The American Journal of Drug and Alcohol Abuse, 37:111, 2011Copyright Informa Healthcare USA, Inc.ISSN: 0095-2990 print / 1097-9891 onlineDOI: 10.3109/00952990.2010.540279

FULL REVIEW

Pharmacokinetic drug interactions and adverse consequencesbetween psychotropic medications and pharmacotherapy forthe treatment of opioid dependence

Ali S. Saber-Tehrani, M.D., Robert Douglas Bruce, M.D., M.A., M.Sc. and Frederick L. Altice,M.D, M.A.

Yale University AIDS Program, Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine,Yale University, New Haven, CT, USA

Background: Psychiatric comorbidities amongopioid-dependent patients are common. Manymedications used to treat both conditions aremetabolized through complimentary cytochromeP450 isoenzymes. When medication-assistedtreatment for opioid dependence is concurrently usedwith psychotropic medications, problematicpharmacokinetic drug interactions may occur.Methods: We reviewed relevant English languagearticles identified through the MedLine, Scopus, andEmbase databases from 1950 to December 2009 usingthe specific generic names of medications andkeywords such as pharmacokinetics and druginteractions with buprenorphine, methadone, andnaltrexone. Selected references from these articleswere reviewed. Additionally, a review was conductedof abstracts and conference proceedings from nationaland international meetings from 1990 to 2009. A totalof 60 studies were identified and reviewed. Results:Clinical case series and carefully controlledpharmacokinetic interaction studies have beenconducted between methadone, buprenorphine, ornaltrexone and some psychoactive medications.Important pharmacokinetic drug interactions havebeen demonstrated within each class of medicationsaffecting either methadone and buprenorphine orpsychoactive drugs. Few studies, however, have beenconducted with naltrexone. Conclusions and ScientificSignificance: Several interactions between methadone,buprenorphine, or naltrexone and psychoactivemedications are described and may have important

Address correspondence to: Frederick L. Altice, Yale AIDS Program, Section of Infectious Diseases, Department of Internal Medicine, YaleSchool of Medicine, Yale University, 135 College Street, Suite 323, New Haven, CT 06510, USA. Tel: +203 737 2883. Fax: +203 7374051. E-mail: frederick.altice@yale.edu

clinical consequences. To optimize care, cliniciansmust be alerted to these interactions.

Keywords: methadone, buprenorphine, naltrexone, psychoactivemedications, drug interactions

INTRODUCTION

Opioid dependence remains a major global health issuethat is associated with significant negative medical andsocial consequences. Methadone, buprenorphine, and nal-trexone are evidence-based pharmacological treatmentsfor opioid dependence and have consistently been demon-strated to be safe and effective. Although pharmacoki-netic interactions between pharmacological therapiesfor opioid dependence and HIV therapies have beenreviewed, there remains a paucity of information in theinteractions between these therapies and the treatmentof a more prevalent condition, mental illness (1,2). Theprevalence of comorbid psychiatric illnesses is manytimes greater among patients with opioid dependencethan among the general population, thus requiring con-comitant treatment for both conditions (co-occurring dis-orders) to achieve optimal outcomes. Despite this urgentclinical need, continued concerns regarding the misuse ofmethadone or buprenorphine when combined with otherpsychotropic medications persist (1).

Methadone-maintained patients are often concomi-tantly prescribed psychotropic medications because ofthe high prevalence of psychiatric comorbidity observedamong individuals with opioid dependence (35).Furthermore, some psychotropic medications have the

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potential for abuse and there are reports in the literaturethat some methadone-maintained patients may abuse orbe prescribed by a clinician a psychoactive medicationsuch as benzodiazepines (6), selective serotonin reuptakeinhibitors (SSRIs) (79), antipsychotics (10), tricyclicantidepressants (11), and others that have been associatedwith altered metabolism or synergistic toxicities (e.g.,prolongation of the QT interval) with medication-assistedtherapy, such as methadone.

Case series, for example, from methadone mainte-nance programs suggest that approximately one-thirdof patients use benzodiazepines in any given month(1214). Although these medications are sometimes pre-scribed for the treatment of anxiety disorders in patients,they are frequently taken in excess of prescribed dosesor purchased for self-consumption (6,15). Although theetiology of this use is diverse, potential explanationsinclude the high level of underlying anxiety disorderssuch as post-traumatic stress disorder or self-managementof concomitant stimulant use (15). More concerning isthat benzodiazepines have been identified in 5080% ofheroin-related deaths (16), in 63.7% of methadone-relateddeaths (17), and in up to 80% of buprenorphine-relateddeaths (18).

Appropriate clinical use of these medications requiresan understanding of the principles of both pharmacokinet-ics and pharmacodynamics. Pharmacokinetics, describedas what the body does to the drug, includes pro-cesses such as absorption, distribution, localization intissues, biotransformation, and excretion, whereas phar-macodynamics, or what the drug does to the body,refers to the physiological effects of a drug and thebodys compensatory homeostatic adjustments to thepresence of the drug (19). Given the potential forthe serious adverse events, it is important to betterunderstand the relative safety of methadone, buprenor-phine, and naltrexone when taken in combination withother psychoactive drugs. We therefore review theclinical and pharmacokinetic data between the treat-ments for opioid dependence (methadone, buprenorphine,and naltrexone) and a list of broadly prescribed psy-chotropic medications that may be commonly coadmin-istered.

METHODS

We reviewed relevant English language articles identi-fied through the MedLine, Scopus, and Embase databasesfrom 1950 to December 2009 using specific medica-tion names and keywords such as pharmacokinetic ordrug interactions and buprenorphine, methadone, and nal-trexone. Selected references from these articles werereviewed. Additionally, abstracts and conference pro-ceedings from national and international meetings from1991 to 2009 were reviewed using conference proceed-ings citation index provided by Web of Science. A totalof 60 studies were identified and reviewed.

Methadone, Buprenorphine, and NaltrexoneMetabolismDetailed metabolism of each of these medications hasbeen reported previously (2,20). Briefly, methadoneundergoes oxidative metabolism through multiplecytochrome P450 isoenzymes, including CYP 2B6, 3A4,2C19, 2D6, and 2C8 (2124). Methadone is a racemicmixture of R and S enantiomers, of which (R)-methadoneis the most active compound (25). Metabolism at CYP2B6 and CYP 2C19 is stereo-selective, and this mayexplain why the plasma concentration ratio of R/S-methadone is variable (22,26). Methadone is metabolizedto an inactive metabolite a risk for opioid withdrawalwhen given with inducing medications. The two mostimportant dose-dependent adverse effects of methadoneare respiratory depression and cardiac rhythm disordersrelated to QT interval prolongation (27) with, in somecases, sudden death through polymorphic ventriculartachycardias such as torsade de pointes (28).

Buprenorphine is N-dealkylated to norbuprenorphineprimarily by CYP 3A4 and CYP 2C8 (2931). Bothbuprenorphine and norbuprenorphine are glucuronidatedby uracil diphosphateglucuronosyl transferases (UGTs).The role and importance of UGT has been describedpreviously (3239). Although there were limitations tosome of these reports (34), such as not being con-ducted under predefined conditions that compare one iso-form to another, other studies conducted under uniformconditions provide further insight into UGTs pharma-cological mechanisms with buprenorphine (38,39). Forexample, UGT 1A8 does not appear to be involvedin the glucuronidation of either buprenorphine or nor-buprenorphine (38,39). Buprenorphine glucuronidationis, however, principally glucuronidated by UGT 1A3with less involvement by 2B6 and 1A1 and much lessinvolvement by 2B17. Norbuprenorphine glucuronida-tion is also principally glucuronidated by UGT 1A3with less involvement from 1A1 and much less from2B17 and 2B7 (38,39). The relative lack of metabolismof norbuprenorphine by UGT 2B7 is a major differ-ence between parent compound and oxidative metabo-lite. Two in vitro studies suggest that buprenorphineand its major active metabolite norbuprenorphine areinhibitors of CYP 2D6 and CYP 3A4; however, becauseof relatively high dissociation constant (K i) for inhibi-tion, they are not predicted to cause clinically importantdrug interactions with other drugs metabolized by majorhepatic P450 isoenzymes at therapeutic concentrations(40,41).

