonly, in combination with other drugs and/or cardiac risk factors – may influence cardiac rhythm disturbances (prolonged QTc
interval and/or torsade de pointes; see Leavitt and Krantz 2003).
Generic Name
Asthma Medications Accolate, Zyflo Prevention and control of Proposed in the literature (Vlessides 2005) due to zafirlukast, zileuton asthma symptoms. CYP450 inhibition (Flockhart 2005), but not clinically verified. Cardiac Medications Cordarone, Cardizem, Heart rhythm stabilizers, Recently proposed in the literature (Vlessides 2005) amiodarone, diltiazem Diltia, Tiazac, Cardioquin, possibly due to CYP450 inhibition (Flockhart 2005), Quinaglute, Dura-Tabs, but not otherwise verified. cimetidine Tagamet H2-receptor antagonist CYP450 enzyme inhibitor (Bochner 2000; for GI disorders. Dawson and Vestal 1984; Sorkin and Ogawa 1983; Strang 1999). ciprofloxacin Cipro Quinolone antibiotic. Inhibition of select CYP450 enzymes (Eap et al. 2002; Herrlin et al. 2000). delavirdine Rescriptor NNRTI antiretroviral. Predicted effect due to CYP450 enzyme inhibition (Gourevitch 2001; McCance-Katz et al. 2004, 2005); manufacturer suggests methadone dose may need to be decreased (Rescriptor PI 2001). Dizac, Valium, Valrelease Control of anxiety and Mechanism undetermined (Eap et al. 2002; Iribarne et al. 1996; Preston et al. 1984, 1986) but unlikely due to metabolic interaction (Foster et al. 1999; Pond et al. 1982) and effect sporadic (Levy et al. 2000). dihydroergotamine D.H.E., Migranal Migraine treatment. Predicted due to CYP3A4 enzyme inhibition (Van Beusekom and Iguchi 2001). disulfiram Antabuse Alcoholism treatment. Sedation in patients noted with higher doses of disulfiram (Bochner 2000), but some reports inconclusive (Tong et al. 1980). ethanol (acute use) Wine, beer, whiskey, etc. Euphoric, sedative. Competition for CYP450 enzymes or CYP450 inhibition (Borowsky and Lieber 1978; Kreek 1976, 1984; Quinn et al. 1997). fluconazole Diflucan
Anti-fungal
antibiotic.
CYP450 enzyme inhibition (Eap et al. 2002);
increased methadone levels (Cobb et al. 1998;
Gourevitch 2001); clinical significance
uncertain (Levy et al. 2000, Tamuri et al. 2002).

Other azole antifungals may potentially influence
opioid toxicity: e.g., itraconazole, ketoconazole
,
voriconazole.

grapefruit
juice or whole fruit
Inhibits intestinal CYP3A4 (Bailey et al. 1998;
Dresser et al. 2000; Hall et al. 1999) and P-gp
(Benmebarek et al. 2004; Dresser et al. 2000;
Eagling et al. 1999; Eap et al. 2002); although,
there is some conflicting evidence (Kharasch
et al. 2004). This effect is not expected with
other fruits/juices (Karlix 1990).

Methadone-Drug Interactions, Page 18
Pain-Topics.org Table 4 CONTINUED: Drugs That May Raise SML and/or Increase Methadone Effects
macrolide antibiotics EES, Erythrocin, Eryzole, Anti-infective. Predicted due to strong inhibition of CYP3A4 enzyme. Ilosone, Prevpac, Biaxin Cardiac and metabolic effects not expected with azithromycin (Eap et al. 2002). moclobemide Aurorix, MAO-inhibitor Case reported, possibly due to CYP450 enzyme inhibition (Eap et al. 2002; Gram et al. 1995). metronidazole Flagyl Anti-infective. Proposed in the literature (Vlessides 2005) due to CYP3A4 inhibition (Michalets 1998), but unverified. "natural" supplements Cat's claw, Chamomile, Herbal products used for Not studied specifically with methadone – predicted uncaria tomentosa, Echinacea, Goldenseal (may gastrointestinal therapy, potential effect due to strong CYP3A4 enzyme matricaria recutita, be ingredient in various immune system inhibition (Scott and Elmer 2002, Van Beusekom and echinacea angustifolia, product brands) enhancement, others. Iguchi 2001). hydrastis canadensis, quercetin omeprazole Prilosec Treatment of acid- In animal studies, possibly affects methadone related GI disorders. absorption (de Castro et al. 1996; Strang 1999). Prozac, Luvox, Paxil,
Treatment of Possible mild elevations of SML due to variable Serzone, Zoloft depression and inhibition of CYP450 enzymes (Begre et al. 2002; compulsive disorders. Batki et al. 1993; Bertschy 1996; Eap et al. 2002; Hamilton et al. 1988, 2000; Levy et al. 2000; nefazodone, Richelson 1997). Strongest effect seen with
sertralinefluvoxamine (Alderman and Frith 1999;
Bertschy et al. 1994; DeMaria and Serota 1999;
Eap et al. 1997).

