Buprenorphine/Naloxone

Transcription

1 ADIS DRUG EVALUATION Drugs 2009; 69 (5): /09/ /$55.55/0 ª 2009 Adis Data Information BV. All rights reserved. Buprenorphine/Naloxone A Review of its Use in the Treatment of Opioid Dependence Jennifer S. Orman and Gillian M. Keating Wolters Kluwer Health Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Philadelphia, Pennsylvania, USA Various sections of the manuscript reviewed by: J. Bell, The Langton Centre, Surry Hills, New South Wales, Australia; G.S. Brigham, Maryhaven, Columbus, Ohio, USA; C.M. Renzelli, Gateway Rehabilitation Center, Aliquippa, Pennsylvania, USA; S.E. Robinson, Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, USA; E.M. Sellers, Ventana Clinical Research Corporation, Toronto, Ontario, Canada; B.A. Sproule, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; D.R. Wesson, CNS Medications Development, Oakland, California, USA. Data Selection Sources: Medical literature published in any language since 1980 on buprenorphine-naloxone, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were buprenorphine/naloxone or buprenorphine-naloxone or buprenorphine and naloxone or buprenorphine naloxone combination or buprenorphine naloxone co-administration. Searches were last updated 20 March Selection: Studies in patients with opioid dependence who received the combination of buprenorphine and naloxone. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Buprenorphine/naloxone, opioid dependence, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability. Contents Summary Introduction Pharmacodynamic Properties Buprenorphine Naloxone Buprenorphine/Naloxone Pharmacokinetic Properties Absorption and Distribution Metabolism and Elimination Special Patient Populations Potential Drug Interactions Therapeutic Efficacy Maintenance Therapy Comparison with Placebo Comparisons with Methadone Different Counselling and/or Medication-Dispensing Regimens In Real World Settings

2 578 Orman & Keating 4.2 Medically-Supervised Withdrawal Therapy Comparisons with Clonidine Shorter Versus Longer Tapering Schedules In Adolescents and Young Adults Retrospective Trials Tolerability Dosage and Administration Place of Buprenorphine/Naloxone in the Treatment of Opioid Dependence Summary Abstract Pharmacological Properties Buprenorphine/naloxone (Suboxone Ò ) comprises the partial m-opioid receptor agonist buprenorphine in combination with the opioid antagonist naloxone in a 4 : 1 ratio. When buprenorphine/naloxone is taken sublingually as prescribed, the naloxone exerts no clinically significant effect, leaving the opioid agonist effects of buprenorphine to predominate. However, when buprenorphine/naloxone is parenterally administered in patients physically dependent on full agonist opioids, the opioid antagonism of naloxone causes withdrawal effects, thus reducing the abuse potential of the drug combination. Buprenorphine/naloxone is an effective maintenance therapy for opioid dependence and has generally similar efficacy to methadone, although more data are needed. Less frequent dispensing of buprenorphine/naloxone (e.g. thrice weekly) does not appear to compromise efficacy and can improve patient satisfaction. Buprenorphine/naloxone is more effective than clonidine as a medicallysupervised withdrawal therapy. Moreover, buprenorphine/naloxone is a generally well tolerated medically-supervised withdrawal and maintenance treatment. Thus, sublingual buprenorphine/naloxone is a valuable pharmacotherapy for the treatment of opioid dependence. Buprenorphine is a partial agonist at the m-opioid receptor and an antagonist at the k-opioid receptor. It has high binding affinity at both receptors and competes with other agonists, such as methadone, heroin (diamorphine) and morphine, at the m-opioid receptor. Opioid agonist effects of buprenorphine are less than the maximal effects of full opioid agonists, such as morphine, and are limited by a ceiling effect. The drug may produce a lower degree of physical dependence than full opioid agonists (e.g. heroin, morphine or methadone). Naloxone is an opioid antagonist without agonist properties. In the absence of opioid agonism by other drugs it exhibits no pharmacodynamic activity when administered in recommended doses. When opioids are present, naloxone prevents or reverses their effects. Limited sublingual absorption and almost complete first-pass metabolism restrict the effects of naloxone when it is administered sublingually in recommended doses. Following sublingual administration in an opioid-dependent population, buprenorphine/naloxone administered in a 4 : 1 ratio has similar physiological and subjective effects to buprenorphine alone at equivalent buprenorphine doses. However, when administered parenterally to individuals dependent on full opioid agonists, this dose ratio increased opioid antagonist effects relative to buprenorphine alone. Therapeutic Efficacy In a 52-week pivotal trial of buprenorphine/naloxone maintenance therapy for opioid dependence, both buprenorphine/naloxone and buprenorphine alone

