Pharmacodynamics of Diazepam Co-Administered with Methadone Or

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Drug and Alcohol Dependence 91 (2007) 187–194

Pharmacodynamics of diazepam co-administered with methadone or buprenorphine under high dose conditions in opioid dependent patients Nicholas Lintzeris a,b,∗, Timothy B. Mitchell a, Alyson J. Bond a, Liam Nestor c, John Strang a a National Addiction Centre, Institute of Psychiatry, Kings College London, and South London and Maudsley NHS Trust, P.O. Box 48, 4 Windsor Walk, Denmark Hill, London SE5 8AF, United Kingdom b National Drug and Alcohol Research Centre, UNSW, Australia c Institute of Neuroscience, Trinity College, University of Dublin, Dublin, Ireland Received 26 May 2006; received in revised form 30 April 2007; accepted 24 May 2007

Abstract Background: Benzodiazepine abuse is common among methadone- and buprenorphine-maintained patients; however interactions between these drugs under high dose conditions have not been adequately examined under controlled conditions. Objective: To investigate the effects of co-administering diazepam with methadone or buprenorphine under high dose conditions. Design: Double-blind, randomly ordered, 2 × 2 cross-over design in which the effects of diazepam dose (0 mg versus 40 mg) and opioid dose (100% versus 150% normal dose) were examined over four sessions in methadone- and buprenorphine-maintained patients. Participants: Four methadone- and seven buprenorphine-prescribed patients without concurrent dependence on other substances or signiﬁcant medical co-morbidity. Measures: Physiological (pulse rate, blood pressure, pupil size, respiratory rate and peripheral SpO2), subjective (ARCI, VAS ratings) and performance (reaction time, cancellation task and Digit Symbol Substitution Test, DSST) measures were taken prior to and for 6 h post-dosing. Results: High dose diazepam was associated with time-dependent increases in the intensity of subjective drug effects (strength of drug effect, sedation) and decreases in psychological performance (reaction time, DSST) for both methadone and buprenorphine patients. These effects were generally independent of the opioid dose administered. High dose opioid administration (150% normal dose) was associated with reductions in overall SpO2 levels and performance (reaction time, DSST) in the methadone patients, but had virtually no impact on pharmacodynamic responses in the buprenorphine group. Conclusion: High dose diazepam signiﬁcantly alters subjective drug responses and psychological performance in patients maintained on methadone and buprenorphine. © 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Methadone; Buprenorphine; Benzodiazepines; Diazepam; Pharmacodynamic; Interactions

1. Introduction motor and cognitive performance, respiratory depression and even overdose death. This paper examines pharmacodynamic Methadone and buprenorphine substitution treatment have responses for methadone and buprenorphine co-administered consistently been shown to be safe and effective in the treatment with diazepam under high dose conditions. of heroin dependence. Nevertheless, there continue to be con- Benzodiazepines are widely used by heroin dependent indi- cerns regarding the misuse of these medications, and particularly viduals and by patients in opioid substitution treatment. Reports in combination with other sedatives, such as benzodiazepines from methadone maintenance programs suggest that approxi- and alcohol. Such combinations have been associated with mately one-third of patients use benzodiazepines in any given a variety of drug-related harms, including sedation, impaired month (Ball and Ross, 1991; Darke, 1994; Stitzer et al., 1981). This high level of use may be in response to the high incidence of psychiatric co-morbidity in this population (Farre et al., 1998; ∗ Corresponding author. Tel.: +61 431 585 515. Kandel et al., 2001; Marsden et al., 2000), and/or for abuse E-mail address: [email protected] (N. Lintzeris). (intoxication) purposes (Stitzer et al., 1981).

