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Methadone-Drug* Interactions (PDF file size 169K)
(*Medications, illicit drugs, & other substances)

The Importance of Drug Interactions

Pharmacotherapy is increasingly complicated by the introduction of new drugs and the use of multidrug regimens for acute or chronic disease, which can result in clinically important drug interactions. A drug interaction occurs 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; Piscitelli and Rodvold 2001).

During clinical use spanning more than 35 years, oral methadone has proven to be a well-tolerated medication with minimal adverse reactions when prescribed in appropriate doses and taken daily as a component of methadone maintenance treatment (MMT; Kreek 1973; Novick et al. 1993). However, there are potential methadone-drug interactions – involving prescribed medications, illicit drugs, OTC products, and other substances – which sometimes can be difficult to predict, may be potentially harmful, and/or can lead to treatment failures (Harrington et al. 1999; Levy et al. 2000).

Metabolic Basics

Most drugs are foreign to the human body and are broken down (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 (CYP) enzymes, that facilitate those reactions. These enzymes evolved as a protective mechanism more than 3 billion years ago to cope with a growing number of environmental chemicals, food toxins, and drugs (Hardman et al. 1996; Richelson 1997).

There are more than 28 CYP enzymes encoded by different genes (Flexner and Piscitelli 2000; Shannon 1997). Each is designated by a combination of numbers and letters: for example, 3A4 and 2D6 which are important in methadone metabolism. CYP enzymes reside mainly in the liver, but also may be present in other organs.

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 produce extremely low drug levels (Flexner and Piscitelli 2000).

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, and inhibitors; such as at http://drug-interactions.com (Flockhart 2003).

Methadone Metabolism

Methadone is usually readily absorbed, with about 80% of the administered dose passing into the bloodstream during stabilized MMT and the remainder metabolized in the GI tract and liver; although, for reasons described below, absorption can range from 35% to 100% (Eap et al. 2002, Moolchan et al. 2001). The three formulations of oral methadone used in MMT – solid tablets, dispersible tablets, and premixed liquid – have been demonstrated as intrinsically equal in terms of their absorption and metabolism (Gourevitch et al. 1999); however, patient reactions to each formulation may vary, possibly due to psychosomatic factors in some cases.

Methadone is metabolized primarily by CYP3A4, secondarily by CYP2D6, and to a smaller extent by CYP1A2 and additional enzymes that are under study (see Table).

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 (Leavitt et al. 2000). This enzyme also is found in the gastrointestinal tract, so methadone metabolism actually begins 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 variable breakdown of methadone (Levy et al. 2000).

Another metabolic protein of some importance is P-glycoprotein (P-gp), which is found in the intestine and other tissues (Matheny et al. 2001). 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).

Drugs that induce the activity of enzymes involved in methadone metabolism can accelerate its breakdown, abbreviate the duration of methadone’s effects, lower the serum methadone level (SML), and possibly precipitate an abstinence (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 can act on certain enzymes to affect methadone metabolism. For example, CYP2D6 is entirely absent in a small proportion of the population, 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 in CYP-enzyme presence and activity means that SMLs can vary 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 this 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, the time course of sign/symptom development can be a guide as to whether enzyme induction or inhibition is involved. Overmedication reactions developing within a few days after concurrent drug administration are likely due to CYP inhibition. In contrast, CYP induction may take a week or much longer to emerge, producing withdrawal signs/symptoms (Antoniou and Tseng 2002; Faragon and Piliero 2003; Gourevitch and Friedland 2000; Wolff et al. 2000).

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 in the days following to cause withdrawal that requires increased methadone. Conversely, if a CYP inducer is discontinued, 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 and have little to do with altered drug metabolism. For example, the additive effects of methadone when combined with other central nervous system (CNS) depressants may cause hypotension, sedation, respiratory depression, or coma (Leavitt 2003; Methadose PI 2000). Also, polysubstance abuse in MMT patients may put them at greater risk of adverse additive interactions with other 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). Although the clinical significance of this is still under investigation, 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 MMT 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). Several points might be kept in mind (Kramer 2000):

Just because certain drugs can interact does not mean that they will, or indicate to what extent.
If a patient is responding unexpectedly or unfavorably to methadone – with signs/symptoms of under- or overmedication – a search for potentially interacting substances (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.
When an interaction is suspected, adjustments of medication dosages with followup monitoring, substitutions of non-interacting agents, or other therapeutic modifications might be made.

