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Methadone-Drug Interactions

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Methadone-Drug Interactions (PDF file size 784K)

Meds

Alphabetical Listing by Generic & Brand Names

Researched & Compiled by Stewart B. Leavitt, PhD, Editor, AT Forum
Sponsored by an educational grant from Mallinckrodt Inc.

How to Use This Booklet
Methadone is readily absorbed and then metabolized by several cytochrome P450 (CYP) enzymes (see Table). Other drugs/substances interacting with those same enzymes may affect methadone metabolism and the resulting serum methadone levels.

P450 Enzymes Metabolizing Methadone
CYP3A4	Primary metabolizing enzyme.
CYP2D6	Secondary role (methadone also can inhibit this enzyme in some cases).
CYP1A2 CYP2C9, CYP2C19	Possibly involved (clinical significance is still under investigation).
CYP2B6	Newly proposed as important.

Drugs/substances listed here include only those that have been mentioned in the published literature as definitely or possibly interacting with methadone. Some interactions are predicted as being probable based on case reports, laboratory experiments, or pharmacologic principles rather than clinical trials. Additional interactions might be possible, based on metabolic pathways of co-administered drugs, and manufacturers' literature might be consulted in that regard.

Principles worth remembering, include:

Just because certain drugs/substances can interact does not mean that they will, or indicate to what extent.
Methadone works best at adequate therapeutic doses; however, due to individual variability in methadone absorption and metabolism, it becomes difficult to predict in advance the effects of drug combinations and what adjustments might be necessary.
If a patient is responding unexpectedly or unfavorably to methadone a search for potentially interacting substances would be appropriate;
a comprehensive history from the patient can be important.
When an interaction is suspected, adjustments of medication dosages with followup monitoring, substitutions of non-interacting agents, or other therapeutic modifications might be made.
For additional information and resource references, see the special AT Forum White Paper, "Methadone-Drug Interactions," available online at: http://www.atforum.com/SiteRoot/pages/addiction_resources/Drug_Interactions.pdf

Symbols:
	=	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 see: http://QTdrugs.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 contribute to cardiac repolarization disturbances.