Naltrexone, available in both oral and injectableformulations, is highly bioavailable orally (42) andis not metabolized through cytochrome P450 isoen-zymes. Instead, it is predominantly reduced to 6--naltrexol hepatically by dihydrodiol dehydrogenase(43,44). Conjugated naltrexone and conjugated 6--naltrexol are then excreted in the urine (42). There arereports of liver toxicity caused by naltrexone (45,46).Clinicians should keep this fact in mind when they pre-scribe naltrexone with other medications associated with

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METHADONE AND BUPRENORPHINE INTERACTIONS 3

potential liver toxicity. With the exception of diazepam,there is little, if any, expected pharmacokinetic interac-tions with naltrexone. There are, however, case reports ofinteractions between thioridazine and naltrexone (47).

Benzodiazepine MetabolismBenzodiazepines are conjugated hepatically by multipleUGT enzymes to form pharmacologically inactive, water-soluble glucuronide metabolites that are then excretedin the urine. The 3-hydroxy benzodiazepines, oxazepam,lorazepam, and temazepam, by virtue of their 3-hydroxygroup, can be conjugated directly. The 2-keto benzo-diazepines, such as chlordiazepoxide, clorazepate, anddiazepam, must first be oxidatively metabolized into 3-hydroxy derivatives before they can be conjugated. The7-nitro benzodiazepines, clonazepam and nitrazepam, aremetabolized by reduction of the 7-nitro substituents toform inactive amines that are then acetylated beforeexcretion (19).

Other studies have indicated that CYP 2C19 isinvolved in the metabolism of diazepam, and CYP 3A4is involved in the metabolism of alprazolam, clonazepam,midazolam, and triazolam (4854). Flunitrazepam is alsometabolized by CYP 3A4 in humans (48).

Benzodiazepine InteractionsThe epidemiology of benzodiazepine use among opioid-dependent persons and the interactions between benzodi-azepines with methadone or buprenorphine have recentlybeen reviewed by Lintzeris et al. (55).We therefore limitour review on this topic and only provide explanatorymechanisms essential for understanding these interac-tions.

Benzodiazepine Interactions with MethadoneSafety concerns about benzodiazepines and methadonecoadministration (5557), including potentially fatal cen-tral nervous system (CNS) depression, are raised bypractitioners and policy-makers alike (58). During coad-ministration, the CNS depressive effects may be moresynergistic than additive. Data regarding interactionsbetween benzodiazepines and methadone are varied, inpart due to the use of in vitro animal studies and nonther-apeutic doses of medication. Diazepam has been studiedmost for its interactions with methadone (57,5961). Onein vitro study (24) demonstrating competitive inhibitionof diazepam on methadone N-demethylation was limitedby supratherapeutic dosing confirmed by a K i of 50 M;this finding has not been confirmed clinically by suchinteractions in humans (60,61). Flunitrazepam has alsobeen reported to lower the intravenous minimum lethaldose of methadone in rats (62). The differences betweenrats and humans, however, may preclude extrapolation ofthese results to humans for clinical purposes (62). Table 1summarizes these interactions. Further studies are neededto determine whether this effect is a pharmacokineticinteraction or a pharmacodynamic one.

Benzodiazepine Interactions with BuprenorphineAs buprenorphine (63) and most benzodiazepines (5054) undergo extensive metabolism by cytochrome P450(CYP 3A4), metabolic interactions are plausible. Changand Moody (64), however, demonstrated that benzo-diazepines are not potent inhibitors of buprenorphinemetabolism using human liver microsome. Of note, evi-dence for the metabolically activated inhibition of nor-buprenorphine has been shown in the case of midazolamand zolpidem (64,65).

In rats, high doses of midazolam or buprenorphinealone have limited effects on respiratory depression, mea-sured using arterial blood gases, whereas midazolamand buprenorphine appear to be additive or synergis-tic in depressing their respiration and inducing hypoxia(66). The concomitant injection of buprenorphine withmidazolam has recently been reported in Southeast Asia(67,68). The studied subjects have suggested that inject-ing midazolam boosted and prolonged the effects ofbuprenorphine (67). The clinical importance of CYP 3A4inhibition is not established in detail and further studiesare needed to assess the in vivo inhibition potential.

Although flunitrazepam is rarely detected in clini-cal settings due to its rapid degradation in vitro, it issuspected to be involved in a large number of buprenor-phine intoxications and adverse consequences (18,69,70).Studies performed on human microsome preparationshave predicted the absence of in vivo metabolic inter-actions between buprenorphine and flunitrazepam whendosed at therapeutic concentrations (40,71,72).

In humans, both CYP 3A4 and 2C19 are involved inthe metabolic pathways of flunitrazepam to desmethylflunitrazepam and to the third flunitrazepam metabolite,3-OH flunitrazepam (73). This mechanism, however, isnot entirely elucidated in rats. Megarbane et al. (74)demonstrated that rat pretreatment with flunitrazepamalters neither plasma nor striatal buprenorphine distribu-tion. Pretreatment with buprenorphine has had no effectson flunitrazepam disposition, while inducing a threefoldincrease in its main active metabolite, desmethyl flu-nitrazepam, plasma concentration (75). The desmethylflunitrazepam AUC/flunitrazepam AUC ratio, named themetabolism index, has been increased by 41% inbuprenorphine-pretreated rats when compared with 15%in controls (75). This difference resulted in a signifi-cant decrease in PaO2 and an increase in PaCO2 levelsin rats, confirming increased respiratory depression (75).As there are differences among species in metabolism,human studies are needed before extrapolating thesefindings to humans. Similar studies in humans examin-ing flunitrazepam and desmethyl flunitrazepam kinetics,however, have not been performed.

Under pharmacological conditions, projected in vivoinhibition of CYP 3A4-mediated metabolism of fluni-trazepam by buprenorphine is .12.5%. Estimated inhi-bition of buprenorphine N-dealkylation by flunitrazepamin vivo is .08% (72). These results are not significant anddo not support a buprenorphineflunitrazepam metabolicinteraction at the concentrations that occur in humans. Of

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TABLE 1. Interactions between psychotropic medications and methadone or buprenorphine.

Medication Buprenorphine Methadone CommentsBenzodiazepines Caution advised Caution advised Risk of additive effects on

respiratory depression andpsychomotor impairment

Clonazepam No effect (64) Not studied Human in vitro studyDiazepam No effect (64) Inhibition of methadone

N-demethylation with the K i of50 M (24)

Both human in vitro studies

Flunitrazepam FZ Metabolism by .12.5% (72) MTD MLD Human in vitro studyBPN metabolism by .08% (72)

Midazolam IC50 for N-BPNformation = 20.25 M (65)

Not studied Human in vitro study

Selectiveserotoninreuptakeinhibitors

Increased risk of QT prolongationwith MTD

Paroxetine Not studied (R)-MTD metabolism by 41% and(S)-MTD metabolism by 77% (21)

Human in vitro study

Fluoxetine No effect (90) (R)-MTD metabolism (89) Human in vivo studyFluvoxamine BPN metabolism (R)- and (S)-MTD metabolism (23) Opioid withdrawal symptoms have

been described at the sudden stopof fluvoxamine (96)

Human in vivo studyAntipsychotics Increased risk of QT prolongation

with MTDQuetiapine Not studied 333% in (R)-MTD dose (10) Varies with poor versus extensive

metabolizersHuman in vivo study

Olanzapine Not studied No effect (106) Human in vivo studyMood

stabilizers

CarbamazepineNot likely MTD levels (122) Risk of MTD overdose on sudden

cessation of carbamazepineHuman in vivo study

Valproate No effect No effectLithium Not studied Not likely

Tricyclic antide-pressants

TCA toxicity (130) Increased risk of QT prolongationwith MTD, risk of withdrawalsyndromes with sudden cessation

Human in vivo studyAmitriptyline Not studied MTD metabolism (11) Human in vivo studyDesipramine Not studied MTD metabolism (133) Animal in vivo study

Monoamineoxidaseinhibitors

Contraindicated Contraindicated Potential for serotonin syndrome

Note: MLD, minimum lethal dose; MTD, methadone; BPN, buprenorphine.

note, flunitrazepam markedly lowers the intravenous min-imum lethal dose of buprenorphine in rats (sixfold) (62).

