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

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: [email protected] 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.
Methadone and its role in drug-related fatalities in Cologne REFERENCES
1989–2000. Forensic Sci Int 2003; 132(3):195–200.
17. Darke S, Duflou J, Kaye S. Comparative toxicology of fatal 1. McCance-Katz EF, Mandell TW. Drug interactions of clinical heroin overdose cases and morphine positive homicide vic- importance with methadone and buprenorphine. Am J Addict tims. Addiction 2007; 102(11):1793–1797.
18. Kintz P. Deaths involving buprenorphine: A compendium of 2. Bruce RD, Altice FL, Gourevitch MN, Friedland GH.
French cases. Forensic Sci Int 2001; 121(1–2):65–69.
Pharmacokinetic drug interactions between opioid agonist 19. Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxi- therapy and antiretroviral medications: Implications and man- olytics and hypnotics: Benzodiazepines, buspirone, zoplicone, agement for clinical practice. J Acquir Immune Defic Syndr and zolpidem. Cell Mol Neurobiol 1999; 19(4):533–552.
20. Bruce RD, McCance-Katz E, Kharasch ED, Moody DE, 3. Kandel DB, Huang FY, Davies M. Comorbidity between pat- Morse GD. Pharmacokinetic interactions between buprenor- terns of substance use dependence and psychiatric syndromes.
phine and antiretroviral medications. Clin Infect Dis 2006; Drug Alcohol Depend 2001; 64(2):233–241.
4. Farre M, Teran MT, Roset PN, Mas M, Torrens M, 21. Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8, Cami J. Abuse liability of flunitrazepam among methadone- and CYP2D6 in the metabolism of (R)- and (S)-methadone maintained patients. Psychopharmacology (Berl) 1998; in vitro. Drug Metab Dispos 2003; 31(6):742–747.
22. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel 5. Marsden J, Gossop M, Stewart D, Rolfe A, Farrell M.
K, Kharasch ED. Role of CYP2B6 in stereoselective Psychiatric symptoms among clients seeking treatment for human methadone metabolism. Anesthesiology 2008; 108(3): drug dependence. Intake data from the National Treatment Outcome Research Study. Br J Psychiatry 2000; 176:285– 23. Begre S, von Bardeleben U, Ladewig D, Jaquet-Rochat S, Cosendai-Savary L, Golay KP, Kosel M, Baumann P, Eap 6. Peles E, Schreiber S, Adelson M. Tricyclic antidepres- CB. Paroxetine increases steady-state concentrations of (R)- sants abuse, with or without benzodiazepines abuse, in methadone in CYP2D6 extensive but not poor metabolizers. J former heroin addicts currently in methadone maintenance Clin Psychopharmacol 2002; 22(2):211–215.
treatment (MMT). Eur Neuropsychopharmacol 2008; 18(3): 24. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, Beaune P, Menez JF. Involvement of cytochrome P450 3A4 7. Carpenter KM, Brooks AC, Vosburg SK, Nunes EV. The enzyme in the N-demethylation of methadone in human liver effect of sertraline and environmental context on treating microsomes. Chem Res Toxicol 1996; 9(2):365–373.
depression and illicit substance use among methadone main- 25. Kristensen K, Christensen CB, Christrup LL. The mu1, tained opiate dependent patients: A controlled clinical trial.
mu2, delta, kappa opioid receptor binding profiles of Drug Alcohol Depend 2004; 74(2):123–134.
methadone stereoisomers and morphine. Life Sci 1995; 56(2): 8. Hamilton SP, Klimchak C, Nunes EV. Treatment of depressed methadone maintenance patients with nefazodone. A case 26. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism series. Am J Addict 1998; 7(4):309–312.
of methadone N-demethylation by cytochrome P4502B6 and 9. Petrakis I, Carroll KM, Nich C, Gordon L, Kosten T, 2C19. Chirality 2004; 16(1):36–44.
