A D D I C T I O N T R E A T M E N T Methadone-Drug* Interactions (*Medications, illicit drugs, & other substances)
Stewart B. Leavitt, PhD; Editor, AT Forum
The Importance of Drug Interactions
thereby slow the metabolism of drugs that are substrates for
Pharmacotherapy is increasingly complicated by the intro-
those particular enzymes, which may result in excessively high
duction of new drugs and the use of multidrug regimens for
drug levels and related toxic effects (Levy et al. 2000). Other
acute or chronic disease, which can result in clinically important
drugs are inducers; they boost the activity of specific CYP
drug interactions. A drug interaction occurs when the amount or
enzymes resulting in more rapid metabolism of substrate drugs,
action of a drug in the body is altered – usually increased or
which may produce extremely low drug levels (Flexner and
decreased – by the presence of another drug or multiple drugs
(Bochner 2000; Piscitelli and Rodvold 2001).
Co-administered drugs that merely share the same metabolic
During clinical use spanning more than 35 years, oral
pathway – that is, are substrates for the same CYP enzymes –
methadone has proven to be a well-tolerated medication with
may compete with each other. The “winning drug” could garner
minimal adverse reactions when prescribed in appropriate doses
more enzyme activity, thus diminishing metabolism of the other
and taken daily as a component of methadone maintenance treat-
drug and intensifying its effects (Hardman et al. 1996). Readers
ment (MMT; Kreek 1973; Novick et al. 1993). However, there
may wish to consult current sources listing drugs that are
are potential methadone-drug interactions – involving prescribed
CYP450-enzyme substrates, inducers, and inhibitors; such as at
medications, illicit drugs, OTC products, and other substances –
http://drug-interactions.com (Flockhart 2003).
which sometimes can be difficult to predict, may be potentiallyharmful, and/or can lead to treatment failures (Harrington et al. Methadone Metabolism
Methadone is usually readily absorbed, with about 80% of
the administered dose passing into the bloodstream during stabi-
lized MMT and the remainder metabolized in the GI tract and
Most drugs are foreign to the human body and are broken
liver; although, for reasons described below, absorption can
down (metabolized) by chemical reactions into molecules that
range from 35% to 100% (Eap et al. 2002, Moolchan et al.
can be more easily eliminated (Flexner and Piscitelli 2000). A
2001). The three formulations of oral methadone used in MMT
primary metabolic pathway involves the actions of proteins,
– solid tablets, dispersible tablets, and premixed liquid – have
called cytochrome P450 (CYP) enzymes, that facilitate those
been demonstrated as intrinsically equal in terms of their absorp-
reactions. These enzymes evolved as a protective mechanism
tion and metabolism (Gourevitch et al. 1999); however, patient
more than 3 billion years ago to cope with a growing number of
reactions to each formulation may vary, possibly due to psycho-
environmental chemicals, food toxins, and drugs (Hardman et al.
Methadone is metabolized primarily by CYP3A4, secondar-
There are more than 28 CYP enzymes encoded by different
ily by CYP2D6, and to a smaller extent by CYP1A2 and addi-
genes (Flexner and Piscitelli 2000; Shannon 1997). Each is des-
tional enzymes that are under study (see Table).
ignated by a combination of numbers and letters: for example,
CYP3A4, the most abundant metabolic enzyme in the body,
3A4 and 2D6 which are important in methadone metabolism.
can vary 30-fold between individuals in terms of its presence
CYP enzymes reside mainly in the liver, but also may be present
and activity in the liver (Leavitt et al. 2000). This enzyme also is
found in the gastrointestinal tract, so methadone metabolism
A substrate is any drug metabolized by one or more CYP
actually begins before the drug enters the circulatory system
enzymes, and more than half of all medications that undergo
(Hardman et al. 1996). The amount of this enzyme in the intes-
metabolism are CYP3A4 substrates (Piscitelli and Rodvold,
tine can vary up to 11-fold, partially accounting for variable
2001). Some drugs are inhibitors of specific CYP enzymes and
breakdown of methadone (Levy et al. 2000).
increased methadone. Conversely, if a CYP inducer is discontin-
P450 Enzymes Metabolizing Methadone
ued, SMLs may rise to toxic levels unless careful methadone
Primary enzyme (can also be induced by methadone
dose reductions are implemented in response to clinical signs of
Some methadone-drug interactions primarily relate to how
Secondary role (methadone can inhibit this enzyme in
certain drug combinations may adversely affect physiological
Possibly involved (clinical significance is still under
response in the patient and have little to do with altered drug
metabolism. For example, the additive effects of methadone
when combined with other central nervous system (CNS)
Newly proposed as important methadone metabolizer.