troleandomycin TAO Antibiotic (similar to Expected due to CYP450 enzyme inhibition (Beusekom erythromycin). and Iguchi 2001). urinary alkalinizers
Bicitra, Polycitra
Treatment of kidney
Alkaline (higher pH) urine decreases
(e.g., sodium
stones, gout therapy.
methadone excretion by kidneys (Kalvik et al.
1996; Strang 1999).
verapamil Calan, Covera-HS, Isoptin Cardiac drug Predicted effect due to CYP450 enzyme and strong P- (Ca++-channel blocker). glycoprotein inhibition (Levy et al. 2000). Methadone-Drug Interactions, Page 19
Pain-Topics.org NOTE: Drug Brand Names begin with capital letters and are registered trademarks of their respective manufacturers.
All others are generic agents. The listings here may not be all-inclusive of drugs/brands that might be contraindicated or interact with methadone. Furthermore, clinical experiences with medications may differ, as there are often individual variations in methadone metabolism and reactions to any drug, substance, or combination of therapies. Interactions resulting in acute SML increases are of special concern, since they may produce signs/symptoms of overmedication and possible overdose. In individuals with cardiac risk factors, methadone's combination with other drugs having arrhythmogenic potential may influence cardiac rhythm disturbances. ; = contraindicated with methadone (may cause opioid withdrawal, possibly severe). * = may result in altered metabolism or unpredictable interactions with methadone. ↑ = increases serum methadone level (SML) and/or increases methadone effects. ↓ = decreases serum methadone level (SML) and/or decreases methadone effects. ♥ = drug has been associated with cardiac rhythm disturbances (prolonged QTc interval and/or torsade de pointes) and should be used cautiously with methadone. For latest listings se Levels of Evidence (The following colors/typefaces are used in the tables to designate the certainty of interactions):
„ Interaction demonstrated via published clinical studies and/or by the specific pharmacology of methadone.
„ Based on case series reports and/or laboratory investigations in animals or tissues (in vitro).
„ Proposed in the literature, but predicted from general pharmacologic principles and/or sporadic anecdotal cases.
Effect With Methadone
abacavir (ABC)
Also decreases ABC peak concentration.
Proposed due to CYP450 inhibition. Nifedipine increase proposed. Agenerase
Also may decrease Agenerase (amprenavir).
Aldactone Possible CYP450 induction. Common CYP450 pathway; possible additive effects with methadone.
alfentanil
Common CYP450 pathway; possible additive effects with methadone.
alprazolam Potential interaction, additive CNS depression. Due to CYP450 enzyme induction. amiodarone Proposed due to CYP450 inhibition. amitriptyline Possible increased TCA toxicity; uncertain effect on methadone. amobarbital Due to CYP450 enzyme induction. amprenavir
Also may decrease amprenavir.
amylobarbitone Due to CYP450 enzyme induction. Due to CYP450 enzyme induction. Sedation reported. Increased sedative effects if abused. aprobarbital Due to CYP450 enzyme induction. ascorbic acid Proposed due to more rapid urinary excretion. May cause opioid withdrawal.
Methadone-Drug Interactions, Page 20
Pain-Topics.org Possible due to CYP450 inhibition. Aventyl Possible increased TCA toxicity; uncertain effect on methadone. AZT (zidovudine)
AZT concentration increased and side effects common.
barbiturates Due to CYP450 enzyme induction. benzodiazepines Potential interaction, additive CNS depression. Biaxin Strong CYP3A4 inhibition. Decreases methadone urinary excretion.
Increased sedative effects if abused. Buprenex
Displaces methadone on µ-opioid receptors.
Displaces methadone on µ-opioid receptors.
butabarbital Due to CYP450 enzyme induction. butalbital Due to CYP450 enzyme induction. Due to CYP450 enzyme induction. butorphanol
Displaces methadone on µ-opioid receptors.
Predicted due to CYP450 inhibition. Proposed interaction, common CYP450 pathway. May cause opioid withdrawal.