3 Buprenorphine/Naloxone: A Review 579 increased the percentage of opioid-negative urine samples and decreased patients self-reported craving for opioids compared with placebo during a 4-week, doubleblind treatment period. In addition, a 17-week, randomized, single-centre trial comparing maintenance therapy with buprenorphine/naloxone and methadone indicated no significant between-treatment difference in the percentage of opioid-negative urine samples. A 6-month, randomized, multicentre, maintenance therapy trial in opioiddependent patients also demonstrated that buprenorphine/naloxone-based stepped care (with transition to methadone as necessary) was noninferior to methadone in terms of retention in treatment. A 24-week, randomized, parallel-group trial, a 13-week, randomized trial of observed versus unobserved administration of buprenorphine/naloxone, and two 3-week, randomized, crossover studies also assessed the efficacy of buprenorphine/naloxone maintenance therapy with different counselling and/or medication-dispensing regimens. There were no significant differences in the reduction of illicit opioid use across study arms. However, patients appeared to prefer administration schedules in which they were less frequently required to attend a clinic or office for medication dispensing; unobserved, compared with observed, administration did not compromise treatment efficacy. The proportion of patients both completing treatment and providing an opioid-free urine sample at treatment end was higher in patients receiving tapering doses of buprenorphine/naloxone than clonidine during medically-supervised 13-day withdrawal therapy in two randomized, open-label, multicentre studies, one in inpatients and one in outpatients. A longer tapering schedule (28 vs 7 days) did not improve outcome in opioiddependent patients in a randomized, open-label, multicentre, outpatient study. Significantly more patients receiving the 7- than the 28-day tapering schedule had a opioid-negative urine test at the end of the taper period, with no significant between-group differences at 1 or 3 months post-taper. A 12-week tapering schedule of buprenorphine/naloxone was associated with better short-term treatment outcomes than a 14-day medically-supervised withdrawal regimen in adolescents and young adults aged years enrolled in a randomized, open-label, multicentre, outpatient study. Longer term, there were no significant differences between the regimens in terms of self-reported opioid use or injecting. Tolerability Four weeks therapy with buprenorphine/naloxone was generally well tolerated in the pivotal, 52-week trial of buprenorphine/naloxone as a maintenance therapy for opioid dependence, and differences in the overall rate of adverse events were not significant between treatment groups. Across treatment groups, the most commonly reported adverse events were headache, withdrawal syndrome, pain, nausea and insomnia. Of these adverse events, only the occurrence of withdrawal syndrome was significantly different across treatment groups, and this occurred with greater frequency in the placebo group than the buprenorphine/naloxone and buprenorphine alone groups. In the»48-week, open-label assessment of safety included in this trial, treatment-related adverse events that occurred in >10% of patients were insomnia, constipation, nausea, sweating, withdrawal syndrome and headache. Limited tolerability data are available versus active comparators other than buprenorphine alone. Versus clonidine in medically-supervised withdrawal