A concern regarding the combination of benzodiazepines and gle high doses (150% × maintenance dose) of methadone or opioids is the potential for overdose and death. Benzodiazepines buprenorphine. The findings of such research may be rele- have been identified in 50–80% of heroin related deaths (Grass et vant in patient-treatment matching should different patterns of al., 2003; Oliver and Keen, 2003; Stenhouse and Grieve, 2003; diazepam effects be observed in the methadone and buprenor- Ward and Barry, 2001); 40–80% of methadone related deaths phine patients under abuse conditions. (Ernst et al., 2002; Mikolaenko et al., 2002; Pirnay et al., 2004; Wolf et al., 2004; Zador and Sunjic, 2000); and in up to 80% of 2. Methods buprenorphine related deaths (Kintz, 2001; Pirnay et al., 2004). Given the potential for such severe adverse events, it is 2.1. Subjects important to better understand the relative safety of methadone Selection criteria were as follows: (a) aged ≥18 years; (b) participation in and buprenorphine when taken in combination with benzodi- methadone or buprenorphine treatment for ≥4 weeks, and on stable doses for azepines. This may be an important factor in the selection of ≥2 weeks within the range of 30–100 mg for methadone patients, or between 4 pharmacotherapies for opioid dependent patients. Whilst there and 16 mg for buprenorphine patients; (c) a history of benzodiazepine use, but has been some animal research comparing the effects of ben- no use within the past 2 weeks (confirmed by urine drug screen (UDS)); (d) zodiazepines in combination with methadone or buprenorphine not currently dependent on heroin, cocaine or alcohol, and able to abstain from these substances for at least 2 days prior to each session; (e) no significant med- (reviewed in Lintzeris et al., 2006b), there has been little human ical or psychiatric condition, including severe hepatic disease (liver function research. Earlier research by this group (Lintzeris et al., 2006b) tests (LFTs) more than three times greater than normal range); (f) not preg- examined the effects of single therapeutic doses of diazepam nant (confirmed by urinary ␤hcG); (g) no use of psychotropic medications, or (0, 10 and 20 mg) in stable, methadone- or buprenorphine- other medications known to have significant interaction with either methadone, maintained individuals without significant co-morbidity (e.g. buprenorphine or diazepam. The study was conducted under conditions of vol- untary informed consent with approval from the Institute of Psychiatry Human current benzodiazepines or alcohol dependence, or taking med- Research Ethics Committee. ications known to interact with methadone, buprenorphine or diazepam). Key findings indicated that therapeutic doses 2.2. Design of diazepam had minimal effect on physiological parameters (pulse, blood pressure, SpO2, respiratory rate), but resulted in The study used a double-blind, randomly ordered, 2 × 2 within-subject increased subjective effects (e.g. sedation), and performance design to investigate the effects of different doses of diazepam (0 mg or deficits (simple reaction time, DSST), particularly in patients 40 mg) and the prescribed maintenance opioid (100% or 150% of daily maintenance dose) in patients maintained on methadone or buprenorphine. The four maintained on methadone. diazepam/opioid dose conditions were: (1) 0 mg diazepam + 100% maintenance Whilst this research suggests that therapeutic doses of dose; (2) 40 mg diazepam + 100% maintenance dose; (3) 0 mg diazepam + 150% diazepam appear to be relatively safe in this population, many maintenance dose and (4) 40 mg diazepam + 150% maintenance dose. Each of the concerns regarding interactions between benzodiazepines subject participated in a total of four testing sessions (one for each drug con- and opioids occur in the context of medication abuse—with the dition), with a wash-out period of at least 4 (usually 7) days, during which serial measurements of subjective drug effects, psychomotor performance and use of large doses of benzodiazepines, large doses of methadone physiological responses were made prior to, and for 6 h following drug adminis- or buprenorphine or both, on an episodic or regular basis (Kintz, tration. Placebo formulations of diazepam and methadone/buprenorphine were 2001; Pirnay et al., 2004; Zador and Sunjic, 2000). However, used to control for differences in the taste and volume of administered drugs there has been little research examining the effects of high dose in the diazepam=0mgandmaintenance dose = 100% dose conditions. A block benzodiazepines in opioid dependent individuals. One previous randomised-dosing schedule was used, with sequential allocation by the study pharmacist. study (Preston et al., 1984) examined the interaction of high doses of diazepam (up to 40 mg) in combination with 100%, 2.3. Procedures and measures 150% or 200% of normal daily methadone doses (50–60 mg) in five patients. High dose diazepam in combination with higher All testing sessions were conducted under controlled conditions in a room than normal methadone doses led to greater subjective and phys- with consistent lighting and temperature. Prior to each session, subjects were iologic effects than either drug alone. In contrast, there has screened with a urine drug screen (EMIT tests for opiates, cocaine, benzodi- been no systematic or laboratory examination of this issue in azepines, amphetamines) and breath alcohol reading. After baseline measures (see below), subjects were administered either their normal daily dose of buprenorphine maintained individuals, although field work sur- methadone (10 mg/ml oral solution) or buprenorphine (sublingual 2 mg or 8 mg veys suggest that the use of buprenorphine in combination with Subutex® tablets) in addition to a placebo (equivalent to an extra 50% of the high doses of benzodiazepines is not uncommon in some settings maintenance dose), or 150% of their daily maintenance dose. Simultaneously, (Nielsen et al., 2005). subjects were administered either diazepam (40 mg; 2 mg/ml) or an equivalent The aim of this research was to examine the pharma- amount of the placebo diazepam solution. All subjects and researchers involved in data collection and analysis were blinded to dose conditions at each test codynamic effects of methadone and buprenoprhined co- session. administered with diazepam under high dose conditions—that Physiological measures were recorded at baseline (0), 0.5, 1, 1.5, 2, 2.5, is, between high dose diazepam and high dose methadone 3, 4, 5 and 6 h after dosing. Pulse rate, blood pressure (sitting) and peripheral or buprenorphine in a substitution maintenance population SpO2 were measured using a Pulse Oximeter (KTMED Model KTPS-01). Pupil not dependent on benzodiazepines. Specifically, the research size and respiratory rate (over 1 min) were measured manually (using a rule and stopwatch, respectively). Subjective measures of drug effects included the objectives were to examine physiological, subjective and perfor- Addiction Research Centre Inventory (ARCI) MBG subscale (measuring eupho- mance measures in stable methadone or buprenorphine patients ria), PCAG subscale (measuring sedation) and LSD (dysphoria) (Martin et al., administered single high doses of diazepam (40 mg) and sin- 1971), completed at 0, 1, 2, 3 and 5 h after dosing. Subjects also completed N. Lintzeris et al. / Drug and Alcohol Dependence 91 (2007) 187–194 189