Rounsaville B. Fluoxetine treatment of depressive disorders in 27. Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson methadone-maintained opioid addicts. Drug Alcohol Depend K. A community-based evaluation of sudden death associ- ated with therapeutic levels of methadone. Am J Med 2008; 10. Uehlinger C, Crettol S, Chassot P, Brocard M, Koeb Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 L, Brawand-Amey M, Eap CB. Increased (R)-methadone 28. Hanon S, Seewald RM, Yang F, Schweitzer P, Rosman J.
plasma concentrations by quetiapine in cytochrome P450s and Ventricular arrhythmias in patients treated with methadone ABCB1 genotyped patients. J Clin Psychopharmacol 2007; for opioid dependence. J Interv Card Electrophysiol 2010; 11. Plummer JL, Gourlay GK, Cherry DA, Cousins MJ.
29. Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolism Estimation of methadone clearance: Application in the man- study of buprenorphine: Evidence for new metabolic path- agement of cancer pain. Pain 1988; 33(3):313–322.
ways. Drug Metab Dispos 2005; 33(5):689–695.
12. Wedekind D, Jacobs S, Karg I, Luedecke C, Schneider U, 30. Moody DE, Slawson MH, Strain EC, Laycock JD, Spanbauer Cimander K, Baumann P, Ruether E, Poser W, Havemann- AC, Foltz RL. A liquid chromatographic-electrospray Reinecke U. Psychiatric comorbidity and additional abuse of ionization-tandem mass spectrometric method for determina- drugs in maintenance treatment with l- and d,l-methadone.
tion of buprenorphine, its metabolite, norbuprenorphine, and a World J Biol Psychiatry 2008; 9:1–10.
coformulant, naloxone, that is suitable for in vivo and in vitro 13. Ball JC, Corty E, Erdlen DL, Nurco DN. Major patterns of metabolism studies. Anal Biochem 2002; 306(1):31–39.
polydrug abuse among heroin addicts. NIDA Res Monogr 31. Kobayashi K, Yamamoto T, Chiba K, Tani M, Shimada N, Ishizaki T, Kuroiwa Y. Human buprenorphine N-dealkylation 14. Darke S, Swift W, Hall W. Prevalence, severity and correlates is catalyzed by cytochrome P450 3A4. Drug Metab Dispos of psychological morbidity among methadone maintenance clients. Addiction 1994; 89(2):211–217.
32. Cheng Z, Radominska-Pandya A, Tephly TR. Studies and intrinsic clearance of phenacetin, tolbutamide, alprazolam on the substrate specificity of human intestinal UDP- and midazolam in adenoviral P450 transfected HepG2 cells, lucuronosyltransferases 1A8 and 1A10. Drug Metab Dispos and comparison with hepatocytes and in vivo. Drug Metab 33. Cheng Z, Radominska-Pandya A, Tephly TR. Cloning and 50. von Moltke LL, Greenblatt DJ, Harmatz JS, Shader RI.
expression of human UDP-glucuronosyltransferase (UGT) Alprazolam metabolism in vitro: Studies of human, mon- 1A8. Arch Biochem Biophys 1998; 356(2):301–305.
key, mouse, and rat liver microsomes. Pharmacology 1993; 34. Green MD, King CD, Mojarrabi B, Mackenzie PI, Tephly TR.
Glucuronidation of amines and other xenobiotics catalyzed 51. Andersson T, Miners JO, Veronese ME, Birkett DJ. Diazepam by expressed human UDP-glucuronosyltransferase 1A3. Drug metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin 35. Coffman BL, Rios GR, King CD, Tephly TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab 52. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interac- 36. Coffman BL, King CD, Rios GR, Tephly TR. The glu- tions. Clin Pharmacokinet 1997; 32(3):210–258.
curonidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab tial of selective serotonin reuptake inhibitors. Int Clin Psychopharmacol 1996; 11(Suppl. 5):31–61.