The Tables on the inside three pages list substances specifically mentioned in the scientific literature that either: A) should be avoided with methadone, B) raise or lower SMLs and/or increase/decrease methadone’s effects, or C) are themselves altered by their combination with methadone. There have been a limited number of clinical studies investigating methadone interactions with specific drugs; therefore, some interactions are predicted as being probable based on case reports, laboratory experiments, 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
buprenorphine, butorphanol, dezocine, nalbuphine, pentazocine	Buprenex, Subutex, Suboxone, Stadol, Dalgan, Nubain, Talwin	Analgesics with some opioid-antagonist activity.	Can displace methadone on µ-opioid receptors to cause withdrawal (DeMaria 2003; Kalvik et al. 1996).
opioid antagonists – naltrexone, nalmefene, naloxone	Depade, ReVia, Revex, Narcan	Treatment of alcoholism, or blockade or reversal of opioid effects.	Interaction displaces methadone on µ-opioid receptors, causing severe withdrawal (DeMaria 2003; Kalvik et al. 1996, Strang 1999).
tramadol	Ultram	Synthetic analgesic.	Potentially may cause withdrawal in persons already 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
benzodiazepines – alprazolam, alorazepate, estazolam, flurazepam, midazolam, triazolam	Xanax, Tranxene, ProSom, Dalmane, Versed, Halcion	Sedatives.	Potential interaction due to common P450 metabolic pathway with methadone (Harrington et al. 1999). May cause additive CNS depression (Strang 1999).
cannabis	Marijuana, hash, hemp, pot	Psychotropic agent.	Interaction proposed due to common CYP3A4 pathway with methadone (Harrington et al. 1999).
didanosine (ddl, buffered tablet)	Videx	NRTI antiretroviral.	Decrease in ddl concentration (Rainey et al. 2000). Effect not seen with enteric-coated ddl (Faragon and Piliero 2003; Friedland et al. 2002).
dextromethorphan	Robitussin, Vicks, Delsym, Touro DM	Cough medicine.	Increased levels/effects of dextromethorphan proposed (Levy et al. 2000).
interferon-alfa + ribavirin	Rebetron (possibly also pegylated interferon, e.g., Pegasys)	Antihepatitis C treatment.	Side effects can mimic opioid withdrawal symptoms and methadone dose is often increased (Schafer 2001; Sylvestre 2002).
monoamine oxidase (MAO) inhibitors	Nardil, Parnate, others	Antidepressants.	Potential adverse reactions with methadone (Methadose PI 2000).
nifedipine	Procardia, Adalat	Cardiac medication (Ca-channel blocker).	Possible increase in nifedipine proposed (Levy et al. 2000; Strang 1999).
opioids – alfentanil, hydrocodone, fentanyl, meperidine, morphine, oxycodone, propoxyphene	Alfenta, Vicodin, Sublimaze, Demerol, Duramorph, MS Contin, OxyContin, Darvon	Analgesics.	Common P450 pathways with methadone; possible additive effects. Long-acting excitatory metabolites of meperidine and propoxyphene can reach toxic levels (Harrington et al. 1999).
stavudine (d4T)	Zerit	NRTI antiretroviral.	Decrease in d4T concentration; no effect on methadone (Rainey et al. 2000).
TCAs – amitriptyline, desipramine, imipramine, nortriptyline	Elavil, Norpramin, Tofranil, Pamelor, others	Tricyclic antidepressants (TCAs).	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).
