The American Journal on Addictions, 19: 59–72, 2009Copyright C© American Academy of Addiction PsychiatryISSN: 1055-0496 print / 1521-0391 onlineDOI: 10.1111/j.1521-0391.2009.00007.x

Benzodiazepines, Methadone and Buprenorphine:Interactions and Clinical Management

Nicholas Lintzeris, PhD,1 Suzanne Nielsen, PhD2

1Sydney South West Area Health Service and University of Sydney, Sydney, Australia2Turning Point Alcohol and Drug Centre, and Monash University, Melbourne, Australia

Benzodiazepines (BZDs) are widely used by heroin usersnot in treatment, and by patients in methadone and buprenor-phine (BPN) treatment. This review examines the epidemi-ology of BZD use by opioid users, and the range of harms thatare associated with BZD use in this group, including the asso-ciation of BZD use with opioid-related mortality. Preclinicaland clinical data regarding pharmacokinetic and pharma-codynamic interactions between methadone, buprenorphine,and BZDs are reviewed. An overview of treatment approachesfor managing BZD use in this population is presented, in-cluding strategies for minimizing abuse and addressing BZDdependence. (Am J Addict 2009;19:59–72)

INTRODUCTION

Benzodiazepines (BZDs) are widely used by patients inopioid-assisted therapy (OAT). Studies of OAT populationsconsistently identify that patients taking BZDs experiencegreater levels of drug-related harms than non-BZD users.This paper examines the patterns of BZD use, the range ofharms reported, the preclinical and experimental humandata regarding pharmacokinetic (PK), and pharmacody-namic interactions, and summarizes key clinical aspects ofassessment and treatment of BZD use in opioid substitu-tion treatment.

THE EPIDEMIOLOGY OF BZD USE BY OPIOIDUSERS

BZD use is widely reported by opioid-dependent drugusers, including nontreatment and treatment populations.In samples of methadone maintenance populations, life-time use of BZDs is reported to be between 66% and

Received June 19, 2009; revised August 9, 2009; acceptedSeptember 12, 2009.

Address correspondence to Dr. Lintzeris, RPAH, DrugHealth Services, Level 6 King George V Building, MissendenRoad, Camperdown NSW, Australia 2050. E-mail: nlintzer@mail.med.usy.edu.au.

100%1–3 with current use as identified by positive urinaly-sis for BZD of between 51% and 70%.2,4–6 Similar propor-tions have been reported in studies of buprenorphine (BPN)treatment7–9 and in heroin users not in treatment.10–12 Itmust be emphasized that not all opioid users will experi-ence harms or have abuse or dependent patterns of BZDuse.

Estimates of problematic BZD abuse or dependencein these groups vary from 18% to 50%.2,6,13–15 Two re-cent studies have specifically examining BZD use in OATpopulations. In France, Lavie and colleagues9 employedstructured assessment approaches and estimated a lifetimeprevalence of BZD use of 67%, current prevalence (past 30days) of nonproblematic BZD use of 15.3%, BZD abuseof 6.5%, and dependence 24.1% in a group of 170 BPN-maintained patients. In Canada, Brands and colleaguesidentified similar proportions in a group of 172 methadonemaintenance patients at treatment entry—29% had notused BZD in the preceding 12 months, 36% were “occa-sional” users, and 35% were described as “regular or prob-lem” users.16

In addition to high levels of BZD use, significant pro-portions of BZD users in some reports describe parenteralroutes of administration, including injecting2,17–19 and in-tranasal (“snorting”).2,20

CORRELATES OF BZD USE

A number of potential reasons have been cited for thehigh levels of BZD use among opiate users. BZD maybe used in response to high levels of psychological dis-tress, including depression, and anxiety disorders, con-ditions that are regularly reported to be more commonin opioid-dependent individuals than in general popula-tions.21,22 Brand et al. (2008) and Lavie et al. (2009) bothreported higher levels of depression and anxiety symptomsin BZD-dependent OAT patients compared with irregu-lar or non-BZD users. Brands et al. (2008) found that

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amongst OAT patients that did not use BZD anxiety wasself-reported by 18% of patients, this increased to 32%among occasional BZD users and 52% amongst regularor problem users. Lavie et al. (2009) found that 42% ofproblematic BZD users scored above a cut-off of 20 on theBeck Anxiety Index compared with 19% of nonusers. How-ever, it is not possible from these cross-sectional studies toidentify the extent to which BZD use is in response to un-derlying psychological disorders, or indeed contributing topsychological distress as a result of withdrawal or reboundphenomena in long-term, high dose, BZD-dependent pa-tients.23 Another potential reason for BZD use may be toassist with sleep problems, which are frequently reportedby methadone patients.24 Sleep disturbances in turn mayarise from comorbid psychiatric disorders (depression, anx-iety), concurrent substance use (alcohol, stimulants), ormethadone-related sleep apnea.25

BZD use may also be linked to other substance use.BZDs are used to relieve anxiety, agitation, sleep problemsoccurring during alcohol or opiate withdrawal,26,27 or inassociation with psychostimulant use.9

Studies have also highlighted the intoxicating effects ofBZDs as contributing to the high levels of use, with pa-tients reporting greater drug effects when combining BZDswith methadone, as identified in survey1,3,4 and laboratorystudies.28

Once a patient has become BZD dependent, then de-pendence itself will drive continued use. Many patients willidentify increased anxiety or sleep problems following re-duction or cessation of use as evidence of the therapeuticbenefits of BZD use, rather than rebound or withdrawalsyndromes. Indeed, there appears to be a poor understand-ing by many drug users of the potential harms associatedwith high dose or dependent BZD use. For example, onlyone-third of identified BZD abusing or dependent patientsidentified BZDs as a problematic drug.9 This may be con-tributed to by the widespread availability, legal status, andsocial acceptability of BZD in the community, and theperception that as pharmaceutical medications they arenot associated with problems. Among a sample of opioid-dependent polydrug users it has been reported that phar-maceuticals such as BZDs are perceived as “less risky”compared to illicit drugs.29

Examination of individual characteristics of BZD-usingOAT patients reflects many of the above factors. Studieshave consistently shown BZD-using methadone patients tohave higher levels of psychopathology (including depres-sion and anxiety), higher levels of polydrug use, poorer psy-chosocial functioning (including unemployment and crimi-nal activity), greater blood-borne virus (BBV) injecting riskpractices and greater overdose history, and often highermethadone doses than non-BZD users.1,2,4,10,16,30,31 Sim-ilar findings have been reported in BPN treatment pop-ulations.9 However, it remains unclear from these studieswhether these poor outcomes reflect “premorbid” patientcharacteristics (ie, drug users with poor psychosocial health

and “risk-takers” are more likely to use BZDs), or whetherthese outcomes are a result of interactions between BZDsand opioids. Psychopharmacology research addressing thisissue is reviewed below.

