T:\uk\lada\lada37(1)\finals\lada_a_540279.dvi

The American Journal of Drug and Alcohol Abuse, 37:1–11, 2011Copyright Informa Healthcare USA, Inc.
ISSN: 0095-2990 print / 1097-9891 onlineDOI: 10.3109/00952990.2010.540279 Pharmacokinetic drug interactions and adverse consequences
between psychotropic medications and pharmacotherapy for
the 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 clinical consequences. To optimize care, clinicians
Background: Psychiatric comorbidities among
must be alerted to these interactions.
opioid-dependent patients are common. Many
medications used to treat both conditions are
Keywords: methadone, buprenorphine, naltrexone, psychoactive
metabolized through complimentary cytochrome
P450 isoenzymes. When medication-assisted
treatment for opioid dependence is concurrently used
INTRODUCTION
with psychotropic medications, problematic
pharmacokinetic drug interactions may occur.
Opioid dependence remains a major global health issue Methods: We reviewed relevant English language
that is associated with significant negative medical and articles identified through the MedLine, Scopus, and
social consequences. Methadone, buprenorphine, and nal- Embase databases from 1950 to December 2009 using
trexone are evidence-based pharmacological treatments the specific generic names of medications and
for opioid dependence and have consistently been demon- keywords such as pharmacokinetics and drug
strated to be safe and effective. Although pharmacoki- interactions with buprenorphine, methadone, and
netic interactions between pharmacological therapies naltrexone. Selected references from these articles
for opioid dependence and HIV therapies have been were reviewed. Additionally, a review was conducted
reviewed, there remains a paucity of information in the of abstracts and conference proceedings from national
interactions between these therapies and the treatment and international meetings from 1990 to 2009. A total
of a more prevalent condition, mental illness (1,2). The of 60 studies were identified and reviewed. Results:
prevalence of comorbid psychiatric illnesses is many Clinical case series and carefully controlled
times greater among patients with opioid dependence pharmacokinetic interaction studies have been
than among the general population, thus requiring con- Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 conducted between methadone, buprenorphine, or
comitant treatment for both conditions (co-occurring dis- naltrexone and some psychoactive medications.
orders) to achieve optimal outcomes. Despite this urgent Important pharmacokinetic drug interactions have
clinical need, continued concerns regarding the misuse of been demonstrated within each class of medications
methadone or buprenorphine when combined with other affecting either methadone and buprenorphine or
psychotropic medications persist (1).
psychoactive drugs. Few studies, however, have been
Methadone-maintained patients are often concomi- conducted with naltrexone. Conclusions and Scientific
tantly prescribed psychotropic medications because of Significance: Several interactions between methadone,
the high prevalence of psychiatric comorbidity observed buprenorphine, or naltrexone and psychoactive
among individuals with opioid dependence (3–5).
medications are described and may have important
Furthermore, some psychotropic medications have the 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 potential for abuse and there are reports in the literature Methadone, Buprenorphine, and Naltrexone
that some methadone-maintained patients may abuse or Metabolism
be prescribed by a clinician a psychoactive medication Detailed metabolism of each of these medications has such as benzodiazepines (6), selective serotonin reuptake been reported previously (2,20). Briefly, methadone inhibitors (SSRIs) (7–9), antipsychotics (10), tricyclic antidepressants (11), and others that have been associated cytochrome P450 isoenzymes, including CYP 2B6, 3A4, with altered metabolism or synergistic toxicities (e.g., 2C19, 2D6, and 2C8 (21–24). Methadone is a racemic prolongation of the QT interval) with medication-assisted mixture of R and S enantiomers, of which (R)-methadone is the most active compound (25). Metabolism at CYP Case series, for example, from methadone mainte- 2B6 and CYP 2C19 is stereo-selective, and this may nance programs suggest that approximately one-third explain why the plasma concentration ratio of R/S- of patients use benzodiazepines in any given month methadone is variable (22,26). Methadone is metabolized (12–14). Although these medications are sometimes pre- to an inactive metabolite – a risk for opioid withdrawal scribed for the treatment of anxiety disorders in patients, when given with inducing medications. The two most they are frequently taken in excess of prescribed doses important dose-dependent adverse effects of methadone or purchased for self-consumption (6,15). Although the are respiratory depression and cardiac rhythm disorders etiology of this use is diverse, potential explanations related to QT interval prolongation (27) with, in some include the high level of underlying anxiety disorders cases, sudden death through polymorphic ventricular such as post-traumatic stress disorder or self-management tachycardias such as torsade de pointes (28).