The adverse consequences of coadministering buprenorphine and benzodiazepines have been described for anumber of different benzodiazepines (76,77), most ofwhich do not demonstrate the ability to inhibit buprenorphine metabolism, including alprazolam, -hydroxy-alprazolam, chlordiazepoxide, norchlordiazepoxide,clonazepam, 3-hydroxy-7-acetamidoclonazepam, demoxepam, diazepam, nordiazepam, oxazepam, estazolam,flurazepam, lorazepam, nitrazepam, temazepam, andtriazolam (64).

High-dose diazepam has been associated with time-dependent increases in the intensity of subjective med-ication effects and decreases in psychological per-formance in buprenorphine-maintained patients (55).Buprenorphine, when combined with clonazepam, nor-diazepam, oxazepam, or bromazepam at therapeu-tic doses, has not influenced respiration or arterialexchange in rats, when compared with buprenorphinealone. Combinations of oxazepam or nordiazepam withbuprenorphine, however, have significantly deepenedsedation in rats (78). These differences are probablybecause of the unique properties of each benzodiazepine

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METHADONE AND BUPRENORPHINE INTERACTIONS 5

molecule. However, to date, the molecular basis for theseobservations remains to be determined.

With the exception of midazolam, these resultsstrengthen animal studies and observations in humansthat suggest the adverse interactions between benzodi-azepines and buprenorphine most probably arise from apharmacodynamic mechanism rather than a pharmacoki-netic one (66,79).

Given the disparity between the findings from in vitroand in vivo studies and the clinical findings reportedfrom the case series, pharmacodynamic studies examin-ing the safety of escalating doses of benzodiazepines inbuprenorphine-maintained patients are needed.

Benzodiazepine Interactions with NaltrexoneThere seems to be little likelihood of pharmacokineticdrug interactions occurring in vivo between naltrex-one and most benzodiazepines. The studies on humanliver microsomal preparations demonstrate that benzodi-azepines inhibit dihydrodiol dehydrogenase, the enzymeresponsible for the formation of 6--naltrexol from nal-trexone (44), by less than 20% (44). Moreover, as acomplete mu-opioid receptor antagonist, one might notanticipate any pharmacodynamic interactions.

Interestingly, naltrexone does increase the sedativeeffects of diazepam and delay the time to reach peakblood diazepam levels. The precise mechanism by whichnaltrexone alters the time to peak concentration is notknown, but it is possibly due to a delay in diazepamabsorption (80). Naltrexone increases the half-life ofdiazepam from 4.0 h to 4.3 h, but the area under thecurve (AUC) remains unchanged (80), perhaps suggest-ing that this would not result in any clinically significantpharmacodynamic interaction.

SSRIs MetabolismPharmacokinetic interactions caused by metabolic inhibi-tion of CYP isoenzyme activity represent the majority ofthe interactions reported with the SSRIs (81). Althoughmembers of this class of medications are quite similarin their antidepressant activity and side effect profiles(82), they differ substantially in their chemical struc-ture, metabolism, pharmacokinetics, and their inhibitoryeffects on the cytochrome P450 system.

Fluoxetine is mainly excreted in urine, with less than10% excreted unchanged or as fluoxetine N-glucuronide(83). It has been suggested that CYP 2C9 plays a piv-otal role in the N-demethylation of fluoxetine with apossible contribution of the CYP 2C19 and a CYP 3A4isoform (83). Fluoxetine strongly inhibits CYP 2D6 (84).Norfluoxetine, a major metabolite of fluoxetine, is also astrong inhibitor of CYP 3A4 (85).

Fluvoxamines main route of elimination is throughhepatic metabolism that has been found to be associ-ated with CYP 2D6 polymorphism and also CYP 1A2activity. Paroxetine undergoes extensive metabolism inthe liver to form more hydrophilic excretable compounds(83). Paroxetine is the most potent inhibitor of CYP 2D6

among all SSRIs (86) but, unlike fluoxetine and fluvox-amine, paroxetine is also a mild inhibitor of CYP 1A2,CYP 2C9, CYP 2C19, and CYP 3A4 (84).

The metabolism of citalopram leads to two pharma-cologically active metabolites with two enantiomers foreach. It has been shown that CYP 2C19 and CYP 2D6each play a role in the biotransformation of citalopram(83). The N-demethylation of sertraline correlates withthe activity of CYP 3A4 (87).

SSRIs InteractionsSSRIs Interactions with MethadoneDepressive disorders are highly prevalent among thosewith substance use disorders (88), and patients prescribedmethadone are also commonly prescribed SSRIs. Thereare reports of pharmacodynamic interactions betweenmethadone and different SSRIs. For example, fluox-etine significantly increases (R)-methadone concentra-tions (84,89). It inhibits CYP 3A4 and CYP 2D6,both of which are involved in methadone metabolism(84,90), although CYP 3A4 is considered to have amore prominent role compared with CYP 2D6 (21,9193). Fluvoxamine is a nonselective inhibitor of CYP1A2, CYP 2C9, CYP 2C19, CYP 2D6, and CYP3A4 and increases concentrations of both (R)- and(S)-methadone (89,90,94,95). Additionally, opioid with-drawal symptoms have been described when fluvoxam-ine is suddenly stopped, because fluvoxamine discon-tinues inhibiting 2D6 and 3A4, allowing for increasedmetabolism of methadone and development of with-drawal symptoms (96).

Paroxetine inhibits CYP 2D6 more than fluoxetine ornorfluoxetine (50) and is also an inhibitor of CYP 3A4(21,84). Paroxetine significantly increases the concentra-tions of both enantiomers of methadone (23), which isdue to inhibition of not only CYP 3A4 but also CYP 2D6and, to a minor extent, CYP 2C8 (21). Whether discon-tinuation of paroxetine can result in withdrawal is yetto be studied. Pharmacodynamic studies, however, haveyet to examine the association between paroxetine andincreased methadone levels and until they are done, clin-icians should be alert to the effects of SSRIs on serummethadone levels and the possible need for adjusting themethadone dose, especially after sudden discontinuationof SSRI medications.

SSRIs Interactions with BuprenorphineBuprenorphine is metabolized primarily throughcytochrome P450 3A4, whereas fluoxetine and fluvox-amine inhibit 2D6 and 3A4 in vitro. Iribarne et al. (90),however, demonstrated that fluoxetine does not inhibitbuprenorphine dealkylation in vitro but norfluoxetineinhibits buprenorphine metabolism. Fluvoxamine, onthe contrary, has been shown to inhibit buprenorphinedealkylation uncompetitively. There have been instancesof drug interactions such as the interaction betweendelavirdine and buprenorphine that can cause a changein the buprenorphine metabolism but does not resultin any clinical manifestations (97). Further studies are

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needed in this field to determine if these interactionsare clinically meaningful. Because buprenorphine is apartial opioid agonist at the mu-opioid receptor, it isunlikely that increases in buprenorphine levels wouldresult in respiratory depression and death; however,increased levels of buprenorphine have been associatedwith increased sedation (2). Further studies are needed toclarify these interactions.

Antipsychotic Medication MetabolismOne of the major advantages of novel antipsychoticsover classical compounds is their negligible effect onhepatic drug-metabolizing enzymes (98). Unlike olderantipsychotics, such as phenothiazines, which are potentinhibitors of CYP 2D6 (99), novel antipsychotics are onlyweak in vitro inhibitors of P450 isoenzymes at therapeuticconcentrations (100,101).