A major concern regarding BZD use in opiate usersis their potential contribution to opioid-related deaths.Studies of methadone-related deaths vary in the propor-tion of cases in which BZD were identified, from low lev-els (eg, fewer than 10% of 106 methadone-related over-doses in Texas,32 20% of 3,298 methadone deaths in theUnited Kingdom33) to high levels of approximately 80%of methadone-related deaths reported in Australian stud-ies.34,35 The variations may reflect different access to un-supervised methadone; for example increased supervisionof methadone dosing in the United Kingdom resultedin a reduction in deaths compared to higher numbersof “methadone-only” deaths when supervised methadonedosing was less common.33 Similarly, high levels of BZDshave been identified in BPN-related deaths, often in therange of 80% or more deaths.36–39 In particular, injectingBPN and/or BZD use has been identified as increased riskof death in these cases.38,39 There is insufficient data toknow whether the combination buprenorphine-naloxoneproduct may be a safer option because of its reduced abuseliability40 and the potential protective properties of nalox-one if the product is injected. Nielsen and colleagues (2007)examined incidence of opioid toxicity in BZD-using pa-tients with experience of both methadone and BPN treat-ment.7 Subjects identified significantly more episodes of se-vere drowsiness and nonfatal overdoses during methadonethan BPN treatment, suggesting that there may be a differ-ential safety profile of the two opioids in combination withBZDs.

TYPES OF BZDS USED

The types of BZD more frequently used by injectingdrug users (IDUs) and those in OAT, suggest that thereare international similarities, and regional and temporaldifferences. More commonly reported BZDs used by OATpatients consistently include diazepam, flunitrazepam, andalprazolam, with generally lower levels of oxazepam, ni-trazepam, chlordiazepoxide, and clonazepam reported instudies.1−3,17,41,42 However, it remains unclear as to whetherthese merely reflect local availability, local prescriber anddrug user trends and familiarity, or whether certain BZDshave an inherent greater abuse liability.1,3,43,44

Certain pharmacological properties may contribute toabuse liability. It has been suggested that BZDs with morerapid onset of action, such as diazepam, alprazolam, flu-nitrazepam, temazepam, and midazolam, are more likelyto be abused than slow-onset BZDs (eg, oxazepam, clon-azepam, nitrazepam).43,45 Onset of action is largely relatedto route of administration, lipophilicity of the drug,46 andreceptor affinity.

60 Benzodiazepine and OAT Interactions January–February 2010

Short-acting BZDs (eg, alprazolam, temazepam, mida-zolam) are also more likely to contribute to rebound orwithdrawal symptoms in dependent individuals,44 therebyreinforcing continued use. Furthermore, certain prepara-tions may be more easily injected. For example, temazepamwas commonly injected by Australian drug users whenavailable as gel capsules, however temazepam injectingalmost ceased after the gel capsules were removed fromthe market.47 There has been little laboratory researchexamining the abuse liability of different BZDs in opi-ate substitution patients. Farre and colleagues45 reportedthat in methadone-maintained individuals, high-dose flu-nitrazepam (4 mg) produced greater levels of drug “high” oreuphoria than triazolam (up to 0.75 mg), whereas triazolamproduced higher levels of sedation, but with delayed peakeffects. In other respects (physiological and performancemeasures), there were no distinct differences between thedrugs. The authors reported that these laboratory studiesconfirmed the greater abuse potential of flunitrazepam re-ported in epidemiological studies.

Other placebo-controlled studies have examined theabuse liability of different BZDs in individuals with his-tories of drug abuse, but not enrolled in OAT. These studiesconfirm that BZDs with faster onset of action and greatersubjective effects (diazepam, lorazepam, alprazolam) havegreater abuse liability than chlordiazepoxide, oxazepam,and halazepam.48 Laboratory studies have also confirmedthe greater abuse potential of flunitrazepam compared totriazolam, in nonopioid-dependent drug users.45,49

LABORATORY STUDIES OF BZD INTERACTIONSWITH METHADONE AND BUPRENORPHINE

Potential mechanisms for drug interactions betweenBZDs and OAT medications include PK interactions—usually at the level of interactions in the metabolism orprotein binding of drugs, and pharmacodynamic interac-tions at the site of drug action, usually through receptorsystems.

PK DATA

A potential PK mechanism for interactions betweenBZDs and methadone or BPN is through shared CYP en-zyme metabolic pathways. Many BZDs are metabolized bythe CYP450 (typically 3A4) enzyme system. For example,diazepam is metabolized by CYP3A4 and CYP2C19, whileflunitrazepam, alprazolam, clonazepam, and midazolamare largely metabolized by CYP3A4.50 It is thought thatmost BZDs are weak competitive inhibitors of CYP3A4enzymes.51

Interactions with MethadoneMethadone is metabolized by multiple CYP isoforms

to inactive metabolites; the isoforms CYP2B6, 2C19, and

3A4 are thought to be the most active, with lesser roles forCYP2C9 and CYP2D6.52 Methadone can also act as an in-hibitor of CYP2D6.53 Early animal research suggested po-tential PK interactions between diazepam and methadone.Spaulding et al. examined liver methadone concentrationsfollowing large diazepam doses in methadone-dependentrats, reporting that diazepam was a noncompetitive in-hibitor of methadone metabolism.54 Shah et al.55 and Liuet al.56 reported that diazepam administered 1 hour beforemethadone resulted in increased methadone concentrationsin hepatic and brain tissues, decreased urinary and hep-atic methadone metabolites—again suggesting an inhibi-tion of methadone metabolism. In vitro research using hu-man liver microsomes demonstrated that N-demethylationof methadone by CYP3A4 was competitively inhibited bydiazepam, with modeling suggesting potentially clinicallysignificant inhibition of methadone.57 These studies how-ever are in contrast to more recent research indicating BZDsare only weak inhibitors of 3A4, insufficient to cause clini-cally relevant interactions.51