37. King CD, Green MD, Rios GR, Coffman BL, Owens IS, 54. Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Shader RI.
Bishop WP, Tephly TR. The glucuronidation of exoge- Alprazolam is another substrate for human cytochrome P450- nous and endogenous compounds by stably expressed rat 3A isoforms. J Clin Psychopharmacol 1998; 18(3):256.
and human UDP-glucuronosyltransferase 1.1. Arch Biochem 55. Lintzeris N, Mitchell TB, Bond AJ, Nestor L, Strang J. Pharmacodynamics of diazepam co-administered with 38. Chang Y, Moody DE. Glucuronidation of buprenorphine methadone or buprenorphine under high dose conditions in and norbuprenorphine by human liver microsomes and opioid dependent patients. Drug Alcohol Depend 2007; 91(2– UDP-glucuronosyltransferases. Drug Metab Lett 2009; 3(2): 56. Lintzeris N, Mitchell TB, Bond A, Nestor L, Strang 39. Rouguieg K, Picard N, Sauvage FL, Gaulier JM, Marquet J. Interactions on mixing diazepam with methadone P. Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine Psychopharmacol 2006; 26(3):274–283.
metabolism and relationship with the main UGT polymor- 57. Preston KL, Griffiths RR, Stitzer ML, Bigelow GE, Liebson phisms in a bank of human liver microsomes. Drug Metab IA. Diazepam and methadone interactions in methadone maintenance. Clin Pharmacol Ther 1984; 36(4):534–541.
40. Umehara K, Shimokawa Y, Miyamoto G. Inhibition of human 58. Ernst E, Bartu A, Popescu A, Ileutt KF, Hansson R, Plumley drug metabolizing cytochrome P450 by buprenorphine. Biol N. Methadone-related deaths in Western Australia 1993–99.
Aust N Z J Public Health 2002; 26(4):364–370.
41. Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM.
59. Eap CB, Buclin T, Baumann P. Interindividual variability Interaction of buprenorphine and its metabolite norbuprenor- of the clinical pharmacokinetics of methadone: Implications phine with cytochromes p450 in vitro. Drug Metab Dispos for the treatment of opioid dependence. Clin Pharmacokinet 42. Verebey K. The clinical pharmacology of naltrexone: 60. Preston KL, Griffiths RR, Cone EJ, Darwin WD, Gorodetzky Pharmacology and pharmacodynamics. NIDA Res Monogr CW. Diazepam and methadone blood levels following con- current administration of diazepam and methadone. Drug 43. Gonzalez JP, Brogden RN. Naltrexone. A review of its phar- Alcohol Depend 1986; 18(2):195–202.
macodynamic and pharmacokinetic properties and therapeutic 61. Pond SM, Tong TG, Benowitz NL, Jacob P, III, Rigod J.
efficacy in the management of opioid dependence. Drugs Lack of effect of diazepam on methadone metabolism in Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 methadone-maintained addicts. Clin Pharmacol Ther 1982; 44. Porter SJ, Somogyi AA, White JM. Kinetics and inhibition of the formation of 6beta-naltrexol from naltrexone in human 62. Borron SW, Monier C, Risede P, Baud FJ. Flunitrazepam liver cytosol. Br J Clin Pharmacol 2000; 50(5):465–471.
variably alters morphine, buprenorphine, and methadone 45. Atkinson RL, Berke LK, Drake CR, Bibbs ML, Williams lethality in the rat. Hum Exp Toxicol 2002; 21(11):599–605.
FL, Kaiser DL. Effects of long-term therapy with naltrex- 63. Iribarne C, Picart D, Dreano Y, Bail JP, Berthou F.
one on body weight in obesity. Clin Pharmacol Ther 1985; Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes. Life Sci 1997; 46. Pfohl DN, Allen JI, Atkinson RL, Knopman DS, Malcolm RJ, Mitchell JE, Morley JE. Naltrexone hydrochloride (Trexan): 64. Chang Y, Moody DE. Effect of benzodiazepines on the A review of serum transaminase elevations at high dosage.
metabolism of buprenorphine in human liver microsomes. Eur J Clin Pharmacol 2005; 60(12):875–881.