The major metabolic pathways of olanzapine includedirect N-glucuronidation, mediated by UGT 1A4,and N-demethylation, mediated by CYP 1A2 (102).Minor pathways of olanzapine biotransformationinclude N-oxidation, catalyzed by flavin-containingmonooxygenase-3 system, and 2-hydroxylation, metabo-lized by CYP 2D6 (101,102). Olanzapine does not inhibitP450 isoenzymes (102) and therefore should not haveany significant pharmacokinetic interactions.

Quetiapine, a dibenzothiazepine derivative, is exten-sively metabolized in the liver by sulfoxidation to form itsmajor, but inactive, sulfoxide metabolite. Eleven metabo-lites have been identified. N- and O-dealkylation alsooccur as lesser metabolic pathways (103). Quetiapine andits metabolites were found to be weak inhibitors of theactivity of cytochrome P450 enzymes (CYP 1A2, 2C9,2C19, 2D6, and 3A4) and are, therefore, not expected toproduce clinically relevant inhibition in vivo (104).

Antipsychotic Medication InteractionsUehlinger et al. (10) demonstrated that quetiapineincreases plasma concentrations of (R)-methadone, whichis speculated to be due to an interaction with CYP 2D6or the P-glycoprotein transporter system or both. In thisparticular study, however, no pharmacodynamic signsof oversedation caused by increased methadone plasmaconcentrations were described. There are reports of que-tiapine abuse especially among inmates with a historyof drug dependence (105). Further studies are neededto confirm the presence of a pharmacodynamic or phar-macokinetic interaction between quetiapine and otheropioids. Opioid withdrawal symptoms might theoreticallyoccur when quetiapine treatment is abruptly interrupted,but remain unknown until empirically studied.

The addition of olanzapine to patients on stablemethadone doses has not resulted in clinical with-drawal in patients. Moreover, no change in plasmamethadone ratio has been observed in relation to the dosebefore and during the treatment, which suggests a lackof pharmacokinetic interaction between methadone andolanzapine (106).

QT Interval ProlongationRecent studies document methadones ability to prolongthe QT interval that can result in torsade de pointes(107109). Psychotropic medications such as chlorpro-mazine, intravenous haloperidol, ziprasidone, levomepro-mazine, aripiprazole, and sultopride have been foundto significantly lengthen the QT interval, whereas oralhaloperidol, bromperidol, olanzapine, quetiapine, risperi-done, and zotepine do not (110). Studies examining thepotential interactions of methadone and antipsychoticmedications on QT prolongation are needed to explore thesafety of concomitant administration because of concernsthat these various medications may have additive effectson QT prolongation when coadministered.

Furthermore, members of SSRI family, especially flu-oxetine, paroxetine, and sertraline, have been associatedwith cardiac rhythm disturbances such as prolonged QTinterval (111113). Moreover, tricyclic antidepressantshave been found to cause defects in the cardiac conduc-tion due to the slowdown in the cardiac depolarizationand expansions in the QT interval that predispose thepatients to cardiac arrhythmias (114116). Consideringmethadones effects on QT interval (107) and the poten-tial for additive effects, caution should be advised oncoadministration of these medications and methadone.

Prescribing higher doses of methadone to improvetreatment outcomes for opioid dependence in recent yearsand the frequent addition of psychotropic medications totreatment regimens are two of the reasons why cliniciansshould be more aware of the possible additive effectsbetween antipsychotic medications and methadone. Itwould be advisable to take careful medical history screen-ing for known cardiac risk factors, perform baseline andfollow-up electrocardiograms, and watch for potentialadditive effects.

Metabolism of Mood StabilizersMood stabilizers are medications used to treat mood dis-orders characterized by intense and sustained mood shiftssuch as in bipolar disorder. Lithium, the first mood sta-bilizer, is not metabolized by the liver. Other describedmood stabilizers, most of which are also categorized asanticonvulsants, include carbamazepine (CBZ), lamotrig-ine, and valproic acid.

CBZ is extensively metabolized in the liver, with onlyabout 3% being excreted unchanged in the urine (117).The main metabolic pathway of CBZ (to its active 10,11-epoxide, CBZ-E) appears to be mediated primarily byCYP 3A4, with a minor contribution by CYP 2C8 (118).This epoxide pathway accounts for about 40% of CBZdisposition. More important, however, is the impact ofCBZ on inducing CYP 3A4, resulting in many poten-tial pharmacokinetic interactions (117). CBZ decreasesthe plasma levels of not only CBZ itself (autoinduc-tion) but also many other medications (heteroinduction).Moreover, if CBZ is discontinued, plasma levels of theseother medications can rise, leading to toxic effects fromthese agents (119).

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METHADONE AND BUPRENORPHINE INTERACTIONS 7

Valproic acid is a fatty acid with biochemical prop-erties such as blocking sodium channels and mod-ulating GABAergic function. Valproic acid is exten-sively metabolized with less than 3% being excretedunchanged in the urine. There are three principal routesof metabolism: (1) conjugations to inactive glucuronides(50%); (2) -oxidation in the mitochondria (40%); and (3)cytochrome P450 oxidation (10%) (117). Valproic acidmay cause clinically relevant pharmacokinetic interac-tions by inhibiting the metabolism of selected substrates,most notably phenobarbital and lamotrigine (120).

Mood Stabilizers InteractionsThe main biotransformation of methadone is the N-demethylation by CYP 3A4 and CYP 2B6 (2124). CBZstrongly induces CYP 3A4 activity (121) and conse-quently accelerates methadone metabolism. In a study on12 methadone maintenance patients, CBZ resulted in asignificant reduction in methadone trough levels, result-ing in mild opioid withdrawal symptoms over 710 days(122). At the cessation of CBZ, there is a reduction inthe metabolism of methadone with a resultant increasein plasma methadone levels, thereby increasing the riskof overdose, an unfortunate adverse event that has beendocumented with CBZ cessation (123). Further pharma-cokinetic studies are needed to determine the extent ofthis effect. Stopping CBZ in the setting of methadonetreatment should include close observation of the patientfor oversedation and opioid overdose and a need formethadone dosage modification.

The induction of CYP 3A4 by CBZ could lead to asignificant reduction of the mean terminal eliminationhalf-life of buprenorphine and methadone that is specu-lated to be clinically relevant (40,41), yet confirmatorystudies are still needed.

Surprisingly, the number of pharmacokinetic studieson valproic acid and buprenorphine or methadone inter-actions is very limited. Kristensen et al. (124) measuredbuprenorphine levels before and after receiving valproicacid in 12 patients and have concluded that no significantinteractions between the two medications occur.

The studies performed on potential interactionsbetween lithium and opioid maintenance drugs arelimited. In a study in 1978 (125), seven methadone-maintained patients were treated with lithium for a month,which resulted in a significant decrease in the methadonedose needed for maintenance. Further studies are neededin this field.

Tricyclic AntidepressantsAntidepressant medications are used in the treatment ofmajor depression, neurosis, panic disorder, and chronicpain and tricyclics are one of the most commonly usedamongst them (126).

Inactivation of tricyclics occurs largely throughcytochrome P450 enzymes, by demethylation of tertiarytricyclics to their secondary amine metabolites, hydrox-ylation, then glucuronidation, and excretion in the urine(127). Tricyclic antidepressant medication metabolism

depends, to different degrees, upon the isoenzymes CYP2D6 (127,128).

Methadone maintenance therapy patients have beenfound to use amitriptyline to achieve euphoria (6,129).Increased tricyclic antidepressant (TCA) toxicity withmethadone coadministration has been reported (130132). In a retrospective study, decreased methadoneclearance was found in patients receiving amitriptyline(11). Liu et al. (133) have shown that desipramine sig-nificantly reduces the analgesic ED50 of methadone inrats. Desipramine treatment has also been found to sig-nificantly reduce the LD50 of methadone. The additionof desipramine to microsomal incubations from nor-mal rat liver has resulted in inhibition of methadoneN-demethylation proportional to the desipramine concen-tration (133). Because of the differences among speciesin their metabolism, human studies are needed beforeextrapolating these findings to humans. Further studiesare required to better understand the underlying mecha-nism of these interactions.