The two available clinical studies in methadone patientssuggest the lack of any significant PK interactions betweenmethadone and diazepam. Pond et al.58 examined the ef-fects of 9 days of treatment with 0.3 mg/kg oral diazepamin four methadone-treated patients, with plasma measuresof methadone and its metabolites before, during, and af-ter diazepam treatment. No differences were reported inplasma levels of methadone or its metabolites, nor in theplasma protein binding of methadone. Preston and col-leagues examined the effects of single doses of diazepam (20and 40 mg) administered at different test sessions in com-bination with 100% and 150% normal methadone doses(50–60 mg) in five patients.59 Concurrent administration ofthe drugs did not significantly alter the time course, Cmax,or area under the curve of methadone, diazepam or itsmetabolite N-desmethyldiazepam than either drug alone,although marked subjective and physiological changes weredescribed (see below). Both studies suggest that the pre-dominant interactions are pharmacodynamic in nature.

Interactions with BuprenorphineBPN is metabolized by N-dealkylation by CYP3A en-

zymes to norbuprenorphine,60 a potent respiratory depres-sant,61 although BPN appears to have a protective effectpreventing respiratory depression caused by the metabo-lite.62 BPN has a relatively low affinity for CYP3A4 andis a weak competitive inhibitor of the enzyme.63 Zhangand colleagues64 demonstrated that BPN and norbuprenor-phine inhibit a range of substrates of the CYP450 enzymes(including 3A and 2D6) at high doses; however, the authorsconcluded that interactions with drugs that are metabolizedby these enzymes are unlikely at therapeutic BPN levels,though possible at extremely high doses.

Several animal studies have specifically examined PK in-teraction between BPN and BZDs. Megarbane et al. found

Lintzeris and Nielsen January–February 2010 61

that at high BPN doses (30 mg/kg), neither plasma norstriatum BPN kinetics were affected by 40 mg/kg fluni-trazepam pretreatment.65 Kilicarslan and Sellers examinedthe effect of the same drugs in an in vitro model using hu-man liver microsomes, with co-administration not affect-ing the plasma concentration or kinetics of either drug.66

Chang and Moody51 examined multiple BZDs and theirmetabolites upon the metabolism of BPN in human livermicrosomes, reporting that only midazolam inhibited BPNmetabolism. Therefore, given the range of BZDs examinedand the limited evidence of a PK interaction, it appearsthat a pharmacodynamic interaction is most likely, at leastat therapeutic doses. The evidence however is not conclu-sive, with a recent study suggesting BPN may effect flu-nitrazepam disposition.67 Pirnay and colleagues examinedthe effect of the combination of very high dose (30 mg/kg)BPN and 40 mg/kg flunitrazepam in rats, demonstratingincreased respiratory toxicity, mediated by an increase inactive flunitrazepam metabolites when both drugs were ad-ministered, although the exact mechanisms of these druginteractions remain unclear.67 Thus, in the absence of anyhuman clinical studies examining PK interactions, the bal-ance of preclinical data suggests minimal PK interactionat therapeutic doses, although potential interactions mayoccur at extremely high doses.

PHARMACODYNAMIC DATA

Several preclinical studies have examined the pharmaco-dynamic interaction between opioids and BZDs. In threein vivo studies using Sprague-Dawley rats, high doses ofBZDs and BPN alone resulted in mild respiratory ef-fects; however, the combination together produced moresevere respiratory depressant effects.65,68,69 Consequently,the ceiling effect to which BPN safety is attributed maynot be present when BPN is co-administered with otherpsychoactive drugs. When co-administered with high-dosediazepam, BPN appeared to act more like a full opioid ag-onist, such as methadone, with a dose-dependent increasein effect.69 However, high-dose BPN with “therapeutic”doses of BZDs did not produce marked respiratory de-pression,70 consistent with findings in human studies ofBPN-dependent individuals.71,72

Unlike BPN, methadone can have a significant effecton respiration in the absence of other psychoactive drugs.The effect of methadone is significantly potentiated by di-azepam administration,69,73 with the most severe respira-tory depression seen in animals naı̈ve to both opioids andBZDs.73

One animal study has examined the lethality of BZDsin combination with different opioids.74 Borron and col-leagues examined the median lethal doses (LD50) ofmorphine, BPN, and methadone in rats, with and with-out pretreatment with flunitrazepam (40 mg/kg). Fluni-trazepam caused the median lethal doses to significantly

decrease for methadone and BPN but not for morphine.The LD50 of BPN in the absence of other drugs was235 mg/kg, an extraordinarily high dose, compared to theLD50 of methadone (23 mg/kg). Flunitrazepam adminis-tration caused the LD50 to reduce for both methadone (to13 mg/kg) and BPN (38 mg/kg—which still represents avery high dose). Time to death was quite rapid (less thanone hour) for methadone and flunitrazepam, comparedwith 24 hours for BPN and flunitrazepam.

CLINICAL STUDIES

There are few studies of pharmacodynamic interac-tions between BZDs and methadone or BPN in opioid-dependent persons. The first study (Pond et al. 1982)58 ad-ministered “therapeutic” diazepam doses (20 mg in men,15 mg in women) in two split daily doses over 9 days topatients taking their usual methadone dose (mean 50 mg).The focus of the research was on kinetic parameters, andthe authors only reported that although patients were“sedated during the diazepam period,” there was no sig-nificant difference in subjective symptoms of opioid in-toxication or withdrawal reported each morning prior todosing. The authors concluded no pharmacodynamic in-teraction, although the low (and split) diazepam doses andlimited outcome assessment were unlikely to detect anysuch interaction.