of concomitant stimulant use (15). More concerning is Buprenorphine is N-dealkylated to norbuprenorphine that benzodiazepines have been identified in 50–80% of primarily by CYP 3A4 and CYP 2C8 (29–31). Both heroin-related deaths (16), in 63.7% of methadone-related buprenorphine and norbuprenorphine are glucuronidated deaths (17), and in up to 80% of buprenorphine-related by uracil diphosphate–glucuronosyl transferases (UGTs).
The role and importance of UGT has been described Appropriate clinical use of these medications requires previously (32–39). Although there were limitations to an understanding of the principles of both pharmacokinet- some of these reports (34), such as not being con- ics and pharmacodynamics. Pharmacokinetics, described ducted under predefined conditions that compare one iso- as what the body does to the drug, includes pro- form to another, other studies conducted under uniform cesses such as absorption, distribution, localization in conditions provide further insight into UGT’s pharma- tissues, biotransformation, and excretion, whereas phar- cological mechanisms with buprenorphine (38,39). For macodynamics, or what the drug does to the body, example, UGT 1A8 does not appear to be involved refers to the physiological effects of a drug and the in the glucuronidation of either buprenorphine or nor- body’s compensatory homeostatic adjustments to the buprenorphine (38,39). Buprenorphine glucuronidation presence of the drug (19). Given the potential for is, however, principally glucuronidated by UGT 1A3 the serious adverse events, it is important to better with less involvement by 2B6 and 1A1 and much less understand the relative safety of methadone, buprenor- involvement by 2B17. Norbuprenorphine glucuronida- phine, and naltrexone when taken in combination with tion is also principally glucuronidated by UGT 1A3 other psychoactive drugs. We therefore review the with less involvement from 1A1 and much less from clinical and pharmacokinetic data between the treat- 2B17 and 2B7 (38,39). The relative lack of metabolism ments for opioid dependence (methadone, buprenorphine, of norbuprenorphine by UGT 2B7 is a major differ- and naltrexone) and a list of broadly prescribed psy- ence between parent compound and oxidative metabo- chotropic medications that may be commonly coadmin- lite. Two in vitro studies suggest that buprenorphine Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 and its major active metabolite norbuprenorphine areinhibitors of CYP 2D6 and CYP 3A4; however, becauseof relatively high dissociation constant (Ki) for inhibi-tion, they are not predicted to cause clinically importantdrug interactions with other drugs metabolized by major hepatic P450 isoenzymes at therapeutic concentrations We reviewed relevant English language articles identi- fied through the MedLine, Scopus, and Embase databases Naltrexone, available in both oral and injectable from 1950 to December 2009 using specific medica- formulations, is highly bioavailable orally (42) and tion names and keywords such as pharmacokinetic or is not metabolized through cytochrome P450 isoen- drug interactions and buprenorphine, methadone, and nal- zymes. Instead, it is predominantly reduced to 6- trexone. Selected references from these articles were β-naltrexol hepatically by dihydrodiol dehydrogenase reviewed. Additionally, abstracts and conference pro- (43,44). Conjugated naltrexone and conjugated 6-β- ceedings from national and international meetings from naltrexol are then excreted in the urine (42). There are 1991 to 2009 were reviewed using conference proceed- reports of liver toxicity caused by naltrexone (45,46).
ings citation index provided by Web of Science. A total Clinicians should keep this fact in mind when they pre- of 60 studies were identified and reviewed.
scribe naltrexone with other medications associated with potential liver toxicity. With the exception of diazepam, Benzodiazepine Interactions with Buprenorphine there is little, if any, expected pharmacokinetic interac- As buprenorphine (63) and most benzodiazepines (50– tions with naltrexone. There are, however, case reports of 54) undergo extensive metabolism by cytochrome P450 interactions between thioridazine and naltrexone (47).