47. Maany I, O’Brien CP, Woody G. Interaction between thiori- 65. Bomsien S, Aderjan R, Mattern R, Skopp G. Effect of psy- dazine and naltrexone. Am J Psychiatry 1987; 144(7):966.
chotropic medication on the in vitro metabolism of buprenor- 48. Otani K. Cytochrome P450 3A4 and benzodiazepines. Seishin phine in human cDNA-expressed cytochrome P450 enzymes.
Shinkeigaku Zasshi 2003; 105(5):631–642.
Eur J Clin Pharmacol 2006; 62(8):639–643.
49. Donato MT, Hallifax D, Picazo L, Castell JV, Houston JB, 66. Gueye PN, Borron SW, Risede P, Monier C, Buneaux F, Gomez-Lechon MJ, Lahoz A. Metabolite formation kinetics Debray M, Baud FJ. Buprenorphine and midazolam act in combination to depress respiration in rats. Toxicol Sci 2002; Psychopharmacol 1999; 19(5 Suppl. 1):23S–35S.
85. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI.
Kamarulzaman A, Altice FL. Case series of buprenor- Drug interactions with newer antidepressants: Role of human phine injectors in Kuala Lumpur, Malaysia. Am J Drug cytochromes P450. J Clin Psychiatry 1998; 59(Suppl. 15): Alcohol Abuse 2008; 34(4):511–517.
68. Ng WL, Mythily S, Song G, Chan YH, Winslow M.
86. Preskorn SH. Effects of antidepressants on the cytochrome Concomitant use of midazolam and buprenorphine and its P450 system. Am J Psychiatry 1996; 153(12):1655–1657.
implications among drug users in Singapore. Ann Acad Med 87. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on 69. Gueye PN, Megarbane B, Borron SW, Adnet F, Galliot- pharmacokinetics and effects on oxidative drug metabolism.
Guilley M, Ricordel I, Tourneau J, Goldgran-Toledano D, Clin Pharmacokinet 1997; 32(Suppl. 1):1–21.
Baud FJ. Trends in opiate and opioid poisonings in addicts 88. Kosten TR, Rounsaville BJ, Kleber HD. A 2.5-year follow-up in north-east Paris and suburbs, 1995–1999. Addiction 2002; of depression, life crises, and treatment effects on abstinence among opioid addicts. Arch Gen Psychiatry 1986; 43(8): 70. Druid H, Holmgren P, Ahlner J. Flunitrazepam: An eval- uation of use, abuse and toxicity. Forensic Sci Int 2001; 89. Eap CB, Bertschy G, Powell K, Baumann P. Fluvoxamine and fluoxetine do not interact in the same way with the metabolism 71. Ibrahim RB, Wilson JG, Thorsby ME, Edwards DJ. Effect of the enantiomers of methadone. J Clin Psychopharmacol of buprenorphine on CYP3A activity in rat and human liver microsomes. Life Sci 2000; 66(14):1293–1298.
90. Iribarne C, Picart D, Dreano Y, Berthou F. In vitro inter- 72. Kilicarslan T, Sellers EM. Lack of interaction of buprenor- actions between fluoxetine or fluvoxamine and methadone phine with flunitrazepam metabolism. Am J Psychiatry 2000; or buprenorphine. Fundam Clin Pharmacol 1998; 12(2): 91. Prost F, Thormann W. Capillary electrophoresis to assess 73. Hesse LM, Venkatakrishnan K, von Moltke LL, Shader RI, drug metabolism induced in vitro using single CYP450 Greenblatt DJ. CYP3A4 is the major CYP isoform mediating enzymes (Supersomes): Application to the chiral metabolism the in vitro hydroxylation and demethylation of flunitrazepam.
of mephenytoin and methadone. Electrophoresis 2003; Drug Metab Dispos 2001; 29(2):133–140.