Preston and colleagues75 examined acute physiologicaland subjective effects following single oral diazepam doses(0, 20, and 40 mg) alone or in combination with 100% and150% usual methadone dose (50–60 mg) in five patients.There were no consistent changes in physiological parame-ters other than diazepam + methadone was associated withgreater pupillary constriction than either drug alone. Sub-jective effects were examined using opioid-sensitive adjec-tive checklists, a visual analogue scale for drug “high” andAddiction Research Center Inventory (ARCI) subscales.Methadone-alone induced dose-dependent changes in sub-jective opioid effects, diazepam-alone induced no signifi-cant opioid effects, whereas the methadone–diazepam com-bination produced greater subjective opioid effects thaneither drug alone. Diazepam 40 mg condition (with orwithout methadone) produced the greatest rating of drug“high,” while the authors reported only minor changesin ARCI scores. In conjunction with the assessment thatthere were no significant PK changes in plasma levels ofmethadone, diazepam, or diazepam metabolites,59 the au-thors concluded that there was a pharmacodynamic inter-action in which both sedation and the opioid-like effectsof methadone are enhanced by high-dose oral diazepam(40 mg), in part explaining the high levels of BZD use bymethadone patients seeking intoxication.

An alternative research approach was used by Spigaand colleagues28 to examine additional methadone self-administration in addition to routine 80 mg methadone

62 Benzodiazepine and OAT Interactions January–February 2010

doses following diazepam doses (0, 5, 10, 20 mg per 70 kgbodyweight) administered 45 minutes prior to methadonedosing. Additional methadone consumption was signifi-cantly lower following 10 and 20 mg diazepam. Participantratings of subjective drug effects were greater followinglower doses of methadone + diazepam (dose dependent),compared with higher doses of methadone and placebo.

The physiological, psychomotor performance, and sub-jective effects of flunitrazepam (1, 2, and 4 mg) and triazo-lam (0.5 and 0.75 mg) were investigated in a randomizedcross-over design in 10 methadone maintenance patients(dose range 40–50 mg).45 Neither BZD produced clin-ically significant physiological changes. All BZD dosessignificantly impaired simple reaction time, high-dose flu-nitrazepam (2 and 4 mg) and both triazolam doses sig-nificantly impaired digit-symbol substitution test (DSST)scores, while only high-dose flunitrazepam (4 mg) impairedthe balance task. High-dose flunitrazepam (4 mg) producedthe greatest subjective changes (“high,” “any effect,” and“drunken”), ARCI-MBG scores (“euphoric” effects), andanger score on the POMS. High-dose triazolam producedthe greatest changes for subjective ratings of “drowsiness”and “performance,” ARCI PCAG (consistent with “seda-tion” effects), and POMS score for depression. Peak sub-jective changes were noted 1–2 hours after flunitrazepam,and 2–3 hours after triazolam dosing. These findings sug-gest differences between the two BZDs, concordant with thereports of frequent abuse of flunitrazepam in methadonepatients.2,8,41 Similar research comparing the effects of flu-nitrazepam and triazolam in nonopioid-dependent individ-uals45,49 highlight the abuse potential of flunitrazepam indrug abusing populations.

Lintzeris and colleagues examined BZD effects inBPN and methadone-maintained subjects.71,76 In theirfirst study, 0, 10, and 20 mg diazepam dose effects wereassessed in 8 methadone- and 8 BPN-maintained pa-tients.71 Diazepam had no significant impact upon phys-iological parameters. The peak effects following diazepamin methadone patients were significantly greater thanplacebo on measures such as “strength of drug effects,”“drug-liking,” and euphoria (ARCI-MBG), while in BPNpatients diazepam produced significantly greater effectsthan placebo for measures of “sedation” (VAS rated andARCI). There were contrasting effects upon performancemeasures—20 mg diazepam in methadone patients resultedin a significant deterioration in reaction time, DSST, andcancellation time; whereas the peak effects of diazepam inBPN patients were less marked, with a significant deterio-ration only in cancellation time.

The same authors examined the effects under “abuse”conditions—0 and 40 mg diazepam in addition to 100%and 150% normal OAT doses in four methadone and sevenBPN-maintained patients.76 Opioid dose alone producedno significant subjective effects in methadone or BPN pa-tients. A dose of 40 mg diazepam produced significantlygreater peak subjective effects on measures of sedation and

strength of drug effect in the methadone group, whereas nosignificant peak drug effects of diazepam were found in theBPN group. A dose of 40 mg diazepam produced some ev-idence of respiratory depression (spO2) in methadone, butnot BPN subjects. Performance measures showed generaldeterioration following 40 mg diazepam in both methadoneand BPN subjects, but were largely unaffected by opioiddose alone. In a similar study design, 2 mg alprazolamwas found to have effects consistent with those seen withdiazepam in OAT patients.77 In this study with greater im-pairment on performance measures and a trend towardsignificant effects of 2 mg alprazolam was observed inmethadone patients.77 In this same study design, thera-peutic doses of alprazolam did not cause significant effectson respiration in BPN-naloxone patients. These findings ofthese laboratory-based studies are in accord with survey re-search suggesting greater subjective and respiratory effectsfollowing BZD use in patients while receiving methadone,rather than BPN treatment.7

Studies of methadone78 and BPN79 patients indicate im-paired memory function compared to healthy controls, al-though it remains unclear whether these deficits are dueto the effects of medication, or reflect underlying patientcharacteristics or concomitant medical or psychiatric con-ditions. Likewise, chronic BZD use is associated with persis-tent memory deficits, suggesting failure to develop markedtolerance to this effect.80,81 It may be expected thereforethat BZDs in OAT populations would be associated withmemory impairment. Lintzeris et al. reported impaired ver-bal memory recall following routine methadone but notBPN dosing, and that BZD doses impaired memory inBPN-treated patients.71 Rapeli et al. also demonstratedimpaired memory in methadone and BPN patients usingBZDs compared to control subjects, which persisted afterseveral months of treatment.82

MECHANISMS OF PHARMACODYNAMICINTERACTIONS

Possible mechanisms for a PK interaction between BZDsand the opioids methadone and BPN may be at the recep-tor level. BZDs act predominately by binding to GABAA-BZD receptor complex in selected CNS neurons. Bindingof a BZD to its receptor increases the GABAA receptor’sresponse to GABA, resulting in an increased chloride ionconduction and a decreased membrane excitability.83 Opi-oids act predominately through the central and periph-eral opioid receptors. There is some animal research tosuggest bidirectional interactions between these two re-ceptor systems. The opioid antagonist naloxone reducescertain BZD effects in rats, such as conflict and aggres-sion.84,85 Intrathecal injection of midazolam and otherBZDs have been shown to enhance analgesia, potentiallymediated by BZDs binding and acting as agonists at kappa(but not mu and selectively to delta) opioid receptors.86

Lintzeris and Nielsen January–February 2010 63

Furthermore, both receptor systems use common intracel-lular transduction pathways,87 a potential mechanism fordrug interaction.