(CYP 3A4), metabolic interactions are plausible. Changand Moody (64), however, demonstrated that benzo-diazepines are not potent inhibitors of buprenorphine Benzodiazepine Metabolism
metabolism using human liver microsome. Of note, evi- Benzodiazepines are conjugated hepatically by multiple dence for the metabolically activated inhibition of nor- UGT enzymes to form pharmacologically inactive, water- buprenorphine has been shown in the case of midazolam soluble glucuronide metabolites that are then excreted in the urine. The 3-hydroxy benzodiazepines, oxazepam, In rats, high doses of midazolam or buprenorphine lorazepam, and temazepam, by virtue of their 3-hydroxy alone have limited effects on respiratory depression, mea- group, can be conjugated directly. The 2-keto benzo- sured using arterial blood gases, whereas midazolam diazepines, such as chlordiazepoxide, clorazepate, and and buprenorphine appear to be additive or synergis- diazepam, must first be oxidatively metabolized into 3- tic in depressing their respiration and inducing hypoxia hydroxy derivatives before they can be conjugated. The (66). The concomitant injection of buprenorphine with 7-nitro benzodiazepines, clonazepam and nitrazepam, are midazolam has recently been reported in Southeast Asia metabolized by reduction of the 7-nitro substituents to (67,68). The studied subjects have suggested that inject- form inactive amines that are then acetylated before ing midazolam “boosted” and prolonged the effects of buprenorphine (67). The clinical importance of CYP 3A4 Other studies have indicated that CYP 2C19 is inhibition is not established in detail and further studies involved in the metabolism of diazepam, and CYP 3A4 are needed to assess the in vivo inhibition potential.
is involved in the metabolism of alprazolam, clonazepam, Although flunitrazepam is rarely detected in clini- midazolam, and triazolam (48–54). Flunitrazepam is also cal settings due to its rapid degradation in vitro, it is metabolized by CYP 3A4 in humans (48).
suspected to be involved in a large number of buprenor-phine intoxications and adverse consequences (18,69,70).
Benzodiazepine Interactions
Studies performed on human microsome preparations The epidemiology of benzodiazepine use among opioid- have predicted the absence of in vivo metabolic inter- dependent persons and the interactions between benzodi- actions between buprenorphine and flunitrazepam when azepines with methadone or buprenorphine have recently dosed at therapeutic concentrations (40,71,72).
been reviewed by Lintzeris et al. (55).We therefore limit In humans, both CYP 3A4 and 2C19 are involved in our review on this topic and only provide explanatory the metabolic pathways of flunitrazepam to desmethyl mechanisms essential for understanding these interac- flunitrazepam 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 flunitrazepam Benzodiazepine Interactions with Methadone alters neither plasma nor striatal buprenorphine distribu- Safety concerns about benzodiazepines and methadone tion. Pretreatment with buprenorphine has had no effects coadministration (55–57), including potentially fatal cen- on flunitrazepam disposition, while inducing a threefold tral nervous system (CNS) depression, are raised by increase in its main active metabolite, desmethyl flu- practitioners and policy-makers alike (58). During coad- nitrazepam, plasma concentration (75). The desmethyl ministration, the CNS depressive effects may be more flunitrazepam AUC/flunitrazepam AUC ratio, named the Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 synergistic than additive. Data regarding interactions “metabolism index,” has been increased by 41% in between benzodiazepines and methadone are varied, in buprenorphine-pretreated rats when compared with 15% part due to the use of in vitro animal studies and nonther- in controls (75). This difference resulted in a signifi- apeutic doses of medication. Diazepam has been studied cant decrease in PaO2 and an increase in PaCO2 levels most for its interactions with methadone (57,59–61). One in rats, confirming increased respiratory depression (75).
in vitro study (24) demonstrating competitive inhibition As there are differences among species in metabolism, of diazepam on methadone N-demethylation was limited human studies are needed before extrapolating these by supratherapeutic dosing confirmed by a K findings to humans. Similar studies in humans examin- this finding has not been confirmed clinically by such ing flunitrazepam and desmethyl flunitrazepam kinetics, interactions in humans (60,61). Flunitrazepam has also been reported to lower the intravenous minimum lethal Under pharmacological conditions, projected in vivo dose of methadone in rats (62). The differences between inhibition of CYP 3A4-mediated metabolism of fluni- rats and humans, however, may preclude extrapolation of trazepam by buprenorphine is .1–2.5%. Estimated inhi- these results to humans for clinical purposes (62). Table 1 bition of buprenorphine N-dealkylation by flunitrazepam summarizes these interactions. Further studies are needed in vivo is .08% (72). These results are not significant and to determine whether this effect is a pharmacokinetic do not support a buprenorphine–flunitrazepam metabolic interaction or a pharmacodynamic one.