zidovudine (AZT)	Retrovir, AZT combinations (e.g., Combivir, Trizivir)	NRTI antiretroviral.	AZT concentration increased 40% with 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	Brands/Examples	Actions/Uses	Notes/References
abacavir (ABC)	Ziagen	NRTI antiretroviral.	Methadone level decreased; also reduces ABC peak concentration (Gourevitch 2001).
amprenavir	Agenerase	PI antiretroviral.	CYP3A4 enzyme induction may decrease methadone levels (Chrisman 2003; Eap et al. 2002). Amprenavir also may be reduced (Faragon and Piliero 2003)
barbiturates – butabarbital, mephobarbital, phenobarbital, pentobarbital, secobarbital, others	Butisol, Mebaral, Nembutal, Phenobarbital, Seconal, others	Barbiturate sedatives and/or hypnotics.	P450 enzyme induction (Kreek 1986); phenobarbital can cause sharp decrease in methadone (Gourevitch 2001). Methadone dose increase usually required.
carbamazepine	Atretol, Tegretol	Anticonvulsant for epilepsy and trigeminal neuralgia.	Strong CYP3A4 enzyme induction may cause withdrawal. Effect not predicted with valproate (Depakote; Bochner 2000; Saxon et al. 1989).
cocaine	Crack, coke, others	Illicit stimulant.	Accelerates methadone elimination (Moolchan et al. 2001).
dexamethasone	Decadron, Hexadrol	Corticosteroid.	CYP3A4 enzyme inducer (Eap et al. 2002).
efavirenz	Sustiva	NNRTI antiretroviral.	Due to CYP3A4 induction, methadone withdrawal is common and dose increase usually required (Eap et al. 2002, McCance-Katz et al. 2002).
ethanol (chronic use)	Wine, beer, whiskey, etc.	Euphoric, sedative.	P450 enzyme induction (Quinn et al. 1997).
fusidic acid	(systemic steroidal)	Antibacterial.	CYP3A4 enzyme induction (Eap et al. 2002; Van Beusekom and Iguchi 2001).
heroin	Smack, scat, others	Illicit opioid.	Decreases free fraction of methadone (Moolchan et al. 2001).
lopinavir + ritonavir	Kaletra	PI antiretroviral.	Withdrawal symptoms may occur requiring methadone dose increase. Latest research suggests effect is not seen with ritonavir alone (Chrisman 2003; McCance-Katz et al. 2003).
nelfinavir	Viracept	PI antiretroviral.	CYP3A4 and PgP induction (Eap et al. 2002), but clinical withdrawal is rare (McCance-Katz et al. in press 2003). Interaction also may mildly decrease nelfinavir (Chrisman 2003).
nevirapine	Viramune	NNRTI antiretroviral.	CYP3A4 enzyme induction may precipitate opioid withdrawal (Eap et al. 2002).
phenytoin	Dilantin	Control of seizures.	Sharp decrease in methadone due to CYP3A4 enzyme induction (Eap et al. 2002; Kreek 1986).
rifampin (rifampicin) and rifampin/isoniazid	Rifadin, Rimactane Rifamate	Treatment of pulmonary tuberculosis.	Induces P450 enzymes; cases of severe withdrawal reported (Eap et al. 2002; Kreek 1986). Effect not seen with rifabutin (Mycobutin: Gourevitch 2001; Levy et al. 2000).
spironolactone	Aldactone	K+ -sparing diuretic.	CYP3A4 induction (Eap et al. 2002).
St. John’s wort (Hypericum perforatum)	Ingredient in various OTC products	Herb used as antidepressant.	Induces CYP 3A4; 47% decrease in methadone (Eich-Höchli et al. 2003; Scot and Elmer 2002).
tobacco	Various brands	Habitual smoking.	Some mixed reports, but most indicate reduced effectiveness of methadone (Moolchan et al. 2001; Tacke et al. 2001).