The mechanisms for additive effects upon respiratory de-pression from combined BZDs and opioids are also poorlyunderstood.88 Respiration is controlled largely throughmedullary respiratory centers with input from periph-eral chemoreceptors and other sources. Both opioid andGABAA receptor systems are present in the brainstem res-piratory centers,89 and again receptor interactions may oc-cur at this level. Megarbane et al. has postulated that BZDintoxication increases upper airway resistance, which com-bined with an opioid-induced reduction of central and pe-ripheral respiratory drive may be sufficient to cause additiverespiratory depression.88

Ventilatory challenge tests indicate that acute opioid usesignificantly reduces the responsiveness of the brainstemrespiratory centers to carbon dioxide, and reduces periph-eral chemoreceptor response to hypoxia, thought largelyto be mediated by mu opiate receptors.90,91 Similar effectshave been reported in stable methadone patients.92 BZDslikewise reduce ventilatory responses to hypoxia and hy-percapnia,93 and animal models suggest that BZDs maypotentiate the respiratory effects of acute opioids,94,95 al-though the underlying mechanisms remain unclear.

IMPLICATIONS FOR CLINICAL PRACTICE

As discussed earlier, BZD-using OAT patients consis-tently report more harms across a spectrum of domainsthan non-BZD users. Many of these harms can be un-derstood by the pharmacodynamic interactions describedin laboratory studies. Concurrent use of high-dose BZDs(eg, 20–40 mg diazepam, 2–4 mg flunitrazepam) can resultin subjective drug effects of euphoria or drug “high” thatmay be sought by some patients, however can also produceimpaired performance and memory, and hence may con-tribute to harms such as high-risk injecting practices, ag-gression, and criminality. In combination with methadoneand (probably less so) BPN, high-dose BZDs can reducerespiration, resulting in fatal and nonfatal overdoses. Long-term BZD dependence may impair mood states, cognitivefunction, memory, and sleep architecture, while BZD with-drawal can precipitate a range of physical, mood, and per-ceptual problems, including seizures.

The impact of BZD abuse and dependence upon broaderOAT treatment outcomes however suggests that BZD useduring OAT is not necessarily associated with poorer out-comes. Most studies have found that BZD use at base-line is not significantly related to methadone treatmentretention.16,96,97 However certain patterns of behavior atbaseline seem to persist during treatment—for example, inone study16 BZD users at treatment entry reported morepolydrug use (cocaine and heroin) at baseline, and contin-ued to use more heroin and cocaine than non-BZD users,

although all subjects improved over time. Of the four ran-domized controlled trials of methadone and BPN main-tenance treatment that reported on BZD use as a treat-ment outcome98 none reported a difference in BZD-positiveurines detected between BPN or methadone groups.

However, given the high prevalence of BZD use in OATpopulations, and the greater reports of harms in this pa-tient population than non-BZD users, particular attentionshould be given to addressing BZD issues in OAT settings.The following describes key principles in the managementof BZD use in OAT settings.

ASSESSMENT

Processes for assessment of patients for opioid substitu-tion treatment are well documented, and include history,physical, and mental state examination, investigations anduse of collateral information. Assessment should specifi-cally address recent and previous BZD use, including fre-quency, amounts, and routes of use, how BZD use altersin relation to other substance use (eg, to ameliorate opiateor alcohol withdrawal, or counter psychostimulant effects).The source of the patient’s BZDs (from doctors, “gray” or“black” markets) should be explored. Assessment shouldaim to determine the extent of BZD dependence (includ-ing withdrawal features), binge or abuse patterns, and anyparticular precipitants to use. This may require several con-sultations, and include urine drug screening and other ob-jective measures (such as reviewing reports of prescriptionsreceived where available) over a period of time.

Adverse events or harms linked to BZD use should beexamined, including uncharacteristic high-risk behaviorswhile intoxicated (including crime, BBV risk practices, mo-tor vehicle accidents, arguments) and overdoses. Harms as-sociated to long-term BZD use should be assessed, such asimpairments of memory and cognition, “emotional blunt-ing,” and withdrawal symptoms such as seizures, perceptualchanges, increased anxiety, or sleep problems (particularlywith short-acting BZDs). These harms or adverse conse-quences can be re-examined at a later stage in motivatingpatients to change their patterns of use, and in monitoringtreatment outcomes.

Relevant concurrent medical and mental health condi-tions should be assessed, including anxiety and depression,neurological conditions (eg, epilepsy), and sleep disorders.In particular, the recent identification of methadone asa possible contributing factor in sleep apnea25 warrantsassessment of sleep disorders, as such patients may beparticularly vulnerable to combined BZDs and high-dosemethadone. An ageing OAT population may also increasethe prevalence of such medical conditions, and other risksassociated with BZD use, such as falls.99,100

In patients already engaged in OAT, a review of treat-ment conditions should be conducted, including fre-quency and attendance at clinical appointments, urine drug

64 Benzodiazepine and OAT Interactions January–February 2010

screening, participation in health and psychosocial servicesaddressing co-morbidities, missed doses or intoxicatedpresentations, level of supervision, and adequacy of themethadone/BPN doses. While there is some evidence tosuggest that low opioid doses may contribute to BZD use(eg, Lavie et al. 2009), concern should also exist regard-ing patients who may exhibit features of over-sedation andrespiratory depression due to concurrent BZD and highmethadone (eg, >150 mg) doses, which may require as-sessment 2–3 hours after dosing, when sedation may begreatest.45,71

An aspect of assessing recent BZD use includes the roleof urine drug testing. BZDs are largely excreted in the urinefollowing hepatic metabolism, however caution is requiredwhen interpreting test results, as tests may identify the BZDconsumed, BZD metabolites, or indeed fail to detect anyBZD due (false negatives) to insensitive pathology pro-cedures.101 Some BZDs such as clonazepam do not haveactive metabolites making interpretation of urine testingless complicated while other BZDs such as diazepam havemultiple metabolites including oxazepam.102 As such, careshould be taken to ensure that metabolites of prescribedmedications are not confused with use of illicit BZDs.Where diazepam is prescribed for example, it may not bepossible to exclude illicit oxazepam use, and equally it isimportant that clinicians should understand that oxaza-pam on toxicology results may only indicate an expectedmetabolite of prescribed diazepam. Clinicians should con-tact their local pathology services where these queries areraised.