interaction at the concentrations that occur in humans. Of TABLE 1. Interactions between psychotropic medications and methadone or buprenorphine.
respiratory depression andpsychomotor impairment N-demethylation with the Ki of50 μM (24) ↓(R)- and (S)-MTD metabolism (23) been described at the sudden stopof fluvoxamine (96) with MTD, risk of withdrawalsyndromes with sudden cessation Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 Note: MLD, minimum lethal dose; MTD, methadone; BPN, buprenorphine.
note, flunitrazepam markedly lowers the intravenous min- High-dose diazepam has been associated with time- imum lethal dose of buprenorphine in rats (sixfold) (62).
dependent increases in the intensity of subjective med- The adverse consequences of coadministering bupren ication effects and decreases in psychological per- orphine and benzodiazepines have been described for a formance in buprenorphine-maintained patients (55).
number of different benzodiazepines (76,77), most of Buprenorphine, when combined with clonazepam, nor- which do not demonstrate the ability to inhibit bupre diazepam, oxazepam, or bromazepam at therapeu- norphine metabolism, including alprazolam, α-hydroxy- tic doses, has not influenced respiration or arterial exchange in rats, when compared with buprenorphine clonazepam, 3-hydroxy-7-acetamidoclonazepam, demox alone. Combinations of oxazepam or nordiazepam with epam, diazepam, nordiazepam, oxazepam, estazolam, buprenorphine, however, have significantly deepened flurazepam, lorazepam, nitrazepam, temazepam, and sedation in rats (78). These differences are probably because of the unique properties of each benzodiazepine molecule. However, to date, the molecular basis for these among all SSRIs (86) but, unlike fluoxetine and fluvox- observations remains to be determined.
amine, paroxetine is also a mild inhibitor of CYP 1A2, With the exception of midazolam, these results CYP 2C9, CYP 2C19, and CYP 3A4 (84).
strengthen animal studies and observations in humans The metabolism of citalopram leads to two pharma- that suggest the adverse interactions between benzodi- cologically active metabolites with two enantiomers for azepines and buprenorphine most probably arise from a each. It has been shown that CYP 2C19 and CYP 2D6 pharmacodynamic mechanism rather than a pharmacoki- each play a role in the biotransformation of citalopram (83). The N-demethylation of sertraline correlates with Given the disparity between the findings from in vitro and in vivo studies and the clinical findings reportedfrom the case series, pharmacodynamic studies examin- SSRIs Interactions
ing the safety of escalating doses of benzodiazepines in buprenorphine-maintained patients are needed.
Depressive disorders are highly prevalent among thosewith substance use disorders (88), and patients prescribedmethadone are also commonly prescribed SSRIs. There Benzodiazepine Interactions with Naltrexone are reports of pharmacodynamic interactions between There seems to be little likelihood of pharmacokinetic methadone and different SSRIs. For example, fluox- drug interactions occurring in vivo between naltrex- etine significantly increases (R)-methadone concentra- one and most benzodiazepines. The studies on human tions (84,89). It inhibits CYP 3A4 and CYP 2D6, liver microsomal preparations demonstrate that benzodi- both of which are involved in methadone metabolism azepines inhibit dihydrodiol dehydrogenase, the enzyme (84,90), although CYP 3A4 is considered to have a responsible for the formation of 6-β-naltrexol from nal- more prominent role compared with CYP 2D6 (21,91– trexone (44), by less than 20% (44). Moreover, as a 93). Fluvoxamine is a nonselective inhibitor of CYP complete mu-opioid receptor antagonist, one might not anticipate any pharmacodynamic interactions.