4 580 Orman & Keating treatment, the number of adverse events reported per patient per day was significantly fewer with buprenorphine/naloxone than clonidine in both the inpatient and outpatient settings. 1. Introduction Psychosocial therapy and pharmacotherapy are the two main modalities for the treatment of opioid dependence. [1] The pharmacological approaches may be divided into two categories, medically-supervised withdrawal (detoxification) and long-term maintenance treatment. Medicallysupervised withdrawal uses an opioid agonist and/or other anti-withdrawal agent (e.g. clonidine) to address the physical dependence component of illicit opioid abuse [2] and facilitate entry into drug-free therapy or transition to treatment with an opioid antagonist, such as naltrexone. [1] As such, medically-supervised withdrawal is most appropriately thought of as a precursor to other treatment rather than a treatment modality in itself. [3] Maintenance treatment uses a long-acting opioid agonist to reduce opioid craving while preventing opioid withdrawal; [3] if there is concomitant use of illicit opioids during maintenance therapy, the maintenance agent should prevent, in a dose-related manner, the euphoria associated with use of the illicit opioid. [3] Maintenance therapy with the long-acting opioid agonist methadone has long been considered the treatment of choice for chronic opioid dependence [4,5] and it is widely used in many countries. [6] However, like heroin (diamorphine), methadone is a full agonist at the m-opioid receptor. Patients dependent on full opioid agonists may experience physical withdrawal when a daily dose is missed. [6] Also, the therapeutic discontinuation can be discouragingly difficult and lengthy for patients. In addition, there is no ceiling to the respiratory depression or sedation effects associated with full agonists (e.g. morphine, methadone); as a result, overdose can be fatal. Finally, with restricted access to methadone and the need for daily observed dosing, treatment of opioid-dependence can be inconvenient and unappealing, and may limit patients ability to sustain employment and limit acceptance of methadone treatment. [6] Fear of potential abuse, misuse and diversion and associated concomitant morbidity and mortality limits the provision of unsupervised take-away administration of methadone. [6,7] Buprenorphine is a partial m-opioid receptor agonist that may be used as an alternative treatment for opioid dependence. While some evidence suggests that methadone may have slight efficacy advantages over buprenorphine in terms of patient retention when both drugs are administered in flexible doses, slow induction onto buprenorphine may have influenced results. [6] However, buprenorphine also has some potential pharmacodynamic advantages over methadone. In particular, as a partial opioid agonist with limited effects at opioid receptors and a ceiling on these effects, buprenorphine may be potentially safer in overdose situations and have an easier withdrawal phase. [6] In contrast to methadone and levacetylmethadol (levomethadyl acetate), buprenorphine can legally be administered in an office-based setting in the US, [1] which may expand access to treatment for opioid dependence. [8] However, as with methadone, illicit diversion of buprenorphine is a substantial issue. [2,9] The combined buprenorphine/naloxone formulation was developed to reduce this problem. [2,10] When taken sublingually as prescribed, the naloxone component of the buprenorphine/naloxone formulation is not readily absorbed, has low bioavailability and does not interfere with the actions of buprenorphine. However, following parental administration of buprenorphine/naloxone in a population dependent on full agonist opioids, naloxone inhibits opioid effects and may cause withdrawal, [10] thus reducing the potential for illicit diversion and abuse of the drug. This article reviews the pharmacological properties of sublingual buprenorphine/naloxone (Suboxone Ò ), as well as its clinical efficacy and tolerability relevant to its use as a maintenance