IS THERE A THERAPEUTIC ROLE FOR BZDSIN OAT PATIENTS?

As with all medications, potential therapeutic benefitsmust be balanced against potential adverse consequences,with recognition that risks are increased in particular sub-groups. Particular caution should be shown in patients with(a) current or previous BZD-related problems—especiallythose with abuse or dependence, and (b) those with con-comitant conditions that increase the vulnerability to BZD-opioid interactions, such as cognitive or memory impair-ment, respiratory depression, use of other sedatives (eg,tricyclic antidepressants, antipsychotics, opioids, alcohol),and those with reduced hepatic clearance of certain BZDs,such as in those with cirrhosis and the elderly.

The primary indications for BZDs are for the man-agement of sleep disorders and anxiety disorders. Theevidence for BZD treatment of sleep or anxiety disor-ders is largely confined to short-term controlled trials ofup to several months duration in nonopioid-dependentpopulations,103,104 and long-term observational studies ofBZD treatment for these indications are difficult to in-terpret due to imprecision in the differentiation of re-lapse, rebound, and withdrawal phenomena. BZDs such as

diazepam and chlordiazepoxide are also indicated in somecountries for the management of acute alcohol withdrawalsyndrome.

Given that many OAT patients presenting with anxi-ety or sleep complaints experience chronic disorders, theseconditions are unlikely to respond to short-term BZDtreatment. As such BZDs should generally be avoidedin OAT patients, with greater emphasis upon alternativetreatment approaches. Nonpharmacological approachesfor anxiety and sleep disorders are often effective and gener-ally recommended—including relaxation training and sleephygiene strategies, cognitive behavioral therapy (CBT) foranxiety disorders.105 Recent reviews of pharmacologicaltreatment for anxiety disorders supported the use of an-tidepressants (selective serotonin reuptake inhibitors) asfirst-line treatment for anxiety disorders,106,107 with fewerrisks of dependence, sedation, cognitive impairment, andoverdose. Specialist assessment and treatment may be indi-cated for those individuals experiencing severe anxiety orsleep disorders.

A common request by patients is for BZDs to assist inagitation and sleep problems associated with withdrawalfrom methadone or BPN maintenance treatment. As with-drawal symptoms from OAT tend to be protracted, lastingweeks to months, the development of BZD dependence inthis population is a genuine concern if BZDs are used forsuch prolonged periods. Additional risks include overdose,in combination with BZDs, in those who relapse to heroinuse following OAT cessation.

Nevertheless, there are patents without histories of BZDmisuse or dependence that may benefit from short courses(eg, up to 2–4 weeks) of BZDs, as an adjunct to psychoso-cial treatment approaches. Strategies to limit adverse eventsand aberrant drug behaviors are described below. The de-velopment of dependence may be minimized by avoidingdaily use of BZDs where possible—for example, restrictinghypnotic BZD use to 3–5 nights per week, with the empha-sis being upon educational and behavioral approaches.

MANAGEMENT OF BZD ABUSE

In this context, BZD abuse refers to high-dose and/orbinge patterns of use that are associated with adverse eventsor harms (eg, overdoses, intoxicated presentations), butnot meeting criteria for significant BZD dependence. Thereis limited role for prescribing BZD in patients with BZDabuse. Efforts should be directed to addressing concurrentpsychiatric, medical, and social conditions, and minimizingthe potential for harms arising from BZD-opioid interac-tions. Strategies to consider include:

• patient education regarding the potential adverseconsequences of BZD use. This should target po-tential “immediate” effects of BZD co-intoxication(eg, impairment of memory, cognition, and judgment,

Lintzeris and Nielsen January–February 2010 65

TABLE 1. Signs and symptoms of benzodiazepine withdrawal123

Common Less common Uncommon

Anxiety Lethargy DelusionsInsomnia Nightmares, agoraphobia ParanoiaRestlessness Feelings of unreality HallucinationsAgitation Depersonalization SeizuresIrritability Panic attacks Persistent tinnitusPoor concentration Nausea, dry retching, decreased appetite, weight loss, DeliriumPoor memory sweatingDysphoria LethargyMuscle tension, aches, and twitching Increased sensory perception, aches and pains, headaches,

palpitations, tremor, blurred visionIncreased temperature, ataxiaMenstrual changes

and how this can in turn lead to high risk behaviorsand harms such as needle sharing, unsafe sex,violence, crime, and driving offences), as well aslonger-term disturbances in sleep and mood.

• regular monitoring and review• ensure supervised dispensing of OAT and limit access

to take-away doses• assess OAT dose: ensure an adequate OAT dose to

prevent opiate withdrawal symptoms. Consider re-ducing high methadone doses (eg, >150 mg) as ameans of reducing overdose risk in patients with fre-quent intoxicated presentations.

• assess OAT medication. BPN in combination withBZDs may carry less risk of respiratory depressionthan full opioid agonists.7,76 As such, BPN may bea safer OAT agent than methadone in patients witha history of BZD-related overdose, although BZD-related deaths have also been reported with BPN high-lighting the need for other precautions.

A contingency management framework can be incorpo-rated into treatment conditions.108,109 For example, treat-ment conditions (eg, take-aways, frequency of reviews) canbe linked to BZD use (eg, UDS results) and evidence ofassociated harms (eg, intoxicated presentations).110 How-ever the degree of monitoring and multidisciplinary inputrequired for such patients may be difficult to apply in pri-mary care or office-based settings, and often such patientsmay benefit from specialist multidisciplinary services. OATtreatment should not generally be discontinued for persis-tent BZD abuse, but requires the implementation of the riskmanagement strategies discussed above.