3A4 and increases concentrations of both (R)- and Interestingly, naltrexone does increase the sedative (S)-methadone (89,90,94,95). Additionally, opioid with- effects of diazepam and delay the time to reach peak drawal symptoms have been described when fluvoxam- blood diazepam levels. The precise mechanism by which ine is suddenly stopped, because fluvoxamine discon- naltrexone alters the time to peak concentration is not tinues inhibiting 2D6 and 3A4, allowing for increased known, but it is possibly due to a delay in diazepam metabolism of methadone and development of with- absorption (80). Naltrexone increases the half-life of diazepam from 4.0 h to 4.3 h, but the area under the Paroxetine inhibits CYP 2D6 more than fluoxetine or curve (AUC) remains unchanged (80), perhaps suggest- norfluoxetine (50) and is also an inhibitor of CYP 3A4 ing that this would not result in any clinically significant (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 2D6 SSRIs Metabolism
and, to a minor extent, CYP 2C8 (21). Whether discon- Pharmacokinetic interactions caused by metabolic inhibi- tinuation of paroxetine can result in withdrawal is yet tion of CYP isoenzyme activity represent the majority of to be studied. Pharmacodynamic studies, however, have the interactions reported with the SSRIs (81). Although yet to examine the association between paroxetine and members of this class of medications are quite similar increased methadone levels and until they are done, clin- in their antidepressant activity and side effect profiles icians should be alert to the effects of SSRIs on serum Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 (82), they differ substantially in their chemical struc- methadone levels and the possible need for adjusting the ture, metabolism, pharmacokinetics, and their inhibitory methadone dose, especially after sudden discontinuation effects on the cytochrome P450 system.
Fluoxetine is mainly excreted in urine, with less than 10% excreted unchanged or as fluoxetine N-glucuronide SSRIs Interactions with Buprenorphine (83). It has been suggested that CYP 2C9 plays a piv- otal role in the N-demethylation of fluoxetine with a cytochrome P450 3A4, whereas fluoxetine and fluvox- possible contribution of the CYP 2C19 and a CYP 3A4 amine inhibit 2D6 and 3A4 in vitro. Iribarne et al. (90), isoform (83). Fluoxetine strongly inhibits CYP 2D6 (84).
however, demonstrated that fluoxetine does not inhibit Norfluoxetine, a major metabolite of fluoxetine, is also a buprenorphine dealkylation in vitro but norfluoxetine inhibits buprenorphine metabolism. Fluvoxamine, on Fluvoxamine’s main route of elimination is through the contrary, has been shown to inhibit buprenorphine hepatic metabolism that has been found to be associ- dealkylation uncompetitively. There have been instances ated with CYP 2D6 polymorphism and also CYP 1A2 of drug interactions such as the interaction between activity. Paroxetine undergoes extensive metabolism in delavirdine and buprenorphine that can cause a change the liver to form more hydrophilic excretable compounds in the buprenorphine metabolism but does not result (83). Paroxetine is the most potent inhibitor of CYP 2D6 in any clinical manifestations (97). Further studies are needed in this field to determine if these interactions QT Interval Prolongation
are clinically meaningful. Because buprenorphine is a Recent studies document methadone’s ability to prolong partial opioid agonist at the mu-opioid receptor, it is the QT interval that can result in torsade de pointes unlikely that increases in buprenorphine levels would (107–109). Psychotropic medications such as chlorpro- result in respiratory depression and death; however, mazine, intravenous haloperidol, ziprasidone, levomepro- increased levels of buprenorphine have been associated mazine, aripiprazole, and sultopride have been found with increased sedation (2). Further studies are needed to to significantly lengthen the QT interval, whereas oral haloperidol, bromperidol, olanzapine, quetiapine, risperi-done, and zotepine do not (110). Studies examining thepotential interactions of methadone and antipsychotic Antipsychotic Medication Metabolism
medications on QT prolongation are needed to explore the One of the major advantages of novel antipsychotics safety of concomitant administration because of concerns over classical compounds is their negligible effect on that these various medications may have additive effects hepatic drug-metabolizing enzymes (98). Unlike older on QT prolongation when coadministered.
antipsychotics, such as phenothiazines, which are potent Furthermore, members of SSRI family, especially flu- inhibitors of CYP 2D6 (99), novel antipsychotics are only oxetine, paroxetine, and sertraline, have been associated weak in vitro inhibitors of P450 isoenzymes at therapeutic with cardiac rhythm disturbances such as prolonged QT interval (111–113). Moreover, tricyclic antidepressants The major metabolic pathways of olanzapine include have been found to cause defects in the cardiac conduc- direct N-glucuronidation, mediated by UGT 1A4, tion due to the slowdown in the cardiac depolarization and N-demethylation, mediated by CYP 1A2 (102).
and expansions in the QT interval that predispose the patients to cardiac arrhythmias (114–116). Considering include N-oxidation, catalyzed by flavin-containing methadone’s effects on QT interval (107) and the poten- monooxygenase-3 system, and 2-hydroxylation, metabo- tial for additive effects, caution should be advised on lized by CYP 2D6 (101,102). Olanzapine does not inhibit coadministration of these medications and methadone.