Visual Analogue Scales (0–100 mm) of ‘strength of drug effect’, ‘drug-liking’ (range 50–100 mg) daily and the mean daily buprenorphine dose and ‘sedation’ at 0, 0.5, 1, 1.5, 2, 3, 4, 5 and 6 h after dosing. Performance was 11.1 ± 2.8 mg (range 8–16 mg). Three methadone (75%) measures were conducted at 0, 1, 3 and 5 h after dosing and included: simple and five buprenorphine (71%) subjects were British Caucasian, visual reaction time, a measure of sensory-motor performance; cancellation of 4 s (cancellation task), a measure of focussed attention (Bond et al., 1974); the the remaining three subjects were Afro-Caribbean. Digit Symbol Substitution Test (DSST), a subtest of the Wechsler Adult Intelli- gence Scale designed to measure coding skills (Wechsler, 1955); and a balance 3.2. Pharmacodynamic responses task, a measure of the ability to maintain whole body equilibrium (Evans et al., 1991). The Subjective and Objective Opiate Withdrawal Scales (Handelsman et al., 1987) were conducted at baseline and at 6 h to ensure subjects were not in Table 1 summarises significant ANOVA effects for the significant opioid withdrawal, a potential confounder upon other measures. Sub- diazepam and opioid dose conditions. High dose diazepam and jects were reimbursed the equivalent of £30 in supermarket vouchers for each opioid administration were associated with significant main and test session completed, and a further £30 for completing all four tests sessions. time-dependent effects on specific pharmacodynamic responses for both the methadone and buprenorphine groups. 2.4. Data analysis