MANAGEMENT OF BZD DEPENDENCE

A key feature of BZD dependence is the emergenceof withdrawal features on attempts to reduce or cease

BZD use, often contributing to long-term BZD use (SeeTable 1 for BZD withdrawal symptoms). The evidence re-garding withdrawal management of BZD dependence hasrecently been systematically reviewed, with 458 subjectsacross eight randomized, controlled trials (RCTs).111 Stud-ies examined gradual tapering regimes over periods of 4weeks to 4 months, comparing the role of adjuvant medi-cations, with mean diazepam equivalent doses of between10 mg and 20 mg across most studies. Noncompletionor use of additional BZDs was reported in between one-third and two-thirds of patients—highlighting low com-pletion rates. The review authors identified that the fol-lowing treatment approaches were generally supported: (a)transfer to a long-acting BZD, (b) period of stabilizationprior to a gradual taper over weeks to months, and (c) lim-ited role for adjuvant medication therapy (including betablockers, some tricyclic antidepressants such as dothiepin,buspirone, progesterone). The only medication shown toameliorate BZD withdrawal and enhance BZD abstinencewas carbamazepine,112 although the effects were modest.There are concerns however in using carbamazepine inmethadone patients, given the propensity for CYP induc-tion and methadone withdrawal symptoms. Similar theo-retical concerns exist for BPN, although clinically relevantinteractions are not reported.

A more recent meta-analysis113 identified several RCTsusing adjuvant medications. In this review, there were in-consistent findings regarding the role of paroxetine.114,115

One RCT found positive findings for trazadone and sodiumvalproate compared to placebo in achieving BZD cessa-tion.116 It should be noted that most controlled studiesin this area were conducted 1–2 decades ago, and therole of newer medications in assisting BZD withdrawalhas not yet been explored in controlled trials. Promisinganecdotal and case reports regarding the role of new gen-eration antidepressants (eg, mirtazepine), new-generationantipsychotic medications (eg, olanzapine, aripiprazole),

66 Benzodiazepine and OAT Interactions January–February 2010

medications that impact upon GABA receptor system (eg,gabapentin), and BZD receptor antagonists (eg, flumaze-nil) warrant further research.

Parr et al.113 also examined the role of psychosocial in-terventions in addition to gradual dose reduction in BZD-dependent people not in OAT. Common features of theseinterventions included relaxation training, symptom man-agement, and cognitive behavioral techniques. Findingsfrom these studies are variable, with positive outcomes frompsychosocial interventions in four of the eight studies.

The difficulties in achieving long-term abstinence fromBZD dependence are highlighted in follow-up studies ofBZD withdrawal. For example, following a BZD reductionregime in a general practice population of older (mean age63 years), low-dose, BZD-dependent, patients (mean base-line diazepam equivalent dose of 8.4 mg), the vast majority(88%) had recommenced BZD use within 15 months ofBZD reduction.117

Despite the high prevalence of BZD dependence inOAT populations, there has been surprisingly little re-search examining optimal treatment approaches in thisgroup. A nonrandomized, controlled, evaluation of BZDmaintenance versus withdrawal was performed in 66 Is-raeli methadone-maintained patients with histories of long-term BZD dependence.118 The study compared clonazepammaintenance (n = 33, mean daily dose 2.64 mg) withclonazepam gradual reduction (n = 33) in a 12-monthtrial. Success was defined by no “on-top” BZD use in themaintenance group, and no BZD use in the withdrawalgroup following clonazepam reduction. Success rates forthe withdrawal group were 27% and 14% at 2 monthsand 12 months, respectively, compared to 79% and 65%of the maintenance group. Axis I psychiatric comorbiditywas positively, and axis II antisocial personality disordernegatively related to treatment success in the maintenancegroup, whereas no predictors of success were identified inwithdrawal group. The authors concluded that clonazepammaintenance was more effective in reducing illicit BZD usethan detoxification, and that clonazepam maintenance wasa useful intervention for BZD-dependent methadone pa-tients. However, this conclusion must be tempered by thelack of objective measures (eg, urinalysis) in the study—additional BZD use was only assessed by self-report andstaff observations of intoxication, and other outcomes (eg,adverse effects) were not reported.

Observational studies of BZD reduction regimes in OATpatients likewise identify poor or modest outcomes. Mc-Duff et al. reported an outpatient alprazolam reduction reg-imen in 22 methadone patients.119 Over half (12, 55%) com-pleted the withdrawal program in approximately 8 weeks,with seven patients showing urine toxicology negative forBZDs on the completion of the reduction, although dura-tion of abstinence following reduction was not reported.Elliot et al. reported difficulties in achieving diazepam re-ductions in this population.120 Outpatient diazepam reduc-tion at a rate of 10% per month was proposed in a group

of methadone patients who had been prescribed long-termdiazepam (mean of 2.9 years, mean baseline dose of 28.9mg). Dose reductions were slower than expected–with amean diazepam dose at 6 months of 18.7 mg. Only 7.5% ofpatients completed their diazepam reduction, and most pa-tients (including completers and noncompleters) continuedto use illicit BZDs. Wickes et al. reported successful out-comes in three of five methadone patients stabilized andreduced on clobazam.121

A recent placebo-controlled RCT reported on the use ofmelatonin in attenuating sleep difficulties during BZD with-drawal in 61 methadone patients.122 Approximately one-third of patients in both conditions successfully completedBZD reductions. Melatonin had no impact on withdrawalcompletion or abstinence rates, but improved sleep qualitycompared to placebo, although those patients who achievedBZD abstinence (irrespective of melatonin) reported great-est sleep improvement. This suggests a possible role formelatonin in patients reporting persistent sleep problemsduring BZD withdrawal. No other controlled studies ofadjuvant medications for BZD withdrawal in OAT popu-lations were identified.

These studies highlight the difficulties in treating thispopulation—either with attempts at maintaining long-termBZDs or in attempting reduction regimes. The concernsregarding maintenance BZD treatment include persistentadditional BZD use and related intoxication harms, con-cerns regarding aberrant behaviors in circumstances wheremedications are not entirely supervised (eg, injecting, di-version to others), and concerns regarding long-term BZDdependence, including long-term impairment of cognition,memory, and psychomotor function impacting upon ac-tivities such as employment, driving, and parenting; moodeffects such as depression, emotional “blunting” and toler-ance resulting in deterioration of anxiety and sleep quality.The concerns regarding graduated withdrawal include re-lapse to illicit or opportunistic BZD abuse or dependence,which may be more erratic than prescribed doses and asso-ciated with more drug-related harms. The evidence at thisstage is inadequate to recommend either strategy. How-ever, given that a proportion of BZD-dependent patients(although a minority of one-third or less) will successfullycomplete a gradual reduction, and as there are no clearpredictors of which patients will be successful in reductionattempts, a trial of gradual BZD reduction regime is war-ranted for BZD-dependent OAT patients, subject to certainconditions aimed at enhancing safety and success rates, andto limit aberrant drug behaviors (see Table 2 for summary).