P450 isoenzymes (102) and therefore should not have Prescribing higher doses of methadone to improve any significant pharmacokinetic interactions.
treatment outcomes for opioid dependence in recent years Quetiapine, a dibenzothiazepine derivative, is exten- and the frequent addition of psychotropic medications to sively metabolized in the liver by sulfoxidation to form its treatment regimens are two of the reasons why clinicians major, but inactive, sulfoxide metabolite. Eleven metabo- should be more aware of the possible additive effects lites have been identified. N- and O-dealkylation also between antipsychotic medications and methadone. It occur as lesser metabolic pathways (103). Quetiapine and would be advisable to take careful medical history screen- its metabolites were found to be weak inhibitors of the ing for known cardiac risk factors, perform baseline and activity of cytochrome P450 enzymes (CYP 1A2, 2C9, follow-up electrocardiograms, and watch for potential 2C19, 2D6, and 3A4) and are, therefore, not expected to produce clinically relevant inhibition in vivo (104).
Antipsychotic Medication Interactions
Metabolism of Mood Stabilizers
Uehlinger et al. (10) demonstrated that quetiapine Mood stabilizers are medications used to treat mood dis- increases plasma concentrations of (R)-methadone, which orders characterized by intense and sustained mood shifts is speculated to be due to an interaction with CYP 2D6 such as in bipolar disorder. Lithium, the first mood sta- or the P-glycoprotein transporter system or both. In this bilizer, is not metabolized by the liver. Other described Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 particular study, however, no pharmacodynamic signs “mood stabilizers,” most of which are also categorized as of oversedation caused by increased methadone plasma anticonvulsants, include carbamazepine (CBZ), lamotrig- concentrations were described. There are reports of que- tiapine abuse especially among inmates with a history CBZ is extensively metabolized in the liver, with only of drug dependence (105). Further studies are needed about 3% being excreted unchanged in the urine (117).
to confirm the presence of a pharmacodynamic or phar- The main metabolic pathway of CBZ (to its active 10,11- macokinetic interaction between quetiapine and other epoxide, CBZ-E) appears to be mediated primarily by opioids. Opioid withdrawal symptoms might theoretically CYP 3A4, with a minor contribution by CYP 2C8 (118).
occur when quetiapine treatment is abruptly interrupted, This epoxide pathway accounts for about 40% of CBZ but remain unknown until empirically studied.
disposition. More important, however, is the impact of The addition of olanzapine to patients on stable CBZ on inducing CYP 3A4, resulting in many poten- methadone doses has not resulted in clinical with- tial pharmacokinetic interactions (117). CBZ decreases drawal in patients. Moreover, no change in plasma the plasma levels of not only CBZ itself (autoinduc- methadone ratio has been observed in relation to the dose tion) but also many other medications (heteroinduction).
before and during the treatment, which suggests a lack Moreover, if CBZ is discontinued, plasma levels of these of pharmacokinetic interaction between methadone and other medications can rise, leading to toxic effects from Valproic acid is a fatty acid with biochemical prop- depends, to different degrees, upon the isoenzymes CYP erties such as blocking sodium channels and mod- ulating GABAergic function. Valproic acid is exten- Methadone maintenance therapy patients have been sively metabolized with less than 3% being excreted found to use amitriptyline to achieve euphoria (6,129).
unchanged in the urine. There are three principal routes Increased tricyclic antidepressant (TCA) toxicity with of metabolism: (1) conjugations to inactive glucuronides methadone coadministration has been reported (130– (50%); (2) β-oxidation in the mitochondria (40%); and (3) 132). In a retrospective study, decreased methadone cytochrome P450 oxidation (10%) (117). Valproic acid clearance was found in patients receiving amitriptyline may cause clinically relevant pharmacokinetic interac- (11). Liu et al. (133) have shown that desipramine sig- tions by inhibiting the metabolism of selected substrates, nificantly reduces the analgesic ED50 of methadone in most notably phenobarbital and lamotrigine (120).