74. Megarbane B, Pirnay S, Borron SW, Trout H, Monier C, 92. Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, Hammig Risede P, Boschi G, Baud FJ. Flunitrazepam does not alter R, Gothuey I, Monnat M, Eap CB. ABCB1 and cytochrome cerebral distribution of buprenorphine in the rat. Toxicol Lett P450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 75. Pirnay S, Megarbane B, Decleves X, Risede P, Borron SW, Bouchonnet S, Perrin B, Debray M, Milan N, Duarte 93. Crettol S, Deglon JJ, Besson J, Croquette-Krokkar M, T, Ricordel I, Baud FJ. Buprenorphine alters desmethylflu- Gothuey I, Hammig R, Monnat M, Huttemann H, Baumann nitrazepam disposition and flunitrazepam toxicity in rats.
P, Eap CB. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treat- 76. Tracqui A, Kintz P, Ludes B. Buprenorphine-related deaths ment. Clin Pharmacol Ther 2005; 78(6):593–604.
among drug addicts in France: A report on 20 fatalities. J Anal 94. Iribarne C, Dreano Y, Bardou LG, Menez JF, Berthou F.
Interaction of methadone with substrates of human hepatic 77. Boyd J, Randell T, Luurila H, Kuisma M. Serious over- cytochrome P450 3A4. Toxicology 1997; 117(1):13–23.
doses involving buprenorphine in Helsinki. Acta Anaesthesiol 95. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. CYP2C9 78. Pirnay SO, Megarbane B, Borron SW, Risede P, Monier C, Fluvoxamine is not a specific CYP1A2 inhibitor. Drug Ricordel I, Baud FJ. Effects of various combinations of benzo- Metab Dispos 1999; 27(12):1519–1522.
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 diazepines with buprenorphine on arterial blood gases in rats.
96. Bertschy G, Baumann P, Eap CB, Baettig D. Probable Basic Clin Pharmacol Toxicol 2008; 103(3):228–239.
metabolic interaction between methadone and fluvoxamine in 79. Sekar M, Mimpriss TJ. Buprenorphine, benzodiazepines addict patients. Ther Drug Monit 1994; 16(1):42–45.
and prolonged respiratory depression. Anaesthesia 1987; 97. McCance-Katz EF, Moody DE, Morse GD, Friedland G, Pade P, Baker J, Alvanzo A, Smith P, Ogundele A, Jatlow P, Rainey 80. Swift R, Davidson D, Rosen S, Fitz E, Camara P. Naltrexone PM. Interactions between buprenorphine and antiretrovi- effects on diazepam intoxication and pharmacokinetics in rals. I. The nonnucleoside reverse-transcriptase inhibitors humans. Psychopharmacology (Berl) 1998; 135(3):256–262.
efavirenz and delavirdine. Clin Infect Dis 2006; 43(Suppl. 4): 81. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interac- 98. Spina E, Scordo MG, D’Arrigo C. Metabolic drug interactions tions: An update. Curr Drug Metab 2002; 3(1):13–37.
with new psychotropic agents. Fundam Clin Pharmacol 2003; 82. Mourilhe P, Stokes PE. Risks and benefits of selective sero- tonin reuptake inhibitors in the treatment of depression. Drug 99. Mulsant BH, Foglia JP, Sweet RA, Rosen J, Lo KH, Pollock BG. The effects of perphenazine on the concentration of nor- 83. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin triptyline and its hydroxymetabolites in older patients. J Clin reuptake inhibitors. Pharmacol Ther 2000; 85(1):11–28.
Psychopharmacol 1997; 17(4):318–321.
84. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI.