Data were entered and analysed using SPSS for Windows (11.0). Pharmaco- 3.2.1. Subjective responses. VAS ratings of strength of drug dynamic responses were analysed with repeated-measures ANOVA to examine effect and sedation were significantly increased in response the effects of diazepam condition (placebo versus 40 mg), opioid dose condi- to high dose diazepam, with maximal levels occurring in tion (100% versus 150% of the daily maintenance dose), and time since dosing most sessions 1–3 h following dosing, and significant diazepam on all pharmacodynamic measures. These ANOVAs were conducted separately × for methadone and buprenorphine. Peak effects (maximal effect compared to and diazepam time interaction effects observed for both baseline) were analysed using paired t-tests to examine the effect of diazepam methadone and buprenorphine (Table 1; Fig. 1). In contrast to the administration relative to placebo. All tests of statistical significance were two- clear effects observed for ratings of strength of drug effect and tailed and used an alpha level of 0.05. sedation, ratings of drug liking showed a less pronounced and sustained increase in response to diazepam (Fig. 1), with a sig- 3. Results nificant diazepam main effect in the buprenorphine group, and a diazepam × opioid dose interaction in the methadone group 3.1. Subject characteristics (Table 1). Diazepam administration was associated with greater peak subjective drug effects which reached significance on mea- Eleven subjects maintained on either methadone (n =4)or sures of sedation and strength of drug effect in the methadone buprenorphine (n = 7) completed all four testing sessions. The group (Fig. 3). No significant effects of diazepam on peak drug mean age (±S.D.) for the methadone and buprenorphine sub- effects were found in the buprenorphine group. Temporal pat- jects was 39.3 ± 11.2 and 37.0 ± 10.7 years, respectively. Two terns of response for the ARCI subscales (MBG, PCAG and methadone (50%) and six buprenorphine (86%) subjects were LSD; not shown) approximated the pattern described for VAS male. The mean daily methadone dose was 68.8 ± 21.7 mg measures; however, the former measures showed only minor

Table 1 Summary of analyses of variance (ANOVA) for effects of diazepam dose, opioid dose and time since dosing Opioid Diazepam Diazepam × time Diazepam × opioid Diazepam × opioid × time FpFpFp Fp Fp

Methadone VAS strength 4.60 0.12 24.2 0.02* 2.53 0.04* 0.11 0.76 1.24 0.32 VAS liking 0.74 0.45 0.61 0.49 0.66 0.72 15.7 0.03* 0.77 0.63 VAS sedation 3.65 0.15 51.7 0.006** 2.19 0.07 0.11 0.76 1.99 0.09 * SpO2 24.4 0.02 2.56 0.21 0.98 0.48 3.09 0.18 0.35 0.95 Reaction time 84.6 0.003** 4.38 0.13 7.10 0.01* 0.35 0.60 0.35 0.79 DSST 31.7 0.01* 4.98 0.11 2.32 0.14 0.16 0.72 0.75 0.55 Buprenorphine VAS strength 0.04 0.85 9.56 0.02* 3.81 0.002** 0.07 0.80 0.44 0.89 VAS liking 0.37 0.56 18.41 0.005** 1.37 0.23 1.05 0.34 0.68 0.71 VAS sedation 0.00 0.97 6.57 0.04* 3.92 0.001** 0.38 0.56 0.51 0.84 PCAG 0.08 0.79 5.01 0.08 1.25 0.32 0.40 0.55 0.41 0.01* Pupil diameter 0.01 0.94 16.14 0.007** 0.64 0.76 1.62 0.25 0.94 0.50 Reaction time 0.58 0.16 8.78 0.03* 3.60 0.03* 1.54 0.26 2.00 0.15 DSST 14.05 0.01* 1.08 0.34 3.67 0.03* 2.50 0.17 0.26 0.86 Cancellation task 2.35 0.18 8.37 0.03* 8.62 0.001** 0.58 0.48 0.76 0.53

Pharmacodynamic responses were analysed with repeated-measures ANOVA to examine the effects of diazepam condition (0 mg vs. 40 mg), opioid dose (100% vs. 150%) and time since dosing. Only measures for which at least one signiﬁcant ANOVA effect was observed are shown. There were no signiﬁcant effects for opioid × time. * p < 0.05. ** p < 0.01. 190 N. Lintzeris et al. / Drug and Alcohol Dependence 91 (2007) 187–194