Monoamine Oxidase InhibitorsThe administration of opioid agonist medications andmonoamine oxidase inhibitors (MAOIs) within 2 weeksof each other is contraindicated. MAOIs can cause aserotonin-like syndrome especially when coadministeredwith some SSRIs (134). Many questions have been raisedregarding the safety of opioid analgesics in patients whowere taking MAOIs (135137).

To the best of our knowledge, there are no serotonintoxicity reports of methadone and MAOI combinationtreatments (134) and although methadone is a weak non-SSRI (138), such reactions are considered unlikely (134).The same is true in the coadministration of buprenorphineand MAOIs. There are no reports on serotonin syndromecaused by interaction of buprenorphine and MAOIs andsuch interactions are not likely (134).

CONCLUSIONS

In vitro and well-designed and conducted pharmacologicstudies in humans have defined an array of pharma-cokinetic and pharmacodynamic interactions with vari-able clinical impact between opioid agonist therapiesand psychoactive medications. Being cognizant of pos-sible synergistic effects of psychotropic medications andmethadone on QT prolongation and the risks involvedare necessary in todays clinical practice. Careful medicalhistory taking, risk stratification, and obtaining a base-line and a follow-up electrocardiogram after a monthof initiating therapy are examples of practices that canhelp clinicians address such risks. Considering the currentgaps in knowledge on pharmacokinetic and pharmacody-namic interactions between opioid agonist therapies andpsychoactive medications and the potential for seriousconsequences, further human subject studies are requiredto better understand the underlying mechanism of theseinteractions.

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Declaration of InterestThe authors report no conflicts of interest. The authorsalone are responsible for the content and writing of thispaper.

REFERENCES

1. McCance-Katz EF, Mandell TW. Drug interactions of clinicalimportance with methadone and buprenorphine. Am J Addict2010; 19(1):23.

2. Bruce RD, Altice FL, Gourevitch MN, Friedland GH.Pharmacokinetic drug interactions between opioid agonisttherapy and antiretroviral medications: Implications and man-agement for clinical practice. J Acquir Immune Defic Syndr2006; 41(5):563572.

3. Kandel DB, Huang FY, Davies M. Comorbidity between pat-terns of substance use dependence and psychiatric syndromes.Drug Alcohol Depend 2001; 64(2):233241.

4. Farre M, Teran MT, Roset PN, Mas M, Torrens M,Cami J. Abuse liability of flunitrazepam among methadone-maintained patients. Psychopharmacology (Berl) 1998;140(4):486495.

5. Marsden J, Gossop M, Stewart D, Rolfe A, Farrell M.Psychiatric symptoms among clients seeking treatment fordrug dependence. Intake data from the National TreatmentOutcome Research Study. Br J Psychiatry 2000; 176:285289.

6. Peles E, Schreiber S, Adelson M. Tricyclic antidepres-sants abuse, with or without benzodiazepines abuse, informer heroin addicts currently in methadone maintenancetreatment (MMT). Eur Neuropsychopharmacol 2008; 18(3):188193.

7. Carpenter KM, Brooks AC, Vosburg SK, Nunes EV. Theeffect of sertraline and environmental context on treatingdepression and illicit substance use among methadone main-tained opiate dependent patients: A controlled clinical trial.Drug Alcohol Depend 2004; 74(2):123134.

8. Hamilton SP, Klimchak C, Nunes EV. Treatment of depressedmethadone maintenance patients with nefazodone. A caseseries. Am J Addict 1998; 7(4):309312.

9. Petrakis I, Carroll KM, Nich C, Gordon L, Kosten T,Rounsaville B. Fluoxetine treatment of depressive disorders inmethadone-maintained opioid addicts. Drug Alcohol Depend1998; 50(3):221226.

10. Uehlinger C, Crettol S, Chassot P, Brocard M, KoebL, Brawand-Amey M, Eap CB. Increased (R)-methadoneplasma concentrations by quetiapine in cytochrome P450s andABCB1 genotyped patients. J Clin Psychopharmacol 2007;27(3):273278.

11. Plummer JL, Gourlay GK, Cherry DA, Cousins MJ.Estimation of methadone clearance: Application in the man-agement of cancer pain. Pain 1988; 33(3):313322.

12. Wedekind D, Jacobs S, Karg I, Luedecke C, Schneider U,Cimander K, Baumann P, Ruether E, Poser W, Havemann-Reinecke U. Psychiatric comorbidity and additional abuse ofdrugs in maintenance treatment with l- and d,l-methadone.World J Biol Psychiatry 2008; 9:110.

13. Ball JC, Corty E, Erdlen DL, Nurco DN. Major patterns ofpolydrug abuse among heroin addicts. NIDA Res Monogr1986; 67:256262.

14. Darke S, Swift W, Hall W. Prevalence, severity and correlatesof psychological morbidity among methadone maintenanceclients. Addiction 1994; 89(2):211217.

15. Stitzer ML, Griffiths RR, McLellan AT, Grabowski J,Hawthorne JW. Diazepam use among methadone maintenancepatients: Patterns and dosages. Drug Alcohol Depend 1981;8(3):189199.

16. Grass H, Behnsen S, Kimont HG, Staak M, Kaferstein H.Methadone and its role in drug-related fatalities in Cologne19892000. Forensic Sci Int 2003; 132(3):195200.

17. Darke S, Duflou J, Kaye S. Comparative toxicology of fatalheroin overdose cases and morphine positive homicide vic-tims. Addiction 2007; 102(11):17931797.

18. Kintz P. Deaths involving buprenorphine: A compendium ofFrench cases. Forensic Sci Int 2001; 121(12):6569.

19. Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxi-olytics and hypnotics: Benzodiazepines, buspirone, zoplicone,and zolpidem. Cell Mol Neurobiol 1999; 19(4):533552.

20. Bruce RD, McCance-Katz E, Kharasch ED, Moody DE,Morse GD. Pharmacokinetic interactions between buprenor-phine and antiretroviral medications. Clin Infect Dis 2006;43(Suppl. 4):S216S223.

21. Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8,and CYP2D6 in the metabolism of (R)- and (S)-methadonein vitro. Drug Metab Dispos 2003; 31(6):742747.

22. Totah RA, Sheffels P, Roberts T, Whittington D, ThummelK, Kharasch ED. Role of CYP2B6 in stereoselectivehuman methadone metabolism. Anesthesiology 2008; 108(3):363374.

23. Begre S, von Bardeleben U, Ladewig D, Jaquet-Rochat S,Cosendai-Savary L, Golay KP, Kosel M, Baumann P, EapCB. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. JClin Psychopharmacol 2002; 22(2):211215.

24. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP,Beaune P, Menez JF. Involvement of cytochrome P450 3A4enzyme in the N-demethylation of methadone in human livermicrosomes. Chem Res Toxicol 1996; 9(2):365373.

25. Kristensen K, Christensen CB, Christrup LL. The mu1,mu2, delta, kappa opioid receptor binding profiles ofmethadone stereoisomers and morphine. Life Sci 1995; 56(2):PL45PL50.

26. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolismof methadone N-demethylation by cytochrome P4502B6 and2C19. Chirality 2004; 16(1):3644.

27. Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, GunsonK. A community-based evaluation of sudden death associ-ated with therapeutic levels of methadone. Am J Med 2008;121(1):6671.

28. Hanon S, Seewald RM, Yang F, Schweitzer P, Rosman J.Ventricular arrhythmias in patients treated with methadonefor opioid dependence. J Interv Card Electrophysiol 2010;28(1):1922.

29. Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolismstudy of buprenorphine: Evidence for new metabolic path-ways. Drug Metab Dispos 2005; 33(5):689695.

30. Moody DE, Slawson MH, Strain EC, Laycock JD, SpanbauerAC, Foltz RL. A liquid chromatographic-electrosprayionization-tandem mass spectrometric method for determina-tion of buprenorphine, its metabolite, norbuprenorphine, and acoformulant, naloxone, that is suitable for in vivo and in vitrometabolism studies. Anal Biochem 2002; 306(1):3139.

31. Kobayashi K, Yamamoto T, Chiba K, Tani M, Shimada N,Ishizaki T, Kuroiwa Y. Human buprenorphine N-dealkylationis catalyzed by cytochrome P450 3A4. Drug Metab Dispos1998; 26(8):818821.