depressants may cause hypotension, sedation, respiratory
Borg and Kreek 2003; Eap et al. 2002; Gerber 2002; Leavitt et al. 2000;
depression, or coma (Leavitt 2003; Methadose PI 2000). Also,
polysubstance abuse in MMT patients may put them at greaterrisk of adverse additive interactions with other drugs (Antonio
Another metabolic protein of some importance is P-glyco-
and Tseng 2002; Harrington et al. 1999; Quinn et al. 1997).
protein (P-gp), which is found in the intestine and other tissues
Another concern involves the recognition of methadone’s
(Matheny et al. 2001). This substance functions as a pump,
potential to affect heart rhythm under certain circumstances
transporting methadone out of cells lining the intestinal wall and
(Leavitt and Krantz 2003). Although the clinical significance of
back into the lumen. Thus, some of the methadone absorbed by
this is still under investigation, comedications that might pro-
the intestine is pumped back out before it ever enters the circu-
duce acute elevations of serum methadone concentrations or
lation. There is up to a 10-fold variation in the amount of intesti-
may in themselves contribute to dysrhythmias should be used
nal P-gp expressed by individuals (Hall et al. 1999, Leavitt et al.
only after considering the risks versus benefits.
2000), and some interactions originally considered solely due to
In cases of MMT patients on elaborate drug regimens – such
intestinal CYP3A4 may involve P-gp as well (Dresser et al.
as multidrug therapies for HIV/AIDS, hepatitis, and/or severe
mental illness – outside consultation with specialists in such
Drugs that induce the activity of enzymes involved in
pharmacotherapies might be advised. For example, many drugs
methadone metabolism can accelerate its breakdown, abbreviate
used for HIV/AIDS therapy interact with each other (Chrisman
the duration of methadone’s effects, lower the serum methadone
2003; Schütz 2002) and their combined effects on methadone
level (SML), and possibly precipitate an abstinence (withdraw-
can be complex (Antoniou and Tseng 2002; Faragon and Piliero
al) syndrome. Conversely, CYP-enzyme inhibitors may slow
methadone metabolism, raise the SML, extend the duration of itseffects, and possibly cause methadone-related toxicity such asoversedation and/or respiratory depression (Eap et al. 2002;
Putting Concepts Into Practice
Leavitt et al. 2000; Methadose PI 2000; Payte et al. 2003; Wolff
Methadone works best when administered in adequate ther-
apeutic doses (Leavitt 2003). However, given the individual
Genetic factors can act on certain enzymes to affect
variability in methadone absorption and metabolism, it becomes
methadone metabolism. For example, CYP2D6 is entirely
difficult to accurately predict the effects of drug combinations in
absent in a small proportion of the population, resulting in
any one patient (Harrington et al. 1999), or how methadone dos-
increased sensitivity to methadone’s effects; conversely, some
ing may need adjustment to compensate for metabolic inducers
persons have high activity of this enzyme and are rapid metabo-
or inhibitors (Wolff et al. 2000). Several points might be kept in
lizers of methadone (Eap et al. 2002).
The variability in CYP-enzyme presence and activity means
• Just because certain drugs can interact does not mean that
that SMLs can vary significantly even in the absence of inter-
they will, or indicate to what extent.
acting substances; some persons can naturally be either exten-
• If a patient is responding unexpectedly or unfavorably to
sive (rapid) or poor (slow) metabolizers of methadone. When
methadone – with signs/symptoms of under- or overmed-
interactions with other drugs occur this could further influence
ication – a search for potentially interacting substances
problematic methadone under- or overmedication (Eap et al.
(prescribed medications, illicit drugs, OTC products, or
2002; Leavitt et al. 2000; Richelson 1997).
other agents) would be appropriate. Taking a comprehen-sive history from the patient can be important in this
When co-prescribing medications with methadone, the time
• When an interaction is suspected, adjustments of medica-
course of sign/symptom development can be a guide as to
tion dosages with followup monitoring, substitutions of
whether enzyme induction or inhibition is involved.
non-interacting agents, or other therapeutic modifications
Overmedication reactions developing within a few days after
concurrent drug administration are likely due to CYP inhibition.