1. Co-ordinate treatment providers—ensure clarity asto which doctor is prescribing. Patients not preparedto reveal which doctors they attend for BZD prescrip-tion are not good candidates, indicating ambivalenceor poor motivation to change.

2. Address comorbidities—including depression,mood, and sleep problems through evidence-based

Lintzeris and Nielsen January–February 2010 67

TABLE 2. Strategies for managing benzodiazepine dependence in OAT patients

1. Coordinate treatment providers2. Address co-occurring medical and psychiatric disorders3. Stabilize on a long-acting BZD4. Attempt gradual reductions5. Limit access to BZD medications6. Identify and address aberrant drug behaviors in the treatment plan7. Undertake regular monitoring, including clinical review, urine testing, and prescription monitoring systems8. Utilize contingency management principles regarding treatment conditions9. Develop a written treatment agreement

10. Document treatment decisions

psychosocial (eg, cognitive-behavioral) and pharma-cological approaches. Treatment of BZD withdrawalshould be seen as more than a prescription. BZDprescription should only occur if patients alsoparticipate in psychosocial approaches to manageanxiety and sleep problems, and attend for regularclinical reviews and monitoring.

3. Stabilize on a long-acting BZD—Diazepam has beenwidely used for this purpose, although clonazepamand clobazam are less widely reported as BZDs ofabuse, and enable easier monitoring of additionalBZD use by urinalysis. Dose conversions betweenBZDs are unreliable, and it is important to differenti-ate the amount of BZDs a patient may report in orderto achieve intoxication, compared to the amount re-quired to avert severe withdrawal symptoms. Doses ofmore than 40 mg diazepam daily are rarely requiredfor the latter indication. Inpatient admission may berequired to stabilize patients reporting very high orerratic BZD use.

4. Attempt gradual reductions—An 8–16 week reduc-tion regime can be initially negotiated, with recogni-tion that some patients require periods of stabiliza-tion along the way. Reductions regimes may extend tomore than 6 months, although this requires a reviewof treatment conditions and ancillary interventions.Such long-term prescribing should include periodicassessment of functional outcomes, such as cogni-tion, memory, mood (depression and anxiety), andsleep.

5. Limit access to BZD medications—Consider daily (orat least frequent) dispensing, along with OAT medica-tions. Patients should understand that prescriptionswill not be provided to accommodate unauthorizeddose escalations. Furthermore, the medications arethe patients responsibility once dispensed, and “lost”tablets are not replaced.

6. Clear understanding between patient and all clini-cians that persistent aberrant drug behaviors will re-sult in discontinuation of the treatment plan and ces-sation of BZD prescribing. Aberrant drug behaviors

include use of additional BZDs, intoxicated presen-tations, missed OAT doses, persistent use of otherdrugs that will precipitate BZD use (such as psychos-timulants) or increase safety concerns (eg, alcohol orheroin).

7. Regular patient monitoring, including clinical re-views, communication with dispensing staff, and reg-ular urine drug screening, ideally with gas chromatog-raphy mass spectometry (GCMS) to differentiateBZD type, which may indicate use of nonprescribedBZDs. Prescription monitoring systems should be uti-lized where available.

8. Contingency management principles regarding con-ditions of treatment. For example, take-away doses ofOAT medication and frequency of dispensing BZDsmay be linked to patients reducing their BZD doseand adhering to the treatment plan.

9. A written treatment agreement signed by the patientand clinicians should be used documenting the aboveconditions.

10. Document treatment decisions—There is minimal ev-idence supporting long-term BZD prescribing in thispopulation, and given the high risk of adverse events,clinicians must be able to defend their decisions andprescribing practices in the event of severe harms suchas overdose and death.

The role of long-term “maintenance” treatment withBZDs for the management of BZD dependence remainsunclear, due to concerns regarding chronic impairment ofcognitive, memory, performance, and mood. This is partic-ularly the case in OAT patients, who may have a range ofconcurrent medical or psychiatric conditions that exacer-bate these problems. A second opinion from a specialist isperiodically warranted.

AREAS FOR FUTURE RESEARCH

There are a number of important areas of future re-search identified in this review, including epidemiological

68 Benzodiazepine and OAT Interactions January–February 2010

and clinical research. Areas for future investigation includethe following:

• Examining if BZD misuse varies as a function of BZDavailability (prescribing) in different countries, as wellas assessing the impact of prescription drug monitor-ing on prescribing, legitimate use and nonmedical use.

• Investigating differences between commonly usedBZDs in dependence liability and on a range of mea-sures of cognitive and performance effects utilizinga within-patient design. Studies would include com-paring different BZDs when co-administered withmethadone and buprenorphine products.

• Evaluation of various nonpharmacological interven-tions (such as motivational enhancement treatment,CM, CBT) and pharmacological approaches (suchas flumazenil, gabapentin, “new” antidepressant orantipsychotic medications) in the treatment of BZDdependence in an OAT population.

• Identification of long-term consequences of BZD usein this population.

CONCLUSION

This review, while not systematic, gives a broad overviewof the research on interactions between methadone, BPN,and BZDs, as well as identifying some considerable researchgaps, such as the underlying mechanisms of pharmacody-namic interactions, or the clinical management of thosewhere concurrent use of opioids and BZDs is detected.The few studies examining interaction in OAT patients arecharacterized by small subject numbers, do not directlycompare the effects of commonly used BZDs, control forbaseline differences between methadone and BPN patients,or examine the effects of long-term chronic use. The clinicalmanagement of OAT patients with concurrent BZDs use isan important area for further research. It is not currentlyknown if this group is at higher risk as a result of their BZDuse, or if these patients are a high-risk group by definition,using BZDs because of their complex psychosocial situa-tion. In either case, safer prescribing practices, and bettertreatment interventions are required to prevent harm, in-cluding mortality, in this group.

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