urinary acidifiers (e.g., ascorbic acid)	Vitamin C (large doses); K-Phos	Dietary supplement; keeps calcium soluble.	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	Brands/Examples	Actions/Uses	Notes/References
cimetidine	Tagamet	H`2`-receptor antagonist for GI disorders.	P450 enzyme inhibitor (Bochner 2000; Strang 1999).
ciprofloxacin	Cipro	Quinolone antibiotic.	Inhibition of CYP3A4 and/or CYP1A2 enzymes (Eap et al. 2002; Herrlin et al. 2000).
delavirdine	Rescriptor	NNRTI antiretroviral.	Predicted effect due to CYP3A4 enzyme inhibition (Gourevitch 2001).
diazepam	Dizac, Valium, Valrelease	Control of anxiety and stress.	Mechanism undetermined (Eap et al. 2002) and effect sporadic (Levy et al. 2000).
dihydroergotamine	D.H.E., Migranal	Migraine treatment.	CYP3A4 enzyme inhibition (Van Beusekom and Iguchi 2001).
disulfiram	Antabuse	Alcoholism treatment.	Sedation noted with higher doses of disulfiram (Bochner 2000).
ethanol (acute use)	Wine, beer, whiskey, etc.	Euphoric, sedative.	Competition for P450 enzymes (Quinn et al. 1997).
fluconazole	Diflucan	Anti-fungal antibiotic.	CYP3A4 enzyme inhibition (Eap et al. 2003); increased methadone levels (Gourvitch 2001); clinical significance uncertain (Levy et al. 2000).
grapefruit	juice or whole fruit	Food.	Inhibits intestinal CYP3A4 (Hall et al. 1999) and PgP (Eap et al. 2002). This effect is not expected with other fruits/juices (Karlix 1990).
ketoconazole	Nizoral	Anti-fungal agent.	Predicted due to CYP3A4 enzyme inhibition (Eap et al. 2002).
macrolide antibiotics – erythromycin, clarithromycin	EES, Erythrocin, Biaxin	Anti-infective.	Predicted due to strong inhibition of CYP3A4 enzyme. Cardiac and metabolic effects not expected with azithromycin (Eap et al. 2002).
moclobemide	Aurorix, Manerix	MAO-inhibitor (antidepressant).	Expected due to CYP2D6 and/or CYP1A2 enzyme inhibition (Eap et al. 2002).
“natural” supplements – uncaria tomentosa, matricaria recutita, echinacea angustifolia, hydrastis canadensis, quercetin	Cat’s claw, Chamomile, Echinacea, Goldenseal (may be ingredient in various product brands)	Herbal products used for gastrointestinal therapy, immune system enhancement, others.	Not studied specifically with methadone – predicted potential effect due to strong CYP3A4 enzyme inhibition (Scott and Elmer 2002, Van Beusekom and Iguchi 2001).
omeprazole	Prilosec	Treatment of acid-related GI disorders.	In animal studies, possibly affects methadone absorption (Strang 1999).
SSRIs – fluoxetine, fluvoxamine, paroxetine, nefazodone, sertraline	Prozac, Luvox, Paxil, Serzone, Zoloft	Treatment of depression and compulsive disorders.	Variable inhibition of CYP2D6 (primarily), CYP3A4, CYP1A2 enzymes (Eap et al. 2002; Levy et al. 2000; Richelson 1997).
troleandomycin	TAO	Antibiotic (similar to erythromycin).	Expected due to CYP3A4 enzyme inhibition (Beusekom and Iguchi 2001).
urinary alkalinizers (e.g., sodium bicarbonate)	Bicitra, Polycitra	Treatment of kidney stones, gout therapy.	Alkaline (higher pH) urine decreases methadone excretion by kidneys (Kalvik et al. 1996; Strang 1999).
verapamil	Calan, Covera-HS, Isoptin	Cardiac drug (Ca ++ -channel blocker).	Predicted effect due to CYP450 enzyme inhibition (Levy et al. 2000).
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).