Drug/Substance	Effect With Methadone
abacavir (ABC)		Also decreases ABC peak concentration.
Adalat		Nifedipine increase proposed.
Agenerase		Also may decrease Agenerase (amprenavir).
Aldactone		CYP3A4 induction.
Alfenta		Common P450 pathway; possible additive effects with methadone.
alfentanil		Common P450 pathway; possible additive effects with methadone.
alprazolam		Potential interaction, additive CNS depression.
Alurate		Due to P450 enzyme induction.
amitriptyline		Possible increased TCA toxicity; uncertain effect on methadone.
amobarbital		Due to P450 enzyme induction.
amprenavir		Also may decrease amprenavir.
Amytal		Due to P450 enzyme induction.
Antabuse		Sedation reported.
aprobarbital		Due to P450 enzyme induction.
ascorbic acid		Due to more rapid urinary excretion.
Atretol		May cause opioid withdrawal.
Aurorix		Expected; CYP2D6 and CYP1A2 inhibition.
Aventyl		Possible increased TCA toxicity; uncertain effect on methadone.
barbiturates		Due to P450 enzyme induction.
benzodiazepines		Potential interaction, additive CNS depression.
Biaxin		Strong CYP3A4 inhibition.
Bicitra		Decreases methadone urinary excretion.
Buprenex		Displaces methadone on μ-opioid receptors.
buprenorphine		Displaces methadone on μ-opioid receptors.
butabarbital		Due to P450 enzyme induction.
butalbital		Due to P450 enzyme induction.
Butisol		Due to P450 enzyme induction.
butorphanol		Displaces methadone on μ-opioid receptors.
Calan		Predicted due to CYP450 inhibition.
cannabis		Proposed interaction, common P450 pathway.
carbamazepine		May cause opioid withdrawal.
Cat's claw		Predicted due to CYP3A4 inhibition.
Chamomile		Predicted due to CYP3A4 inhibition.
cimetidine		P450 enzyme inhibitor.
Cipro		CYP3A4 and/or CYP1A2 inhibition.
ciprofloxacin		CYP3A4 and/or CYP1A2 inhibition.
clarithromycin		Strong CYP3A4 inhibition.
clorazepate		Potential interaction, additive CNS depression.
cocaine		Methadone elimination accelerated.
coke (cocaine)		Methadone elimination accelerated.
Combivir		AZT concentration increased.
Covera-HS		Predicted due to CYP450 inhibition.
crack (cocaine)		Methadone elimination accelerated.
D.H.E.		CYP3A4 enzyme inhibition.
Dalgan		Displaces methadone on μ-opioid receptors
Dalmane		Potential interaction, additive CNS depression.
Darvon		Possible opioid additive effects; long-acting toxic metabolites.
Decadron		CYP3A4 induction.
delavirdine		Predicted due to CYP3A4 inhibition.
Delsym		Increased dextromethorphan effects proposed.
Demerol		Possible opioid additive effects; long-acting toxic metabolites.
Depade		Displaces methadone on μ-opioid receptors.
desipramine		Possible increased TCA toxicity; uncertain effect on methadone.
dexamethasone		CYP3A4 induction.
dextromethorphan		Increased dextromethorphan effects proposed.
dezocine		Displaces methadone on μ-opioid receptors.
diazepam		Effect sporadic, unknown mechanism.
didanosine (ddl buffered tab)		Decrease in ddl (effect not seen with enteric-coated).
Diflucan		CYP3A4 inhibition.
dihydroergotamine		CYP3A4 enzyme inhibition
Dilantin		Sharp decrease, CYP3A4 induction.
disulfiram		Sedation reported.
Dizac		Effect sporadic, unknown mechanism.
doxepin		Possible increased TCA toxicity; uncertain effect on methadone.
Duramorph		Common P450 pathway; possible additive effects with methadone.
E.E.S., Eryped		Strong CYP3A4 inhibition.
Echinacea		Predicted due to CYP3A4 inhibition.
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 P450 enzymes.
ethanol (chronic use)		P450 enzyme induction.
fentanyl		Common P450 pathway; possible additive effects with methadone.
Fioricet		Due to P450 enzyme induction.
Fiorinal		Due to P450 enzyme induction.
fluconazole		CYP3A4 inhibition.
fluoxetine		Variable P450 enzyme inhibition.
flurazepam		Potential interaction, additive CNS depression.
fluvoxamine		Variable P450 enzyme inhibition.
Fucidin		CYP3A4 induction.
fusidic acid (systemic)		CYP3A4 induction.
Goldenseal		Predicted due to CYP3A4 inhibition.
grapefruit		Inhibition of intestinal CYP3A4 and PgP.
Halcion		Potential interaction, additive CNS depression.
hash		Proposed interaction, common P450 pathway.
hemp		Proposed interaction, common P450 pathway.
heroin		Decreases methadone free fraction.
Hexadrol		CYP3A4 induction.
hydrastis canadensis		Predicted due to CYP3A4 inhibition.
hydrocodone		Common P450 pathway; possible additive effects with methadone.
Hypericum perforatum		Significant decrease; CYP 3A4 induction.
Ilosone		Strong CYP3A4 inhibition.
imipramine		Possible increased TCA toxicity; uncertain effect on methadone.
interferon-alfa + ribavirin		Side effects may mimic opioid withdrawal.
Isoptin		Predicted due to CYP450 inhibition.
Kaletra		Effect not seen with ritonavir alone.
ketoconazole		Predicted due to CYP3A4 inhibition.
K-Phos		Due to more rapid urinary excretion.
lopinavir + ritonavir		Effect not seen with ritonavir alone.
Lotusate		Due to P450 enzyme induction.
Luminal		Possibly sharp decrease in methadone.
Luvox		Variable P450 enzyme inhibition.
macrolide antibiotics		CYP3A4 inhibition (not azithromycin).
Manerix		Expected; CYP2D6 and CYP1A2 inhibition.
MAO (monoamine oxidase) inhibitors		Potential adverse interaction.
marijuana		Proposed interaction, common P450 pathway.
matricaria recutita		Predicted due to CYP3A4 inhibition.
Mebaral		Due to P450 enzyme induction.
meperidine		Possible opioid additive effects; long-acting toxic metabolites.
mephobarbital		Due to P450 enzyme induction.
midazolam		Potential interaction, additive CNS depression.
Migranal		CYP3A4 enzyme inhibition.
moclobemide		Expected; CYP2D6 and CYP1A2 inhibition.
morphine		Common P450 pathway; possible additive effects with methadone.
MS Contin		Common P450 pathway; possible additive effects with methadone.
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.