100. Shin JG, Soukhova N, Flockhart DA. Effect of antipsychotic Human cytochromes and some newer antidepressants: drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: Preferential inhibition of CYP2D6. Drug Metab Dispos 120. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006; 61(3): 101. Ring BJ, Binkley SN, Vandenbranden M, Wrighton SA. In vitro interaction of the antipsychotic agent olanzapine with 121. Spina E, Pisani F, Perucca E. Clinically significant pharma- human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and cokinetic drug interactions with carbamazepine. An update.
CYP3A. Br J Clin Pharmacol 1996; 41(3):181–186.
Clin Pharmacokinet 1996; 31(3):198–214.
102. Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM.
122. Kuhn KL, Halikas JA, Kemp KD. Carbamazepine treatment Olanzapine. Pharmacokinetic and pharmacodynamic profile.
of cocaine dependence in methadone maintenance patients Clin Pharmacokinet 1999; 37(3):177–193.
with dual opiate-cocaine addiction. NIDA Res Monogr 1989; 103. Prior TI, Chue PS, Tibbo P, Baker GB. Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol 1999; 123. Benitez-Rosario MA, Salinas Martin A, Gomez-Ontanon E, Feria M. Methadone-induced respiratory depression after dis- 104. DeVane CL, Nemeroff CB. Clinical pharmacokinetics of que- continuing carbamazepine administration. J Pain Symptom tiapine: An atypical antipsychotic. Clin Pharmacokinet 2001; 124. Kristensen O, Lolandsmo T, Isaksen A, Vederhus JK, Clausen 105. Hanley MJ, Kenna GA. Quetiapine: Treatment for substance T. Treatment of polydrug-using opiate dependents during abuse and drug of abuse. Am J Health Syst Pharm 2008; withdrawal: Towards a standardisation of treatment. BMC 106. Bano MD, Mico JA, Agujetas M, Lopez ML, Guillen JL.
Olanzapine efficacy in the treatment of cocaine abuse in 125. Kleber HD, Gold MS. Use of psychotropic drugs in treatment methadone maintenance patients. Interaction with plasma lev- of methadone maintained narcotic addicts. Ann N Y Acad Sci els. Actas Esp Psiquiatr 2001; 29(4):215–220.
107. Pearson EC, Woosley RL. QT prolongation and torsades de 126. Chen Y, Kelton CM, Jing Y, Guo JJ, Li X, Patel NC.
pointes among methadone users: Reports to the FDA sponta- Utilization, price, and spending trends for antidepressants in neous reporting system. Pharmacoepidemiol Drug Saf 2005; the US Medicaid Program. Res Social Adm Pharm 2008; 108. Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G, 127. Gillman PK. Tricyclic antidepressant pharmacology and ther- Tagliamonte A. QTc interval prolongation in patients on long- apeutic drug interactions updated. Br J Pharmacol 2007; term methadone maintenance therapy. Eur Addict Res 2005; 128. Ingelman-Sundberg M. Genetic polymorphisms of cytoc- 109. Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact hrome P450 2D6 (CYP2D6): Clinical consequences, evolu- of methadone treatment on cardiac repolarization and conduc- tionary aspects and functional diversity. Pharmacogenomics J tion in opioid users. Am J Cardiol 2005; 95(7):915–918.
110. Ozeki Y, Fujii K, Kurimoto N, Yamada N, Okawa M, Aoki 129. Cohen MJ, Hanbury R, Stimmel B. Abuse of amitriptyline.
T, Takahashi J, Ishida N, Horie M, Kunugi H. QTc prolon- gation and antipsychotic medications in a sample of 1017 130. Maany I, Dhopesh V, Arndt IO, Burke W, Woody G, patients with schizophrenia. Prog Neuropsychopharmacol O’Brien CP. Increase in desipramine serum levels associated Biol Psychiatry 2010; 34(2):401–405.
with methadone treatment. Am J Psychiatry 1989; 146(12): 111. Barbey JT, Roose SP. SSRI safety in overdose. J Clin Psychiatry 1998; 59(Suppl. 15):42–48.