Am

J D

rug

Alc

ohol

Abu

se D

ownl

oade

d fro

m in

form

ahea

lthca

re.c

om b

y Y

ale

Uni

vers

ity o

n 01

/09/

12Fo

r per

sona

l use

onl

y.

METHADONE AND BUPRENORPHINE INTERACTIONS 9

32. Cheng Z, Radominska-Pandya A, Tephly TR. Studieson the substrate specificity of human intestinal UDP-lucuronosyltransferases 1A8 and 1A10. Drug Metab Dispos1999; 27(10):11651170.

33. Cheng Z, Radominska-Pandya A, Tephly TR. Cloning andexpression of human UDP-glucuronosyltransferase (UGT)1A8. Arch Biochem Biophys 1998; 356(2):301305.

34. Green MD, King CD, Mojarrabi B, Mackenzie PI, Tephly TR.Glucuronidation of amines and other xenobiotics catalyzedby expressed human UDP-glucuronosyltransferase 1A3. DrugMetab Dispos 1998; 26(6):507512.

35. Coffman BL, Rios GR, King CD, Tephly TR. HumanUGT2B7 catalyzes morphine glucuronidation. Drug MetabDispos 1997; 25(1):14.

36. Coffman BL, King CD, Rios GR, Tephly TR. The glu-curonidation of opioids, other xenobiotics, and androgens byhuman UGT2B7Y(268) and UGT2B7H(268). Drug MetabDispos 1998; 26(1):7377.

37. King CD, Green MD, Rios GR, Coffman BL, Owens IS,Bishop WP, Tephly TR. The glucuronidation of exoge-nous and endogenous compounds by stably expressed ratand human UDP-glucuronosyltransferase 1.1. Arch BiochemBiophys 1996; 332(1):92100.

38. Chang Y, Moody DE. Glucuronidation of buprenorphineand norbuprenorphine by human liver microsomes andUDP-glucuronosyltransferases. Drug Metab Lett 2009; 3(2):101107.

39. Rouguieg K, Picard N, Sauvage FL, Gaulier JM, MarquetP. Contribution of the different UDP-glucuronosyltransferase(UGT) isoforms to buprenorphine and norbuprenorphinemetabolism and relationship with the main UGT polymor-phisms in a bank of human liver microsomes. Drug MetabDispos 2010; 38(1):4045.

40. Umehara K, Shimokawa Y, Miyamoto G. Inhibition of humandrug metabolizing cytochrome P450 by buprenorphine. BiolPharm Bull 2002; 25(5):682685.

41. Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM.Interaction of buprenorphine and its metabolite norbuprenor-phine with cytochromes p450 in vitro. Drug Metab Dispos2003; 31(6):768772.

42. Verebey K. The clinical pharmacology of naltrexone:Pharmacology and pharmacodynamics. NIDA Res Monogr1981; 28:147158.

43. Gonzalez JP, Brogden RN. Naltrexone. A review of its phar-macodynamic and pharmacokinetic properties and therapeuticefficacy in the management of opioid dependence. Drugs1988; 35(3):192213.

44. Porter SJ, Somogyi AA, White JM. Kinetics and inhibitionof the formation of 6beta-naltrexol from naltrexone in humanliver cytosol. Br J Clin Pharmacol 2000; 50(5):465471.

45. Atkinson RL, Berke LK, Drake CR, Bibbs ML, WilliamsFL, Kaiser DL. Effects of long-term therapy with naltrex-one on body weight in obesity. Clin Pharmacol Ther 1985;38(4):419422.

46. Pfohl DN, Allen JI, Atkinson RL, Knopman DS, Malcolm RJ,Mitchell JE, Morley JE. Naltrexone hydrochloride (Trexan):A review of serum transaminase elevations at high dosage.NIDA Res Monogr 1986; 67:6672.

47. Maany I, OBrien CP, Woody G. Interaction between thiori-dazine and naltrexone. Am J Psychiatry 1987; 144(7):966.

48. Otani K. Cytochrome P450 3A4 and benzodiazepines. SeishinShinkeigaku Zasshi 2003; 105(5):631642.

49. Donato MT, Hallifax D, Picazo L, Castell JV, Houston JB,Gomez-Lechon MJ, Lahoz A. Metabolite formation kinetics

and intrinsic clearance of phenacetin, tolbutamide, alprazolamand midazolam in adenoviral P450 transfected HepG2 cells,and comparison with hepatocytes and in vivo. Drug MetabDispos 2010; 38(9):14491455.

50. von Moltke LL, Greenblatt DJ, Harmatz JS, Shader RI.Alprazolam metabolism in vitro: Studies of human, mon-key, mouse, and rat liver microsomes. Pharmacology 1993;47(4):268276.

51. Andersson T, Miners JO, Veronese ME, Birkett DJ. Diazepammetabolism by human liver microsomes is mediated by bothS-mephenytoin hydroxylase and CYP3A isoforms. Br J ClinPharmacol 1994; 38(2):131137.

52. Bertz RJ, Granneman GR. Use of in vitro and in vivo data toestimate the likelihood of metabolic pharmacokinetic interac-tions. Clin Pharmacokinet 1997; 32(3):210258.

53. Lane RM. Pharmacokinetic drug interaction poten-tial of selective serotonin reuptake inhibitors. Int ClinPsychopharmacol 1996; 11(Suppl. 5):3161.

54. Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Shader RI.Alprazolam is another substrate for human cytochrome P450-3A isoforms. J Clin Psychopharmacol 1998; 18(3):256.

55. Lintzeris N, Mitchell TB, Bond AJ, Nestor L, StrangJ. Pharmacodynamics of diazepam co-administered withmethadone or buprenorphine under high dose conditions inopioid dependent patients. Drug Alcohol Depend 2007; 91(23):187194.

56. Lintzeris N, Mitchell TB, Bond A, Nestor L, StrangJ. Interactions on mixing diazepam with methadoneor buprenorphine in maintenance patients. J ClinPsychopharmacol 2006; 26(3):274283.

57. Preston KL, Griffiths RR, Stitzer ML, Bigelow GE, LiebsonIA. Diazepam and methadone interactions in methadonemaintenance. Clin Pharmacol Ther 1984; 36(4):534541.

58. Ernst E, Bartu A, Popescu A, Ileutt KF, Hansson R, PlumleyN. Methadone-related deaths in Western Australia 199399.Aust N Z J Public Health 2002; 26(4):364370.

59. Eap CB, Buclin T, Baumann P. Interindividual variabilityof the clinical pharmacokinetics of methadone: Implicationsfor the treatment of opioid dependence. Clin Pharmacokinet2002; 41(14):11531193.

60. Preston KL, Griffiths RR, Cone EJ, Darwin WD, GorodetzkyCW. Diazepam and methadone blood levels following con-current administration of diazepam and methadone. DrugAlcohol Depend 1986; 18(2):195202.

61. Pond SM, Tong TG, Benowitz NL, Jacob P, III, Rigod J.Lack of effect of diazepam on methadone metabolism inmethadone-maintained addicts. Clin Pharmacol Ther 1982;31(2):139143.

62. Borron SW, Monier C, Risede P, Baud FJ. Flunitrazepamvariably alters morphine, buprenorphine, and methadonelethality in the rat. Hum Exp Toxicol 2002; 21(11):599605.

63. Iribarne C, Picart D, Dreano Y, Bail JP, Berthou F.Involvement of cytochrome P450 3A4 in N-dealkylation ofbuprenorphine in human liver microsomes. Life Sci 1997;60(22):19531964.

64. Chang Y, Moody DE. Effect of benzodiazepines on themetabolism of buprenorphine in human liver microsomes. EurJ Clin Pharmacol 2005; 60(12):875881.

65. Bomsien S, Aderjan R, Mattern R, Skopp G. Effect of psy-chotropic medication on the in vitro metabolism of buprenor-phine in human cDNA-expressed cytochrome P450 enzymes.Eur J Clin Pharmacol 2006; 62(8):639643.