Cardioquin Proposed due to CYP450 inhibition. Proposed due to CYP450 inhibition. Cat's claw Predicted due to CYP450 inhibition. Chamomile Predicted due to CYP450 inhibition. chloral hydrate Additive effects, possibly fatal. chlormethiazole Enhanced sedative effects. cimetidine CYP450 enzyme inhibitor. CYP3A4 and/or CYP1A2 inhibition. ciprofloxacin CYP3A4 and/or CYP1A2 inhibition. clarithromycin Strong CYP3A4 inhibition. clomethiazole Enhanced sedative effects. clorazepate Potential interaction, additive CNS depression. cocaine Methadone elimination accelerated. coke (cocaine) Methadone elimination accelerated. Combivir
AZT concentration increased.
Possible CYP2D6 inhibition. Cordarone Proposed due to CYP450 inhibition. Covera-HS Predicted due to CYP450 inhibition. crack (cocaine) Methadone elimination accelerated. cyclizine Increased sedative effects if abused. CYP450 enzyme inhibition. Displaces methadone on µ-opioid receptors.
Potential interaction, additive CNS depression. Possible opioid additive effects; long-acting toxic metabolites.
CYP450 induction. delavirdine Due to CYP450 inhibition. Increased dextromethorphan effects proposed. Possible opioid additive effects; long-acting toxic metabolites.
Displaces methadone on µ-opioid receptors.
desipramine Possible increased TCA toxicity; uncertain effect on methadone. dexamethasone CYP450 induction. dextromethorphan Increased dextromethorphan effects proposed. Methadone-Drug Interactions, Page 21
Pain-Topics.org dezocine
Displaces methadone on µ-opioid receptors.
Effect sporadic, unknown mechanism. didanosine (ddl
Decrease in ddl (effect not seen with enteric-coated).
buffered tab)
Diflucan
CYP3A4 inhibition. Case reports requiring dose reduction reported.
CYP450 enzyme inhibition. Dilantin
Sharp decrease, CYP3A4 induction.
Proposed due to CYP450 inhibition. diltiazem Proposed due to CYP450 inhibition. Distraneurin Enhanced sedative effects. disulfiram Sedation reported. Effect sporadic, unknown mechanism. doxepin Possible increased TCA toxicity; uncertain effect on methadone. Duramorph
Common CYP450 pathway; possible additive effects with methadone.
Dura-Tabs Proposed due to CYP450 inhibition. E.E.S., Eryped Strong CYP3A4 inhibition. Echinacea Predicted due to CYP450 inhibition. Increased sedative effects if abused. efavirenz
Due to CYP3A4/2B6induction, methadone withdrawal common.
Elavil Possible increased TCA toxicity; uncertain effect on methadone. Erythrocin Strong CYP3A4 inhibition. erythromycin Strong CYP3A4 inhibition. Eryzole Strong CYP3A4 inhibition. estazolam Potential interaction, additive CNS depression. ethanol (acute use) Competition for CYP450 enzymes. ethanol (chronic use) CYP450 enzyme induction. fentanyl
Common CYP450 pathway; possible additive effects with methadone.
Due to CYP450 enzyme induction. Due to CYP450 enzyme induction. Proposed due to CYP450 inhibition but unverified. fluconazole
CYP3A4 inhibition. Case reports requiring dose reduction reported.
fluoxetine Variable CYP450 enzyme inhibition. flurazepam Potential interaction, additive CNS depression. fluvoxamine
Variable CYP450 enzyme inhibition.
CYP450 induction. fusidic acid (systemic) CYP450 induction. Goldenseal Predicted due to CYP3A4 inhibition. grapefruit
Inhibition of intestinal CYP3A4 and P-gp.
Potential interaction, additive CNS depression. Proposed interaction, common CYP450 pathway. Proposed interaction, common CYP450 pathway. Hemineurin Enhanced sedative effects. Heminevrin Enhanced sedative effects. Decreases methadone free fraction. CYP3A4 induction. hydrastis canadensis Predicted due to CYP3A4 inhibition. hydrocodone
Common CYP450 pathway; possible additive effects with methadone.
Hypericum perforatum Significant decrease; CYP3A4 and P-gp induction. Ilosone Strong CYP3A4 inhibition. Methadone-Drug Interactions, Page 22
Pain-Topics.org imipramine Possible increased TCA toxicity; uncertain effect on methadone. Potential interaction, additive CNS depression. Insomn-eze Possible increased sedation or methadone effects. interferon-alfa + ribavirin Side effects may mimic opioid withdrawal. Predicted due to CYP450 inhibition. Effect not seen with ritonavir alone.
ketoconazole Predicted due to CYP3A4 inhibition. Proposed due to more rapid urinary excretion. lopinavir + ritonavir
Effect not seen with ritonavir alone.