rats. Desipramine treatment has also been found to sig-nificantly reduce the LD50 of methadone. The addition Mood Stabilizers Interactions
of desipramine to microsomal incubations from nor- The main biotransformation of methadone is the N- mal rat liver has resulted in inhibition of methadone demethylation by CYP 3A4 and CYP 2B6 (21–24). CBZ N-demethylation proportional to the desipramine concen- strongly induces CYP 3A4 activity (121) and conse- tration (133). Because of the differences among species quently accelerates methadone metabolism. In a study on in their metabolism, human studies are needed before 12 methadone maintenance patients, CBZ resulted in a extrapolating these findings to humans. Further studies significant reduction in methadone trough levels, result- are required to better understand the underlying mecha- ing in mild opioid withdrawal symptoms over 7–10 days (122). At the cessation of CBZ, there is a reduction inthe metabolism of methadone with a resultant increase Monoamine Oxidase Inhibitors
in plasma methadone levels, thereby increasing the risk The administration of opioid agonist medications and of overdose, an unfortunate adverse event that has been monoamine oxidase inhibitors (MAOIs) within 2 weeks documented with CBZ cessation (123). Further pharma- of each other is contraindicated. MAOIs can cause a cokinetic studies are needed to determine the extent of serotonin-like syndrome especially when coadministered this effect. Stopping CBZ in the setting of methadone with some SSRIs (134). Many questions have been raised treatment should include close observation of the patient regarding the safety of opioid analgesics in patients who for oversedation and opioid overdose and a need for To the best of our knowledge, there are no serotonin The induction of CYP 3A4 by CBZ could lead to a toxicity reports of methadone and MAOI combination significant reduction of the mean terminal elimination treatments (134) and although methadone is a weak non- half-life of buprenorphine and methadone that is specu- SSRI (138), such reactions are considered unlikely (134).
lated to be clinically relevant (40,41), yet confirmatory The same is true in the coadministration of buprenorphine and MAOIs. There are no reports on serotonin syndrome Surprisingly, the number of pharmacokinetic studies caused by interaction of buprenorphine and MAOIs and on valproic acid and buprenorphine or methadone inter- such interactions are not likely (134).
actions is very limited. Kristensen et al. (124) measuredbuprenorphine levels before and after receiving valproicacid in 12 patients and have concluded that no significant CONCLUSIONS
interactions between the two medications occur.
The studies performed on potential interactions In vitro and well-designed and conducted pharmacologic Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 between lithium and opioid maintenance drugs are studies in humans have defined an array of pharma- limited. In a study in 1978 (125), seven methadone- cokinetic and pharmacodynamic interactions with vari- maintained patients were treated with lithium for a month, able clinical impact between opioid agonist therapies which resulted in a significant decrease in the methadone and psychoactive medications. Being cognizant of pos- dose needed for maintenance. Further studies are needed sible synergistic effects of psychotropic medications and methadone on QT prolongation and the risks involvedare necessary in today’s clinical practice. Careful medical Tricyclic Antidepressants
history taking, risk stratification, and obtaining a base- Antidepressant medications are used in the treatment of line and a follow-up electrocardiogram after a month major depression, neurosis, panic disorder, and chronic of initiating therapy are examples of practices that can pain and tricyclics are one of the most commonly used help clinicians address such risks. Considering the current gaps in knowledge on pharmacokinetic and pharmacody- Inactivation of tricyclics occurs largely through namic interactions between opioid agonist therapies and cytochrome P450 enzymes, by demethylation of tertiary psychoactive medications and the potential for serious tricyclics to their secondary amine metabolites, hydrox- consequences, further human subject studies are required ylation, then glucuronidation, and excretion in the urine to better understand the underlying mechanism of these (127). Tricyclic antidepressant medication metabolism Declaration of Interest
15. Stitzer ML, Griffiths RR, McLellan AT, Grabowski J, The authors report no conflicts of interest. The authors Hawthorne JW. Diazepam use among methadone maintenance alone are responsible for the content and writing of this patients: Patterns and dosages. Drug Alcohol Depend 1981; 16. Grass H, Behnsen S, Kimont HG, Staak M, Kaferstein H.
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