Narcan		Displaces methadone on μ-opioid receptors.
Nardil		Potential adverse interaction.
nefazodone		Variable P450 enzyme inhibition.
nelfinavir		Possible decrease also in nelfinavir.
Nembutal		Due to P450 enzyme induction.
nevirapine		Possible opioid withdrawal syndrome.
nifedipine		Nifedipine increase proposed.
Nizoral		Predicted due to CYP3A4 inhibition.
Norpramin		Possible increased TCA toxicity; uncertain effect on methadone.
nortriptyline		Possible increased TCA toxicity; uncertain effect on methadone.
Nubain		Displaces methadone on μ-opioid receptors.
omeprazole		Possibly affects methadone absorption.
opioid analgesics		Common P450 pathway; possible additive effects with methadone.
oxycodone		Common P450 pathway; possible additive effects with methadone.
OxyContin		Common P450 pathway; possible additive effects with methadone.
Pamelor		Possible increased TCA toxicity; uncertain effect on methadone.
Parnate		Potential adverse interaction.
paroxetine		Variable P450 enzyme inhibition.
Paxil		Variable P450 enzyme inhibition.
Pegasys		Side effects may mimic opioid withdrawal.
pegylated interferon		Side effects may mimic opioid withdrawal.
pentazocine		Displaces methadone on μ-opioid receptors.
pentobarbital		Due to P450 enzyme induction.
phenobarbital		Possibly sharp decrease in methadone.
phenobarbital		Due to P450 enzyme induction.
phenytoin		Sharp decrease, CYP3A4 induction.
Polycitra		Decreases methadone urinary excretion.
pot (marijuana)		Proposed interaction, common P450 pathway.
Prevpac		CYP3A4 inhibition (contains clarithromycin).
Prilosec		Possibly affects methadone absorption.
Procardia		Nifedipine increase proposed.
propoxyphene		Possible opioid additive effects; long-acting toxic metabolites
ProSom		Potential interaction, additive CNS depression.
protriptyline		Possible increased TCA toxicity; uncertain effect on methadone.
Prozac		Variable P450 enzyme inhibition.
quercetin		Predicted due to CYP3A4 inhibition.
Rebetron		Side effects may mimic opioid withdrawal.
Rescriptor		Predicted due to CYP3A4 inhibition.
Retrovir		AZT concentration increased.
Revex		Displaces methadone on μ-opioid receptors.
ReVia		Displaces methadone on μ-opioid receptors.
ribavirin + interferon-alfa		Side effects may mimic opioid withdrawal.
Rifadin		Possibly severe; P450 induction.
Rifamate		Possibly severe; P450 induction.
rifampicin		Possibly severe; P450 induction.
rifampin		Possibly severe; P450 induction.
rifampin/isoniazid		Possibly severe; P450 induction.
Rimactane		Possibly severe; P450 induction.
ritonavir + lopinavir		Effect not seen with ritonavir alone.
Robitussin		Increased dextromethorphan effects proposed.
scat (heroin)		Decreases methadone free fraction.
secobarbital		Due to P450 enzyme induction.
Seconal		Due to P450 enzyme induction.
sertraline		Variable P450 enzyme inhibition.
Serzone		Variable P450 enzyme inhibition.
Sinequan		Possible increased TCA toxicity; uncertain effect on methadone.
smack (heroin)		Decreases methadone free fraction.
sodium bicarbonate		Decreases methadone urinary excretion.
spironolactone		CYP3A4 induction.
SSRI antidep.		Variable P450 enzyme inhibition.
St. John's wort		Significant decrease; CYP3A4 induction.
Stadol		Displaces methadone on μ-opioid receptors.
stavudine (d4T)		Decreased d4T concentration.
Sublimaze		Common P450 pathway; possible additive effects with methadone.
Suboxone		Displaces methadone on μ-opioid receptors.
Subutex		Displaces methadone on μ-opioid receptors.
Surmontil		Possible increased TCA toxicity; uncertain effect on methadone.
Tagamet		P450 enzyme inhibitor.
talbutal		Due to P450 enzyme induction.
Talwin		Displaces methadone on μ-opioid receptors.
TAO		Expected due to CYP3A4 inhibition.
Tegretol		May cause opioid withdrawal.
tobacco		Possible; reports mixed.
Tofranil		Possible increased TCA toxicity; uncertain effect on methadone.
Touro DM		Increased dextromethorphan effects proposed.
tramadol		Potential withdrawal in persons taking opioids.
Tranxene		Potential interaction, additive CNS depression.
triazolam		Potential interaction, additive CNS depression.
tricyclic antidepressants (TCAs)		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 CYP3A4 inhibition.
Tuinal		Due to P450 enzyme induction.
Ultram		Potential withdrawal in persons taking opioids.
Uncaria tomentosa		Predicted due to CYP3A4 inhibition.
urinary acidifiers		Due to more rapid urinary excretion.
urinary alkalinizers		Decreases methadone urinary excretion.
Valium		Effect sporadic, unknown mechanism.
Valrelease		Effect sporadic, unknown mechanism.
verapamil		Predicted due to CYP450 inhibition.
Versed		Potential interaction, additive CNS depression.
Vicks (cough med)		Increased dextromethorphan effects proposed.
Vicodin		Common P450 pathway; possible additive effects with methadone.
Videx (ddl buffered tablet)		Decrease in ddl (effect not seen with enteric-coated).
Viracept		Possible decrease also in Viracept.
Viramune		Possible opioid withdrawal syndrome.
vitamin C (high dose)		Due to more rapid urinary excretion.
Vivactil		Possible increased TCA toxicity; uncertain effect on methadone.
wine, beer, whiskey (acute use)		Competition for P450 enzymes.
wine, beer, whiskey (acute use)		P450 enzyme induction.
Xanax		Potential interaction, additive CNS depression.
Zerit (d4T)		Decreased d4T concentration.
Ziagen		Also decreases Ziagen peak concentration.
zidovudine (AZT)		AZT concentration increased.
Zoloft		Variable P450 enzyme inhibition.

Published by:
Clinco Communications, Inc.
P.O. Box 685
Mundelein, IL 60060
www.atforum.com
Editor: Stewart B. Leavitt, PhD
Publisher: Sue Emerson

© 2004 Stewart B. Leavitt, PhD
Addiction Treatment Forum is made possible by an educational grant from Mallinckrodt Inc., a manufacturer of methadone and naltrexone.

April 2004