References

Antoniou T, Tseng AL. Interactions between recreational drugs and antiretroviral agents. Ann Pharmacother. 2002;36:1598-1613.

Bochner F. Drug interactions with methadone: pharmacokinetics. In Hummeniuk R, Ali R, White J, Hall W, Farrell M. Proceeding of Expert Workshop on the Induction and Stabilisation of Patients Onto Methadone. Monograph Series 39.

Canberra: Commonwealth of Australia; 2000: 93-110. Available at: http://www.health.gov.au.

Borg L, Kreek MJ. The pharmacology of opioids. In Graham AW, et al. (eds). Principles of Addiction Medicine. 3rd ed. Chevy Chase MD: American Society of Addiction Medicine; 2003: 141-153.

Chrisman CR. Protease inhibitor-drug interactions: proceed with caution. J Critical Illness. 2003;18(4):185-188.

DeMaria Jr PA. Methadone drug interactions. J Maint Addict. 2003;2(3):69-74.

Dresser GK, Spence DJ, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38(1):41-57.

Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-1193.

Eich-Höchli D, Oppliger R, Golay KP, Baumann P, Eap CB. Methadone maintenance treatment and St. John’s wort. Pharmacopsychiatry. 2003;36:35-37.

Faragon JJ, Piliero P. Drug interactions associated with HAART: Focus on treatments for addiction and recreational drugs. AIDS Read. 2003;13(9):433-450.

Flexner C, Piscitelli SC. Managing drug-drug interactions in HIV disease. Medscape. 2000.

Flockhart D. Cytochrome P450 drug interaction table: Indiana University School of Medicine. Available at: http://drug-interactions.com. Updated April 11, 2003.

Friedland G, Rainey P, Jatlow P, Andrews L, Damle B, McCance-Katz E. Pharmacokinetics (pK) of didanosine (ddI) from encapsulated enteric coated bead formulation (EC) vs chewable tablet formulation in patients (pts) on chronic methadone therapy. Paper presented at: 14th International AIDS Conference; July 7-12, 2002; Barcelona, Spain

Gerber JG. Interactions between methadone and antiretroviral medications. Paper presented at: 3rd International Workshop on Clinical Pharmacology of HIV Therapy [NIDA-sponsored]; April 13, 2002; Washington, DC. Available at: http://www.drugabuse.gov/MeetSum/CPHTWorkshop/Gerber.html.

Gourevitch MN, Friedland GF. Interactions between methadone and medications used to treat HIV infection: a review. Mt Sinai J Med. 2000;67(5-6):429-436.

Gourevitch MN, Hartel D, Tenore P, et al. Three oral formulations of methadone. A clinical and pharmacodynamic comparison. J Subst Abuse Treat. 1999;17(3):237-241.

Gourevitch MN. Interactions between HIV-related medications and methadone: an overview. Mt Sinai J Med. 2001;68(3):227-228.

Hall SD, Thummel KE, Watkins PB. Molecular and physical mechanisms of first-pass extraction. Drug Metab Disp. 1999;27(2):161-166.

Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (eds). Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:3-63.

Harrington RD, Woodward JA, Hooton TM, Horn JR. Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and g-hydroxybutyrate. Arch Intern Med. 1999;159:2221-2224.

Herrlin K, Segerdahl M, Gustafsson LL, Kalso E. Methadone, ciprofloxacin, and adverse drug reactions [letter]. Lancet. 2000;356(9247).

Kalvik A, Isaac P, Janecek E. Help for heroin dependence: what pharmacists need to know about methadone maintenance therapy. Pharmacy Practice. 1996;12(10):43-54.

Karlix J. Pharmacists Corner [untitled discussion on fruit juice and medication levels in blood serum]. Prescription Plus. Ronkonkoma, NY: Lifecare Pharmaceuticals Services; 1990:15.

Kramer TAM. Polypharmacy. Medscape Mental Health. 2000;5(3). Available at: http://www.medscape.com.

Kreek MJ. Drug interactijons with methadone in humans. In: Braude MC, Ginzburg HM (eds). Strategies for Research on the Interactions of Drugs of Abuse. NIDA Research Monograph 68. 1986:193-225.

Kreek MJ. Medical safety and side effects of methadone in tolerant individuals. JAMA. 1973;223:665-668.

Leavitt SB, Krantz MJ. Cardiac Safety in MMT. Addiction Treatment Forum. Special Report; 2003. Available at: http://www.atforum.com/SiteRoot/pages/rxmethadone/cardiacmmt.shtml.

Leavitt SB. Methadone dosing and safety in the treatment of opioid addiction. Addiction Treatment Forum. Special Report. 2003. Available at: http://www.atforum.com/SiteRoot/pages/addiction_resources/DosingandSafetyWP.pdf.

Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P. When ‘enough’ is not enough: new perspectives on optimal methadone maintenance dose. Mt Sinai J Med. 2000;67(5-6):404-411.

Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M (eds). Metabolic Drug Interactions. Philadelphia, PA: Lippincott Williams & Wilkins; 2000.

Matheny CJ, Lamb MW, Brouwer KLR, Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy. 2001;21(7):778-796.

McCance-Katz EF, Gourevitch MN, Arnsten J, et al. Modified directly observed therapy (MDOT) for injection drug users with HIV disease. Am J Addict. 2002;11(4):271-278.

McCance-Katz EF, Jatlow P, Rainey P, Friedland G. Methadone effects on zidovudine (AZT) disposition (ACTG 262). J Acquir Immune Defic Syn Hum Retrovirol. 1998;18:435-443.