Fig. 1. Visual analogue scale ratings (0–100 mm) of strength of drug effect (no effect–very strong), sedation (not sedated–very sedated), and liking of drug effect (dislike very much–like very much) following administration of either 0 mg diazepam (0 mg DIAZ) or 40 mg diazepam (40 mg DIAZ) in combination with either 100% or 150% of the normal maintenance opioid dose (100% OP/150% OP) of methadone (MD, n = 4) or buprenorphine (BPN, n = 7). Data are expressed as mean ± S.E.M. The increase in peak strength of drug effect was marginally non-significant (p = 0.067) for the 40 mg DIAZ + 150% OP condition for the methadone group. increases in response to diazepam. In general, the effects of indicated that mean performance generally decreased in diazepam were not significantly dependent on the opioid dose response to high dose diazepam for both the methadone and administered (100% or 150%), with only one measure showing buprenorphine groups (Fig. 2). These performance deficits were a significant opioid dose × diazepam dose interaction term (rat- maximal in most cases at 1 h post-dosing, with a return to ings of drug liking in the methadone group, Table 1). There were baseline levels evident towards the end of the 6 h observa- no significant main effects for opioid dose on subjective mea- tion period. Performance measures were generally stable when sures in either the methadone or buprenorphine group (Table 1). the buprenorphine and methadone groups received their nor- Peak effects for subjective ratings similarly showed little effect mal dose in the absence of diazepam, suggesting these deficits in response to high dose opioid administration (see examples in were attributable to the actions of diazepam alone and not time- Fig. 3). dependent effects of the normal maintenance opioid dose. For the methadone group, the diazepam dose × time interaction for 3.2.2. Performance outcomes. Temporal patterns for perfor- reaction time was the only diazepam-mediated effect on these mance tasks (DSST, cancellation task and reaction time) performance measures to reach statistical significance using N. Lintzeris et al. / Drug and Alcohol Dependence 91 (2007) 187–194 191

Fig. 2. Performance task outcomes for reaction time, the Digit Symbol Substitution Test (DSST) and cancellation task following administration of either 0 mg diazepam (0 mg DIAZ) or 40 mg diazepam (0 mg DIAZ) in combination with either 100% or 150% of the normal maintenance opioid dose (100% OP/150% OP) of methadone (MD, n = 4) or buprenorphine (BPN, n = 7). Data are expressed as mean ± S.E.M.

ANOVA (Table 1). Peak effect analyses similarly indicated that High dose opioid administration was associated with signif- high dose diazepam (alone and in combination with 150% of icant main effects for reaction time in the methadone group the opioid dose) was associated with a significant impairment and DSST in both the methadone and buprenorphine groups on reaction time (Fig. 3). The lack of significance in peak effect (Table 1). For the methadone group, Figs. 2 and 3 indi- analyses despite marked deterioration in performance for the cate that the effect of high dose methadone (with either cancellation task (>100%) and DSST (∼40%) in the methadone 0 mg or 40 mg diazepam) was to diminish performance on group reflects a lack of statistical power due to a small sample reaction time and the DSST. For the buprenorphine group, size. For the buprenorphine group, statistical significance was ANOVA indicated that the effect of high dose buprenorphine achieved for (i) the main effect of diazepam on reaction time and on DSST involved a small increase in overall perfor- the cancellation task and (ii) the diazepam dose × time interac- mance based on comparison of estimated marginal means. tion terms for both reaction time and the DSST (Table 1). In However, Fig. 3 suggests the latter finding is unreliable addition, peak effect analyses indicated that high dose diazepam given that scores in the high dose buprenorphine+0mg (alone and in combination with 150% of the opioid dose) was diazepam condition (a) were higher than scores in the con- associated with significantly worse performance for reaction trol condition (100% buprenorphine dose+0mg diazepam time, the DSST and the cancellation task in the buprenorphine condition) at baseline and (b) remained very stable follow- patients (Fig. 3). ing drug administration, suggesting that performance did not 192 N. Lintzeris et al. / Drug and Alcohol Dependence 91 (2007) 187–194