The Tables on the inside three pages list substances specifi-
In contrast, CYP induction may take a week or much longer to
cally mentioned in the scientific literature that either: A) should
emerge, producing withdrawal signs/symptoms (Antoniou and
be avoided with methadone, B) raise or lower SMLs and/or
Tseng 2002; Faragon and Piliero 2003; Gourevitch and
increase/decrease methadone’s effects, or C) are themselves
altered by their combination with methadone. There have been a
Potential effects on methadone metabolism also should be
limited number of clinical studies investigating methadone inter-
considered when discontinuing medications. If a drug that
actions with specific drugs; therefore, some interactions are pre-
inhibits CYP enzymes is stopped, methadone serum levels may
dicted as being probable based on case reports, laboratory exper-
decrease in the days following to cause withdrawal that requires
iments, or pharmacologic principles. TABLE ABREVIATIONS, SOURCES, & NOTES 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 with cardiac rhythm disturbances (prolonged QTc interval and/or torsade de pointes)and should be used cautiously with methadone. For regularly updated information, see: http://QTdrugs.org (Woosley 2003). Reference Sources: Whenever possible, current review articles specifically mentioning methadone-drug interactions are cited in the
tables. These may be consulted for further references to primary research reporting on individual drug interactions. Note: Drug brand names are registered trademarks of their respective manufacturers; additional brands may be on the market.
• Some interactions are proposed based on reported cases or laboratory investigations, and/or predicted from pharmacologic
principles (rather than extensive clinical studies).
• Clinical experiences with drugs may differ, as there are often individual variations in methadone metabolism and reactions to
any drug or combination of therapies.
• The tables may not be all-inclusive of drugs/brands that might be contraindicated or interact with methadone. Drugs That Are CONTRAINDICATED with Methadone (May Precipitate Opioid Withdrawal) Generic Name Brands/Examples Actions/Uses Notes/References
Can displace methadone on µ-opioid receptors
to cause withdrawal (DeMaria 2003; Kalvik et al.
Interaction displaces methadone on µ-opioid
receptors, causing severe withdrawal (DeMaria
2003; Kalvik et al. 1996, Strang 1999).
Potentially may cause withdrawal in personsalready taking opioids (Ultram PI 1998). Drugs That May Result in Altered Metabolism or Unpredictable Interactions in Combination with Methadone Generic Name Brands/Examples Actions/Uses Notes/References
metabolic pathway with methadone (Harrington
et al. 1999). May cause additive CNS depression
Interaction proposed due to common CYP3A4
pathway with methadone (Harrington et al. 1999).
Decrease in ddl concentration (Rainey et al.
2000). Effect not seen with enteric-coated ddl(Faragon and Piliero 2003; Friedland et al. 2002).
Increased levels/effects of dextromethorphan
increased (Schafer 2001; Sylvestre 2002).
Potential adverse reactions with methadone
Possible increase in nifedipine proposed (Levy
possible additive effects. Long-acting excitatory
metabolites of meperidine and propoxyphene
can reach toxic levels (Harrington et al. 1999).
Decrease in d4T concentration; no effect onmethadone (Rainey et al. 2000).
Combination with methadone increases TCA toxicity
(DeMaria 2003; Quinn et al. 1997; Richelsson 1997).
Mixed reports of methadone increase or decrease(Eap et al. 2002; Moolchan et al. 2001; Strang 1999).
methadone; more frequent AZT side effects are
possible (McCance-Katz et al. 1998). Drugs That May LOWER SML and/or DECREASE Methadone Effects Generic Name(s) Brands/Examples Actions/Uses Notes/References
Methadone level decreased; also reduces ABCpeak concentration (Gourevitch 2001).
CYP3A4 enzyme induction may decreasemethadone levels (Chrisman 2003; Eap et al. 2002). Amprenavir also may be reduced (Faragonand Piliero 2003)
phenobarbital can cause sharp decrease in
methadone (Gourevitch 2001). Methadone dose
withdrawal. Effect not predicted with valproate
(Depakote; Bochner 2000; Saxon et al. 1989).
Accelerates methadone elimination (Moolchanet al. 2001).
CYP3A4 enzyme inducer (Eap et al. 2002).
Due to CYP3A4 induction, methadone withdrawalis common and dose increase usually required(Eap et al. 2002, McCance-Katz et al. 2002).