Due to CYP450 enzyme induction. Possibly sharp decrease in methadone. Variable CYP450 enzyme inhibition.
macrolide antibiotics CYP3A4 inhibition (not azithromycin). Possible due to CYP450 inhibition. MAO (monoamine Potential adverse interaction. oxidase) inhibitors Marezine (Marzine) Increased sedative effects if abused. marijuana Proposed interaction, common CYP450 pathway. matricaria recutita Predicted due to CYP3A4 inhibition. Due to CYP450 enzyme induction. meclizine Increased sedative effects if abused. Possible increased sedation or methadone effects. meperidine
Possible opioid additive effects; long-acting toxic metabolites.
mephobarbital Due to CYP450 enzyme induction. methylphenidate Possible CYP450 inhibition. metronidazole Proposed due to CYP3A4 inhibition but unverified. midazolam Potential interaction, additive CNS depression. Possible CYP450 enzyme inhibition. moclobemide Possible due to CYP450 inhibition. morphine
Common CYP450 pathway; possible additive effects with methadone.
MS Contin
Common CYP450 pathway; possible additive effects with methadone.
CYP450 induction proposed. CYP450 induction proposed. nalbuphine
Displaces methadone on µ-opioid receptors.
nalmefene
Displaces methadone on µ-opioid receptors.
naloxone
Displaces methadone on µ-opioid receptors.
naltrexone
Displaces methadone on µ-opioid receptors.
Displaces methadone on µ-opioid receptors.
Potential adverse interaction. nefazodone Variable CYP450 enzyme inhibition. nelfinavir
Possible decrease also in nelfinavir; methadone increase rarely needed.
Due to CYP450 enzyme induction. nevirapine
Frequent opioid withdrawal syndrome.
nifedipine Nifedipine increase proposed. Nizoral Predicted due to CYP450 inhibition. Additive effects, possibly fatal. Norpramin Possible increased TCA toxicity; uncertain effect on methadone. nortriptyline Possible increased TCA toxicity; uncertain effect on methadone. Displaces methadone on µ-opioid receptors.
Methadone-Drug Interactions, Page 23
Pain-Topics.org omeprazole Possibly affects methadone absorption. opioid analgesics
Common CYP450 pathway; possible additive effects with methadone.
oxycodone
Common CYP450 pathway; possible additive effects with methadone.
OxyContin
Common CYP450 pathway; possible additive effects with methadone.
Pamelor Possible increased TCA toxicity; uncertain effect on methadone. Potential adverse interaction. paroxetine Variable CYP450 enzyme inhibition. Paxil Variable CYP450 enzyme inhibition. Side effects may mimic opioid withdrawal. pegylated interferon Side effects may mimic opioid withdrawal. pentazocine
Displaces methadone on µ-opioid receptors.
pentobarbital Due to CYP450 enzyme induction. Phenergan Possible increased sedation or methadone effects. CYP450 induction, possibly sharp decrease in methadone.
phenytoin
Sharp decrease, CYP3A4 induction.
Polycitra
Decreases methadone urinary excretion.
pot (marijuana) Proposed interaction, common CYP450 pathway. Prevpac CYP3A4 inhibition (contains clarithromycin). Possibly affects methadone absorption. primidone CYP450 induction proposed. Procardia Nifedipine increase proposed. promethazine Possible increased sedation or methadone effects. Possible opioid additive effects; long-acting toxic metabolites.
Potential interaction, additive CNS depression. protriptyline Possible increased TCA toxicity; uncertain effect on methadone. Prozac Variable CYP450 enzyme inhibition. quercetin Predicted due to CYP450 inhibition. Quinaglute Proposed due to CYP450 inhibition. quinidine Proposed due to CYP450 inhibition. Side effects may mimic opioid withdrawal. Rescriptor Due to CYP450 inhibition. Retrovir
AZT concentration and related side effects increased.
Displaces methadone on µ-opioid receptors.
Displaces methadone on µ-opioid receptors.
ribavirin + interferon-alfa Side effects may mimic opioid withdrawal. Possibly severe; CYP450 induction.
Rifamate
Possibly severe; CYP450 induction (not seen with rifabutin).
rifampicin
Possibly severe; CYP450 induction (not seen with rifabutin).
rifampin
Possibly severe; CYP450 induction (not seen with rifabutin).
Possibly severe; CYP450 induction (not seen with rifabutin).