112. Ohtani H, Odagiri Y, Sato H, Sawada Y, Iga T. A comparative 131. Quinn DI, Wodak A, Day RO. Pharmacokinetic and pharma- pharmacodynamic study of the arrhythmogenicity of antide- codynamic principles of illicit drug use and treatment of illicit pressants, fluvoxamine and imipramine, in guinea pigs. Biol drug users. Clin Pharmacokinet 1997; 33(5):344–400.
132. Richelson E. Pharmacokinetic drug interactions of new 113. Acikalin A, Satar S, Avc A, Topal M, Kuvandk G, Sebe A.
antidepressants: A review of the effects on the metabolism of QTc intervals in drug poisoning patients with tricyclic antide- other drugs. Mayo Clin Proc 1997; 72(9):835–847.
pressants and selective serotonin reuptake inhibitors. Am J 133. Liu SJ, Wang RI. Increased analgesia and alterations in dis- Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Yale University on 01/09/12 tribution and metabolism of methadone by desipramine in the 114. Vieweg WV, Wood MA. Tricyclic antidepressants, QT inter- rat. J Pharmacol Exp Ther 1975; 195(1):94–104.
val prolongation, and torsade de pointes. Psychosomatics 134. Gillman PK. Monoamine oxidase inhibitors, opioid anal- gesics and serotonin toxicity. Br J Anaesth 2005; 95(4): 115. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003; 89(11):1363–1372.
135. El-Ganzouri AR, Ivankovich AD, Braverman B, McCarthy R.
116. Henry JA, Alexander CA, Sener EK. Relative mortality from Monoamine oxidase inhibitors: Should they be discontinued overdose of antidepressants. BMJ 1995; 310(6974):221–224.
preoperatively? Anesth Analg 1985; 64(6):592–596.
117. Ketter TA, Frye MA, Cora-Locatelli G, Kimbrell TA, Post 136. Insler SR, Kraenzler EJ, Licina MG, Savage RM, Starr RM. Metabolism and excretion of mood stabilizers and new NJ. Cardiac surgery in a patient taking monoamine oxidase anticonvulsants. Cell Mol Neurobiol 1999; 19(4):511–532.
inhibitors: An adverse fentanyl reaction. Anesth Analg 1994; 118. Kerr BM, Thummel KE, Wurden CJ, Klein SM, Kroetz DL, Gonzalez FJ, Levy RH. Human liver carbamazepine 137. Michaels I, Serrins M, Shier NQ, Barash PG. Anesthesia metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide for cardiac surgery in patients receiving monoamine oxidase formation. Biochem Pharmacol 1994; 47(11):1969–1979.
inhibitors. Anesth Analg 1984; 63(11):1041–1044.
119. Denbow CE, Fraser HS. Clinically significant hemorrhage due to warfarin-carbamazepine interaction. South Med J 1990; 138. Gillman PK. Serotonin syndrome: History and risk. Fundam Clin Pharmacol 1998; 12(5):482–491.

Source: http://nysam-asam.com/storage/R.%20Douglas%20Bruce%20Article.pdf

Microsoft word - anticipatedfirsttime_generics.doc

Estimated dates are subject to change due to patent litigation, additional patents, exclusivities… Estimated Dates of Possible First Time Generic/ Rx-to-OTC Market Entry 2010 US Retail Brand Name Generic name Common use(s) (in millions)^ Information current as of July 2011. Estimated dates are subject to change due to patent litigation, additional patents, exclusi


BIGORIO 2003 NAUSEA Konsensus zur Best Practice für Palliative Care in der Schweiz – Expertengruppe der Schweiz. Gesellschaft für Palliative Medizin, Plege und Begleitung Einleitung 2. Warum kommt es zu Chronische Nausea (Übelkeit), mit oder ohne Erbrechen, dem Problem? tritt bei 40–70% der Patienten mit fortgeschrittener Tu-morerkrankung auf, aber auch bei vielen and

© 2008-2018 Medical News