Fig. 3. Peak effect relative to baseline for visual analogue scale ratings (absolute change, 0–100 mm) of sedation (not sedated–very sedated) and strength of drug effect (no effect–very strong), oxygen saturation (percentage point change) and for performance task outcomes (% change) for reaction time, the Digit Symbol Substitution Test (DSST) and cancellation task according to the administered dose of diazepam (0 mg or 40 mg DIAZ) and the opioid dose (100% or 150% OP) of methadone (MD, n = 4) or buprenorphine (BPN, n = 7). Data are expressed as mean ± S.E.M. P-values denote significant paired differences relative to the 0 mg DIAZ/100% OP condition. *p < 0.05, **p < 0.01. The increase in peak strength of drug effect was marginally non-significant (p = 0.067) for the 40 mg DIAZ + 150% OP condition for the methadone group. directly improve in response to buprenorphine administra- est SpO2 reading recorded in any subject was 89%, on a single tion. occasion in a methadone subject administered 40 mg diazepam and 150% of the normal methadone dose. In 9 of the 11 subjects, 3.2.3. Physiological responses. Unlike the subjective and SpO2 did not fall below 93% on any occasion. performance measures, physiological parameters were not associated with any consistent pattern of effects according to the 4. Discussion diazepam or opioid dose drug conditions. For the key safety parameter of oxygen saturation (SpO2), the administration This study examined the effects of high dose diazepam of 40 mg diazepam had no significant effects in either the (0 mg versus 40 mg) and high dose opioids (100% versus 150% methadone group or buprenorphine group (Table 1). Higher opi- of daily maintenance dose) in methadone and buprenorphine oid doses had no effect on SpO2 in the buprenorphine group. In maintenance patients, following an earlier study examining ther- the methadone group, higher opioid doses were associated with apeutic doses of these drugs (Lintzeris et al., 2006b). The mean (1) a significant main effect involving lower overall SpO2 lev- daily doses of methadone (68.8 ± 21.7 mg) and buprenorphine els (Table 1), and (2) a larger peak decrease in SpO2 compared (11.1 ± 2.8 mg) are commonly used doses in most substitution to normal opioid dose conditions, although this result was only programs within the UK and internationally. Key findings of the significant in the 0 mg diazepam condition (Fig. 3). The low- study indicated that (1) in both the methadone and buprenorphine N. Lintzeris et al. / Drug and Alcohol Dependence 91 (2007) 187–194 193 groups, high dose diazepam was associated with time-dependent 2006a)). Another main limitation of the study is the small sub- increases in the intensity of subjective drug effects and changes ject numbers, particularly in the methadone group. Although in psychological performance; (2) these effects of diazepam the within-subject design allowed for statistically significant were generally independent of the opioid dose administered changes to be identified, caution is required when generalising and (3) high dose opioid administration was associated with from these results to the wider population of patients in opioid lower SpO2 levels and psychological performance (reaction substitution treatment. time, DSST) in the methadone group, but had no significant Nevertheless, this is the first study of its kind to exam- detrimental effects in the buprenorphine group. ine high dose benzodiazepine effects in buprenorphine patients These findings are clinically useful in assessing the impact alongside a group of methadone patients, and should serve that co-prescription or abuse of diazepam may have in patients as a platform for further research with larger subject num- undergoing opioid substitution treatment. Most changes in phar- bers. Useful directions for further research include the need macodynamic response peaked within 1–2 h of diazepam and to consider alternative forms of benzodiazepine or opioid opioid administration, generally reverting to baseline levels abuse; for example (a) individuals using much higher doses of within the 6-h monitoring period. Therefore, clinical monitoring benzodiazepines (e.g. 100 mg diazepam equivalent), (b) individ- should continue for at least 2 h after the use of these medications uals using alternative benzodiazepines (such as shorter acting if there are safety concerns regarding the use of benzodiazepines benzodiazepines such as temazepam, or those with greater anx- in conjunction with methadone or buprenorphine. The impact of iolytic than sedative/hypnotic effects such alprazolam) or (c) the