Rimactane
Possibly severe; CYP450 induction (not seen with rifabutin).
Ritalin, Ritalin SR CYP450 inhibition. ritonavir + lopinavir
Effect not seen with ritonavir alone.
Robitussin Increased dextromethorphan effects proposed. scat (heroin) Decreases methadone free fraction. secobarbital Due to CYP450 enzyme induction. Due to CYP450 enzyme induction. sertraline Variable CYP450 enzyme inhibition. Variable CYP450 enzyme inhibition. Methadone-Drug Interactions, Page 24
Pain-Topics.org Sinequan Possible increased TCA toxicity; uncertain effect on methadone. smack (heroin) Decreases methadone free fraction. sodium bicarbonate
Decreases methadone urinary excretion.
Additive effects, possibly fatal. spironolactone Expected CYP450 induction. SSRI antidepressants Variable CYP450 enzyme inhibition. St. John's wort Significant decrease; CYP 3A4 and P-gp induction. Displaces methadone on µ-opioid receptors.
stavudine (d4T)
Decreased d4T concentration (unclear clinical significance).
Sublimaze
Common CYP450 pathway; possible additive effects with methadone.
Suboxone
Displaces methadone on µ-opioid receptors.
Displaces methadone on µ-opioid receptors.
Surmontil Possible increased TCA toxicity; uncertain effect on methadone. Due to CYP3A4/2B6 induction, methadone withdrawal common.
CYP450 enzyme inhibitor. Due to CYP450 enzyme induction. Displaces methadone on µ-opioid receptors.
Expected due to CYP450 inhibition. Tegretol
May cause opioid withdrawal.
Proposed due to CYP450 inhibition. Possible; reports mixed. Tofranil Possible increased TCA toxicity; uncertain effect on methadone. Increased dextromethorphan effects proposed. Potential withdrawal in persons taking opioids. Potential interaction, additive CNS depression. triazolam Potential interaction, additive CNS depression. tricyclic Possible increased TCA toxicity; uncertain effect on methadone. trimipramine Possible increased TCA toxicity; uncertain effect on methadone. Trizivir
AZT concentration increased.
troleandomycin Expected due to CYP450 inhibition. Due to CYP450 enzyme induction. Potential withdrawal in persons taking opioids. Potential withdrawal in persons taking opioids. Uncaria tomentosa Predicted due to CYP450 inhibition. urinary acidifiers Proposed due to more rapid urinary excretion. urinary alkalinizers
Decreases methadone urinary excretion.
Effect sporadic, unknown mechanism. Valrelease Effect sporadic, unknown mechanism. verapamil Predicted due to CYP450 inhibition. Potential interaction, additive CNS depression. Vicks (cough med) Increased dextromethorphan effects proposed. Common CYP450 pathway; possible additive effects with methadone.
Videx (ddl buffered
Decrease in ddl (effect not seen with enteric-coated).
Viracept
Possible decrease also in Viracept.
Viramune
Frequent opioid withdrawal syndrome.
vitamin C (very high dose) Proposed due to more rapid urinary excretion. Vivactil Possible increased TCA toxicity; uncertain effect on methadone. Methadone-Drug Interactions, Page 25
Pain-Topics.org wine, beer, whiskey Competition for CYP450 enzymes. (acute use) wine, beer, whiskey CYP450 enzyme induction. (chronic use) Potential interaction, additive CNS depression. zafirlukast Proposed due to CYP450 inhibition. Zerit (d4T)
Decreased d4T concentration (unclear clinical significance).
Also decreases Ziagen peak concentration
zidovudine (AZT)
AZT concentration increased and side effects common.
Proposed due to CYP450 inhibition. Zoloft Variable CYP450 enzyme inhibition. zopiclone Potential interaction, additive CNS depression. Proposed due to CYP450 inhibition. Note: All websites listed below were active on the date access was checked. However, the Internet is a dynamic environment
with frequent changes – specific sites may be discontinued or moved without notice. Disclaimer: Pain Treatment Topics does not endorse the contents provided through or referenced on the websites listed here,
and does not make any assurances regarding the accuracy of information. Methadone-drug interactions is an ongoing area of scientific inquiry and some of the information provided at these websites may be out of date and/or invalid. CYP450 Drug Interaction Reference Tables

Flockhart D. Cytochrome P450 Drug Interaction Tables: Indiana University School of Medicine. Periodically updated. Access checked 9/6/05. Cytochrome P450 Reference Tables. Adapted from: Michalets FL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy. 1998;18(1):84-112. Access checked 9/19/05. Cardiac Concerns

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