McCance-Katz EF, Rainey PM, Friedland G, Jatlow P. The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients. CID. 2003;37(4):476-482.

McCance-Katz EF, Rainey PM, Smith P, et al. Drug interactions between opioid and antiretroviral medications: Interaction between methadone, LAAM, and nelfinavir. Am J Addictions. In press 2003.

Methadose® Oral Concentrate [PI]. St. Louis, MO: Mallinckrodt Inc; 2000.

Moolchan ET, Umbricht A, Epstein D. Therapeutic drug monitoring in methadone maintenance: choosing a matrix. J Addict Dis. 2001;20(2):55-73.

Nillson MI, et al. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharm. 1982;22:337-342.

Novick DM, Richman BL, Friedman JM, et al. The medical status of methadone maintained patients in treatment for 11-18 years. Drug Alcohol Dep. 1993;33:235-245.

Payte JT, Zweben JE, Martin J. Opioid maintenance treatment. In: Graham AW, Schultz TK, Mayo-Smith MF, Ries RK, Wilford BB (eds). Principles of Addiction Medicine. Chevy Chase, MD: American Society of Addiction Medicine; 2003.

Piscitelli SC, Rodvold KA (eds). Drug Interactions in Infectious Diseases. Totowa, NJ: Humana Press; 2001.

Quinn DI, Wodak A, Day RO. Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment of illicit drug users. Clin Pharmacokinet. 1997;33(5):344-400.

Rainey PM, Friedland G, McCance-Katz EF, et al. Interaction of methadone with didanosine and stavudine. J Acquir Immune Defic Syndr. 2000;24(3):241-248.

Richelson E. Pharmacokinetic drug interactions of new antidepressants: a review of the effects on metabolism of other drugs. Mayo Clin Proc. 1997;72:835-847.

Saxon AJ, Wittaker S, Hawker SC. Valproic acid, unlike other anticonvulsants, has no effect on methadone maintenance: two cases. J Clin Psychiatry. 1989;50:228-229.

Scott GN, Elmer GW. Update on natural product-drug interactions. Am J Health Syst Pharm. 2002;59(4):339-347.

Schütz M. Quick reference guide to antiretrovirals. Medscape HIV/AIDS [online]. June 1, 2002.

Schafer M. Psychiatric patients, methadone patients, and earlier drug users can be treated for HCV when given adequate support services. Presentation at: Digestive Disease Week, May 20-23, 2001; Atlanta, Georgia.

Shannon M. Drug-drug interactions and the cytochrome P450 system: an update. Ped Emergency Care. 1997;13(5):350-353.

Strang J (chair). Drug Misuse and Dependence - Guidelines on Clinical Management. The Scottish Office Department of Health. Welsh Office and the Department of Health and Social Services: Norwich, UK; 1999. Available at: http://www.doh.gov.uk/drugdep.htm.

Sylvestre DL. Treating hepatitis C in methadone maintenance patients: an interval analysis. Drug Alcohol Dep. 2002;67(2):117-123.

Tacke U, Wolff K, Finch E, Strang J. The effect of tobacco smoking on subjective symptoms of inadequacy (“not holding”) of methadone dose among opiate addicts in methadone maintenance treatment. Addict Biol. 2001;6(2):137-145. http://www.doh.gov.uk/drugdep.htm

Ultram® [tramadol HCL package insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc; 1998.

Van Beusekom I, Iguchi MY. A Review of Recent Advances in Knowledge About Methadone Maintenance Treatment. Cambridge, UK: Rand Europe; 2001. Available at: http://www.rand.org/publications/MR/MR1396/.

Wolff K, Rostami-Hodjegan A, Hay AWM, Raistrick D, Tucker G. Population-based pharmacokinetic approach for methadone monitoring of opiate addicts: potential clinical utility. Addicion. 2000;95(12):1771-1783.

Woosley RL. Drugs that prolong the QT interval and/or induce torsades de pointes. Updated May 24, 2003. University of Arizona Center for Education and Research on Therapeutics (CERT). Available at: http://www.QTDrugs.org.

Wu D, Otton SV, Sproule BA, et al. Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br J Clin Pharmacol. 1993;35(1):30-34.