subjective and psychological performance changes associ- individuals misusing their methadone, buprenorphine or benzo- ated with high dose diazepam (e.g. impaired reaction time or diazepine medication by injection (Darke et al., 2002; Nielsen concentration) may be relevant to a range of activities in this et al., 2005). Furthermore, there are other clinical contexts that population (e.g. driving skills, employment, parenting, injecting warrant examination; in particular, interactions in methadone and other risk behaviour). Opioid substitution patients should or buprenorphine patients maintained long-term on benzodi- be warned of the likely impact of high dose benzodiazepine azepines. It is likely that tolerance would develop to many of use upon such activities. High dose opioid administration was the physiological and sedative effects of benzodiazepines with also associated with significant effects on psychological perfor- long-term use, such that any effects seen here on pharmacody- mance and SpO2 in the methadone group, suggesting additional namic responses in the methadone and buprenorphine groups cause for concern in patients who abuse their daily prescribed may be less pronounced with longer term use. daily methadone dose. These effects were generally not marked In conclusion, findings from this study indicate that benzo- at the 150% dose condition assessed in this study, but could diazepines significantly influence response to methadone and be clinically relevant at higher dose conditions. The mean peak buprenorphine, impacting upon subjective effects such as seda- reduction in peripheral SpO2 in methadone patients was approx- tion, and performance effects such as attention and psychomotor imately 3% from a baseline of 96%, with only one subject skills. High dose opioid administration was also associated with showing a SpO2 reading below the 90% level used as a clin- significant effects including reduced oxygen saturation and psy- ical cut-off for defining hypoxia (Considine, 2005). The fact chological performance in methadone patients. Caution should that administration of 150% of the maintenance dose had no be shown in the prescribing or use of high dose benzodiazepines significant detrimental effects in the buprenorphine group may in this population. be due to the partial agonist characteristics of buprenorphine or other factors such as opioid tolerance. Conflicts of interest There are a number of limitations to this study that warrant caution in the conclusions that can be made. Most impor- Nick Lintzeris has received honoraria from Schering Plough tantly, we have not made direct statistical comparisons of the (marketing agents for Subutex®) and Reckitt Benckiser (man- methadone and buprenorphine groups as they are different, ufacturers of Subutex®) for facilitating educational programs unmatched subjects. A definitive design for comparing these regarding the use of buprenorphine. John Strang has received treatments would be a cross-over study in which subjects trans- travel expenses and honoraria from Reckitt Benckiser and Scher- fer between methadone and buprenorphine and are tested under ing Plough for attendance at meetings. Tim Mitchell, Alyson different diazepam conditions whilst on each medication. This Bond and Liam Nestor have no conflicts of interest. was not feasible in this study. A cross-over design would also address the fact that it is difficult to identify pharmacologically Acknowledgements equivalent methadone and buprenorphine doses. Treatment outcome literature would suggest that the mean doses of patients The authors wish to acknowledge the contribution of staff in each group (methadone 69 mg versus buprenorphine 11 mg) and clients within the Addictions Directorate of the South Lon- are broadly comparable in reducing heroin use (Mattick et al., don and Maudsley Trust, and particularly the study pharmacist 2002), however, we can be less certain as to the pharmacolog- Godwin Achunine. Rosemont Pharmaceuticals provided the ical equivalence of high dose methadone and buprenorphine, diazepam 5 mg/ml and placebo solutions. Reckitt Benckiser pro- partly due to the difficulties in transferring patients from one vided the placebo tablets for Subutex®. The study was partly medication to another (for discussion of high dose transfers funded by a grant from Reckitt Benckiser. NL was partly sup- between methadone and buprenorphine see (Lintzeris et al., ported through an NHMRC Clinical Research Fellowship. 194 N. Lintzeris et al. / Drug and Alcohol Dependence 91 (2007) 187–194

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