66. Gueye PN, Borron SW, Risede P, Monier C, Buneaux F,Debray M, Baud FJ. Buprenorphine and midazolam act in

Am

J D

rug

Alc

ohol

Abu

se D

ownl

oade

d fro

m in

form

ahea

lthca

re.c

om b

y Y

ale

Uni

vers

ity o

n 01

/09/

12Fo

r per

sona

l use

onl

y.

10 A. S. SABER-TEHRANI ET AL.

combination to depress respiration in rats. Toxicol Sci 2002;65(1):107114.

67. Bruce RD, Govindasamy S, Sylla L, Haddad MS,Kamarulzaman A, Altice FL. Case series of buprenor-phine injectors in Kuala Lumpur, Malaysia. Am J DrugAlcohol Abuse 2008; 34(4):511517.

68. Ng WL, Mythily S, Song G, Chan YH, Winslow M.Concomitant use of midazolam and buprenorphine and itsimplications among drug users in Singapore. Ann Acad MedSingapore 2007; 36(9):774777.

69. Gueye PN, Megarbane B, Borron SW, Adnet F, Galliot-Guilley M, Ricordel I, Tourneau J, Goldgran-Toledano D,Baud FJ. Trends in opiate and opioid poisonings in addictsin north-east Paris and suburbs, 19951999. Addiction 2002;97(10):1295304.

70. Druid H, Holmgren P, Ahlner J. Flunitrazepam: An eval-uation of use, abuse and toxicity. Forensic Sci Int 2001;122(23):136141.

71. Ibrahim RB, Wilson JG, Thorsby ME, Edwards DJ. Effectof buprenorphine on CYP3A activity in rat and human livermicrosomes. Life Sci 2000; 66(14):12931298.

72. Kilicarslan T, Sellers EM. Lack of interaction of buprenor-phine with flunitrazepam metabolism. Am J Psychiatry 2000;157(7):11641166.

73. Hesse LM, Venkatakrishnan K, von Moltke LL, Shader RI,Greenblatt DJ. CYP3A4 is the major CYP isoform mediatingthe in vitro hydroxylation and demethylation of flunitrazepam.Drug Metab Dispos 2001; 29(2):133140.

74. Megarbane B, Pirnay S, Borron SW, Trout H, Monier C,Risede P, Boschi G, Baud FJ. Flunitrazepam does not altercerebral distribution of buprenorphine in the rat. Toxicol Lett2005; 157(3):211219.

75. Pirnay S, Megarbane B, Decleves X, Risede P, BorronSW, Bouchonnet S, Perrin B, Debray M, Milan N, DuarteT, Ricordel I, Baud FJ. Buprenorphine alters desmethylflu-nitrazepam disposition and flunitrazepam toxicity in rats.Toxicol Sci 2008; 106(1):6473.

76. Tracqui A, Kintz P, Ludes B. Buprenorphine-related deathsamong drug addicts in France: A report on 20 fatalities. J AnalToxicol 1998; 22(6):430434.

77. Boyd J, Randell T, Luurila H, Kuisma M. Serious over-doses involving buprenorphine in Helsinki. Acta AnaesthesiolScand 2003; 47(8):10311033.

78. Pirnay SO, Megarbane B, Borron SW, Risede P, Monier C,Ricordel I, Baud FJ. Effects of various combinations of benzo-diazepines with buprenorphine on arterial blood gases in rats.Basic Clin Pharmacol Toxicol 2008; 103(3):228239.

79. Sekar M, Mimpriss TJ. Buprenorphine, benzodiazepinesand prolonged respiratory depression. Anaesthesia 1987;42(5):567568.

80. Swift R, Davidson D, Rosen S, Fitz E, Camara P. Naltrexoneeffects on diazepam intoxication and pharmacokinetics inhumans. Psychopharmacology (Berl) 1998; 135(3):256262.

81. Hemeryck A, Belpaire FM. Selective serotonin reuptakeinhibitors and cytochrome P-450 mediated drug-drug interac-tions: An update. Curr Drug Metab 2002; 3(1):1337.

82. Mourilhe P, Stokes PE. Risks and benefits of selective sero-tonin reuptake inhibitors in the treatment of depression. DrugSaf 1998; 18(1):5782.

83. Hiemke C, Hartter S. Pharmacokinetics of selective serotoninreuptake inhibitors. Pharmacol Ther 2000; 85(1):1128.

84. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI.Human cytochromes and some newer antidepressants:

Kinetics, metabolism, and drug interactions. J ClinPsychopharmacol 1999; 19(5 Suppl. 1):23S35S.

85. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI.Drug interactions with newer antidepressants: Role of humancytochromes P450. J Clin Psychiatry 1998; 59(Suppl. 15):1927.

86. Preskorn SH. Effects of antidepressants on the cytochromeP450 system. Am J Psychiatry 1996; 153(12):16551657.

87. Preskorn SH. Clinically relevant pharmacology of selectiveserotonin reuptake inhibitors. An overview with emphasis onpharmacokinetics and effects on oxidative drug metabolism.Clin Pharmacokinet 1997; 32(Suppl. 1):121.

88. Kosten TR, Rounsaville BJ, Kleber HD. A 2.5-year follow-upof depression, life crises, and treatment effects on abstinenceamong opioid addicts. Arch Gen Psychiatry 1986; 43(8):733738.

89. Eap CB, Bertschy G, Powell K, Baumann P. Fluvoxamine andfluoxetine do not interact in the same way with the metabolismof the enantiomers of methadone. J Clin Psychopharmacol1997; 17(2):113117.

90. Iribarne C, Picart D, Dreano Y, Berthou F. In vitro inter-actions between fluoxetine or fluvoxamine and methadoneor buprenorphine. Fundam Clin Pharmacol 1998; 12(2):194199.

91. Prost F, Thormann W. Capillary electrophoresis to assessdrug metabolism induced in vitro using single CYP450enzymes (Supersomes): Application to the chiral metabolismof mephenytoin and methadone. Electrophoresis 2003;24(15):25772587.

92. Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, HammigR, Gothuey I, Monnat M, Eap CB. ABCB1 and cytochromeP450 genotypes and phenotypes: Influence on methadoneplasma levels and response to treatment. Clin Pharmacol Ther2006; 80(6):668681.

93. Crettol S, Deglon JJ, Besson J, Croquette-Krokkar M,Gothuey I, Hammig R, Monnat M, Huttemann H, BaumannP, Eap CB. Methadone enantiomer plasma levels, CYP2B6,CYP2C19, and CYP2C9 genotypes, and response to treat-ment. Clin Pharmacol Ther 2005; 78(6):593604.

94. Iribarne C, Dreano Y, Bardou LG, Menez JF, Berthou F.Interaction of methadone with substrates of human hepaticcytochrome P450 3A4. Toxicology 1997; 117(1):1323.

95. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. CYP2C9is a principal low-affinity phenacetin O-deethylase:Fluvoxamine is not a specific CYP1A2 inhibitor. DrugMetab Dispos 1999; 27(12):15191522.

96. Bertschy G, Baumann P, Eap CB, Baettig D. Probablemetabolic interaction between methadone and fluvoxamine inaddict patients. Ther Drug Monit 1994; 16(1):4245.

97. McCance-Katz EF, Moody DE, Morse GD, Friedland G, PadeP, Baker J, Alvanzo A, Smith P, Ogundele A, Jatlow P, RaineyPM. Interactions between buprenorphine and antiretrovi-rals. I. The nonnucleoside reverse-transcriptase inhibitorsefavirenz and delavirdine. Clin Infect Dis 2006; 43(Suppl. 4):S224S234.

98. Spina E, Scordo MG, DArrigo C. Metabolic drug interactionswith new psychotropic agents. Fundam Clin Pharmacol 2003;17(5):517538.

99. Mulsant BH, Foglia JP, Sweet RA, Rosen J, Lo KH, PollockBG. The effects of perphenazine on the concentration of nor-triptyline and its hydroxymetabolites in older patients. J ClinPsychopharmacol 1997; 17(4):318321.