P450 enzyme induction (Quinn et al. 1997).
CYP3A4 enzyme induction (Eap et al. 2002; Van
Decreases free fraction of methadone (Moolchanet al. 2001).
Withdrawal symptoms may occur requiringmethadone dose increase. Latest researchsuggests effect is not seen with ritonavir alone(Chrisman 2003; McCance-Katz et al. 2003).
CYP3A4 and PgP induction (Eap et al. 2002), butclinical withdrawal is rare (McCance-Katz et al. in press 2003). Interaction also may mildlydecrease nelfinavir (Chrisman 2003).
CYP3A4 enzyme induction may precipitate opioidwithdrawal (Eap et al. 2002).
Sharp decrease in methadone due to CYP3A4enzyme induction (Eap et al. 2002; Kreek 1986).
withdrawal reported (Eap et al. 2002; Kreek 1986). Effect not seen with rifabutin (Mycobutin:Gourevitch 2001; Levy et al. 2000).
Induces CYP 3A4; 47% decrease in methadone
(Eich-Höchli et al. 2003; Scot and Elmer 2002).
Some mixed reports, but most indicate reduced
effectiveness of methadone (Moolchan et al. 2001; Tacke et al. 2001).
Methadone is excreted by kidneys more rapidly
at lower pH (Nillson et al. 1982; Strang 1999). Drugs That May RAISE SML and/or INCREASE Methadone Effects Generic Name(s) Brands/Examples Actions/Uses Notes/References
P450 enzyme inhibitor (Bochner 2000; Strang
Inhibition of CYP3A4 and/or CYP1A2 enzymes(Eap et al. 2002; Herrlin et al. 2000).
Predicted effect due to CYP3A4 enzyme inhibition(Gourevitch 2001).
Mechanism undetermined (Eap et al. 2002) and
CYP3A4 enzyme inhibition (Van Beusekom andIguchi 2001).
Sedation noted with higher doses of disulfiram(Bochner 2000).
Competition for P450 enzymes (Quinn et al. 1997).
CYP3A4 enzyme inhibition (Eap et al. 2003);increased methadone levels (Gourvitch 2001);clinical significance uncertain (Levy et al. 2000).
Inhibits intestinal CYP3A4 (Hall et al. 1999) andPgP (Eap et al. 2002). This effect is not expectedwith other fruits/juices (Karlix 1990).
Predicted due to CYP3A4 enzyme inhibition (Eapet al. 2002).
Predicted due to strong inhibition of CYP3A4
enzyme. Cardiac and metabolic effects not
expected with azithromycin (Eap et al. 2002).
Expected due to CYP2D6 and/or CYP1A2 enzyme
Not studied specifically with methadone –
predicted potential effect due to strong CYP3A4
enzyme inhibition (Scott and Elmer 2002, Van
In animal studies, possibly affects methadone
Variable inhibition of CYP2D6 (primarily), CYP3A4,
CYP1A2 enzymes (Eap et al. 2002; Levy et al.
Alkaline (higher pH) urine decreases methadone
excretion by kidneys (Kalvik et al. 1996; Strang1999).
Predicted effect due to CYP450 enzyme inhibition
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 elevated methadone levels – alone or, more commonly, in combination with other drugs and/or cardiac risk factors – may contribute to cardiac repolarization disturbances (prolonged QTc interval and/or torsade de pointes; see Leavitt and Krantz 2003). AT Forum is published by Clinco Communications Inc., Mundelein, Illinois, and made possible by an educational A D D I C T I O N T R E A T M E N T grant from Mallinckrodt, Inc., a manufacturer of methadone. Stewart B. Leavitt, PhD, January 2004. References
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Written testimony of Jack Whelan in support of S.477 and S.439 The Honorable Senator Anthony Petruccelli and Representative Michael Costello Joint Committee on Financial Services State House - Commonwealth of Massachusetts Dear Chairmen Petruccelli and Costello and Members of the Committee: My name is Jack Whelan. I live in Andover and I’ve been a resident of Massachusetts my enti
CONTENTS Japanese Journal of Clinical Pharmacology and Therapeutics Special Articles Current Status and Defect on the Development of DDS Preparations Kanji TAKADA Original Investigation of Bioequivalence between MSG203 and Paxil®（Paroxetine HydrochlorideHydrate）after Single Oral Administration in Japanese Healthy Male Subjects：Detailed Study in Different CYP2D6 Phenotypes