100. Shin JG, Soukhova N, Flockhart DA. Effect of antipsychoticdrugs on human liver cytochrome P-450 (CYP) isoforms in

Am

J D

rug

Alc

ohol

Abu

se D

ownl

oade

d fro

m in

form

ahea

lthca

re.c

om b

y Y

ale

Uni

vers

ity o

n 01

/09/

12Fo

r per

sona

l use

onl

y.

METHADONE AND BUPRENORPHINE INTERACTIONS 11

vitro: Preferential inhibition of CYP2D6. Drug Metab Dispos1999; 27(9):10781084.

101. Ring BJ, Binkley SN, Vandenbranden M, Wrighton SA. Invitro interaction of the antipsychotic agent olanzapine withhuman cytochromes P450 CYP2C9, CYP2C19, CYP2D6 andCYP3A. Br J Clin Pharmacol 1996; 41(3):181186.

102. Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM.Olanzapine. Pharmacokinetic and pharmacodynamic profile.Clin Pharmacokinet 1999; 37(3):177193.

103. Prior TI, Chue PS, Tibbo P, Baker GB. Drug metabolism andatypical antipsychotics. Eur Neuropsychopharmacol 1999;9(4):301309.

104. DeVane CL, Nemeroff CB. Clinical pharmacokinetics of que-tiapine: An atypical antipsychotic. Clin Pharmacokinet 2001;40(7): 509522.

105. Hanley MJ, Kenna GA. Quetiapine: Treatment for substanceabuse and drug of abuse. Am J Health Syst Pharm 2008;65(7):611618.

106. Bano MD, Mico JA, Agujetas M, Lopez ML, Guillen JL.Olanzapine efficacy in the treatment of cocaine abuse inmethadone maintenance patients. Interaction with plasma lev-els. Actas Esp Psiquiatr 2001; 29(4):215220.

107. Pearson EC, Woosley RL. QT prolongation and torsades depointes among methadone users: Reports to the FDA sponta-neous reporting system. Pharmacoepidemiol Drug Saf 2005;14(11):747753.

108. Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G,Tagliamonte A. QTc interval prolongation in patients on long-term methadone maintenance therapy. Eur Addict Res 2005;11(1):4449.

109. Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impactof methadone treatment on cardiac repolarization and conduc-tion in opioid users. Am J Cardiol 2005; 95(7):915918.

110. Ozeki Y, Fujii K, Kurimoto N, Yamada N, Okawa M, AokiT, Takahashi J, Ishida N, Horie M, Kunugi H. QTc prolon-gation and antipsychotic medications in a sample of 1017patients with schizophrenia. Prog NeuropsychopharmacolBiol Psychiatry 2010; 34(2):401405.

111. Barbey JT, Roose SP. SSRI safety in overdose. J ClinPsychiatry 1998; 59(Suppl. 15):4248.

112. Ohtani H, Odagiri Y, Sato H, Sawada Y, Iga T. A comparativepharmacodynamic study of the arrhythmogenicity of antide-pressants, fluvoxamine and imipramine, in guinea pigs. BiolPharm Bull 2001; 24(5):550554.

113. Acikalin A, Satar S, Avc A, Topal M, Kuvandk G, Sebe A.QTc intervals in drug poisoning patients with tricyclic antide-pressants and selective serotonin reuptake inhibitors. Am JTher 17(1):3033.

114. Vieweg WV, Wood MA. Tricyclic antidepressants, QT inter-val prolongation, and torsade de pointes. Psychosomatics2004; 45(5):371377.

115. Yap YG, Camm AJ. Drug induced QT prolongation andtorsades de pointes. Heart 2003; 89(11):13631372.

116. Henry JA, Alexander CA, Sener EK. Relative mortality fromoverdose of antidepressants. BMJ 1995; 310(6974):221224.

117. Ketter TA, Frye MA, Cora-Locatelli G, Kimbrell TA, PostRM. Metabolism and excretion of mood stabilizers and newanticonvulsants. Cell Mol Neurobiol 1999; 19(4):511532.

118. Kerr BM, Thummel KE, Wurden CJ, Klein SM, KroetzDL, Gonzalez FJ, Levy RH. Human liver carbamazepinemetabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxideformation. Biochem Pharmacol 1994; 47(11):19691979.

119. Denbow CE, Fraser HS. Clinically significant hemorrhage dueto warfarin-carbamazepine interaction. South Med J 1990;83(8):981.

120. Perucca E. Clinically relevant drug interactions withantiepileptic drugs. Br J Clin Pharmacol 2006; 61(3):246255.

121. Spina E, Pisani F, Perucca E. Clinically significant pharma-cokinetic drug interactions with carbamazepine. An update.Clin Pharmacokinet 1996; 31(3):198214.

122. Kuhn KL, Halikas JA, Kemp KD. Carbamazepine treatmentof cocaine dependence in methadone maintenance patientswith dual opiate-cocaine addiction. NIDA Res Monogr 1989;95:316317.

123. Benitez-Rosario MA, Salinas Martin A, Gomez-Ontanon E,Feria M. Methadone-induced respiratory depression after dis-continuing carbamazepine administration. J Pain SymptomManage 2006; 32(2):99100.

124. Kristensen O, Lolandsmo T, Isaksen A, Vederhus JK, ClausenT. Treatment of polydrug-using opiate dependents duringwithdrawal: Towards a standardisation of treatment. BMCPsychiatry 2006; 6:54.

125. Kleber HD, Gold MS. Use of psychotropic drugs in treatmentof methadone maintained narcotic addicts. Ann N Y Acad Sci1978; 311:8198.

126. Chen Y, Kelton CM, Jing Y, Guo JJ, Li X, Patel NC.Utilization, price, and spending trends for antidepressants inthe US Medicaid Program. Res Social Adm Pharm 2008;4(3):244257.

127. Gillman PK. Tricyclic antidepressant pharmacology and ther-apeutic drug interactions updated. Br J Pharmacol 2007;151(6):737748.

128. Ingelman-Sundberg M. Genetic polymorphisms of cytoc-hrome P450 2D6 (CYP2D6): Clinical consequences, evolu-tionary aspects and functional diversity. Pharmacogenomics J2005; 5(1):613.

129. Cohen MJ, Hanbury R, Stimmel B. Abuse of amitriptyline.JAMA 1978; 240(13):13721373.

130. Maany I, Dhopesh V, Arndt IO, Burke W, Woody G,OBrien CP. Increase in desipramine serum levels associatedwith methadone treatment. Am J Psychiatry 1989; 146(12):16111613.

131. Quinn DI, Wodak A, Day RO. Pharmacokinetic and pharma-codynamic principles of illicit drug use and treatment of illicitdrug users. Clin Pharmacokinet 1997; 33(5):344400.

132. Richelson E. Pharmacokinetic drug interactions of newantidepressants: A review of the effects on the metabolism ofother drugs. Mayo Clin Proc 1997; 72(9):835847.

133. Liu SJ, Wang RI. Increased analgesia and alterations in dis-tribution and metabolism of methadone by desipramine in therat. J Pharmacol Exp Ther 1975; 195(1):94104.

134. Gillman PK. Monoamine oxidase inhibitors, opioid anal-gesics and serotonin toxicity. Br J Anaesth 2005; 95(4):434441.

135. El-Ganzouri AR, Ivankovich AD, Braverman B, McCarthy R.Monoamine oxidase inhibitors: Should they be discontinuedpreoperatively? Anesth Analg 1985; 64(6):592596.

136. Insler SR, Kraenzler EJ, Licina MG, Savage RM, StarrNJ. Cardiac surgery in a patient taking monoamine oxidaseinhibitors: An adverse fentanyl reaction. Anesth Analg 1994;78(3):593597.

137. Michaels I, Serrins M, Shier NQ, Barash PG. Anesthesiafor cardiac surgery in patients receiving monoamine oxidaseinhibitors. Anesth Analg 1984; 63(11):10411044.

138. Gillman PK. Serotonin syndrome: History and risk. FundamClin Pharmacol 1998; 12(5):482491.

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