5 Buprenorphine/Naloxone: A Review 581 treatment and medically-supervised withdrawal agent for opioid-dependent adults. 2. Pharmacodynamic Properties The pharmacodynamic properties of buprenorphine alone and naloxone alone relevant to opioiddependent patients are well established. This section therefore focuses on the main effects of the buprenorphine/naloxone 4 : 1 combination and discusses the pharmacodynamic properties of buprenorphine alone and naloxone alone only briefly. 2.1 Buprenorphine Buprenorphine is a semisynthetic opioid derived from thebaine [11] that acts as a partial m-opioid receptor agonist and an antagonist at the k-opioid receptor. The binding affinity of buprenorphine at both receptors is high (1000- fold higher than morphine) and dissociation from receptors is slow compared with other opioid analgesics (e.g. the dissociation half-time from m-opioid receptors is 166 minutes with buprenorphine vs 7 minutes with fentanyl). [12] The high binding affinity of buprenorphine for the m-opioid receptor and its slow dissociation contribute to its long duration of action. [12] The potency of buprenorphine is 25- to 50-fold higher than morphine at low doses (<0.8 mg). [13] However, because buprenorphine is a partial agonist, the maximal opioid agonist effects of buprenorphine are lower than those of full opioid agonists such as morphine. [14] The opioid agonist effects of buprenorphine are limited by a ceiling effect. [15,16] The asymptotic dose varied across measures in volunteers who had previous exposure to, but were not physically dependent on, opioids and who were receiving sublingual buprenorphine 1 32 mg alone, although for several measures, including respiratory depression, the asymptotic dose was»16 mg. [15] Research assessing the relationship between buprenorphine doses and m-opioid receptor availability supports the potential for a ceiling on buprenorphine effects. [17,18] In five opioid-dependent volunteers, buprenorphine 2, 16 and 32 mg decreased mean whole brain m-opioid receptor availability by 41%, 80% and 84%, respectively, relative to placebo. [17] The CNS and respiratory effects of buprenorphine alone are well known (e.g. positive mood, sedation, respiratory depression). [13,15,16,19,20] Importantly, the ceiling on the opioid agonist effects of buprenorphine also applies to the respiratory depression associated with the drug. [12] For example, in four volunteers previously exposed to opioids but not physically dependent who were receiving sublingual buprenorphine alone, maximal depression of respiration (»4 breaths/ minute) occurred at doses of 4 32 mg. [15] Medical intervention was not required. Despite the evidence of a ceiling effect on buprenorphine-induced respiratory depression, asphyxic deaths among opioid-dependent patients treated with buprenorphine have been reported. [12] While the exact cause of these deaths has not been ascertained, in some cases they have been attributed to the concomitant use of buprenorphine and benzodiazepines. The mechanism by which these two drugs might interact has not been conclusively demonstrated. [12] However, a pharmacodynamic rather than pharmacokinetic interaction is thought likely. [21] As a partial m-opioid receptor agonist with lower intrinsic activity than full agonist opioids but a high binding affinity, buprenorphine competes with other agonists, such as methadone, heroin, morphine and hydromorphone, at the m-opioid site. [1,13,14,20,22] To avoid precipitated withdrawal, it is therefore important that administration of buprenorphine begins after clear signs of opioid withdrawal have manifested. [23] Buprenorphine is thought to produce a low degree of physical dependence. [11] This is largely based on the high doses of naloxone necessary to precipitate withdrawal in buprenorphinemaintained patients (e.g. naloxone dose was»10-fold higher than that previously shown to precipitate withdrawal in morphine- or methadonemaintained volunteers). [24] However, because buprenorphine has a high binding affinity for the m-opioid receptor, these results should be interpreted with caution. Opioid-dependent men receiving maintenance therapy with buprenorphine had higher testosterone

6 582 Orman & Keating levels and were less likely to experience sexual dysfunction than those receiving maintenance therapy with methadone. [25,26] For example, men (n = 54) receiving sublingual buprenorphine 8 20 mg/day had higher mean testosterone levels (17.7 vs 9.7 nmol/l; p < ) and a significantly (p < ) lower incidence of impaired libido (23% vs 83%) and impaired potency (12% vs 72%) than those receiving high-dose methadone. [25] In another study (n = 103), mean testosterone levels (18.5 vs 11.6 nmol/l; p = 0.001) and mean total International Index of Erectile Function (IIEF) scores (61.4 vs 50.4 points; p = 0.048) were higher in buprenorphine than in methadone recipients (higher IIEF scores indicate less dysfunction). [26] Opioid-dependent patients (n = 46) demonstrated significant (p < 0.05) improvement from baseline in measures of concentration and executive function after receiving 8 10 weeks treatment with buprenorphine or methadone, with no significant between-treatment differences. [27] However, compared with healthy controls (n = 24), opioid-dependent patients had impaired psychomotor speed, semantic word fluency and verbal learning. Buprenorphine was less likely to be associated with prolongation of the corrected QT (QTc) interval than methadone [28,29] or levacetylmethadol, [28] according to the results of two studies in opioid-dependent patients (154 [28] and 436 [29] evaluable patients). In one study, significantly (p < 0.001) more patients receiving levacetylmethadol mg or methadone mg than those receiving buprenorphine mg had a QTc interval of >470 msec (males) or >490 msec (females) [28% and 23% vs 0%]. [28] In addition, an increase in QTc interval of >60 msec at any time in the study occurred in significantly (p < 0.001) more levacetylmethadol or methadone than buprenorphine recipients (21% and 12% vs 2%). [28] These findings are supported by the results of a study in which increasing doses of methadone were associated with increases in the QT interval of msec/mg (p = 0.002), whereas there was no association between buprenorphine dose and QTc interval. [29] 2.2 Naloxone Naloxone is an opioid antagonist without agonist properties. [30] In the absence of any opioid agonism by other drugs, naloxone essentially exhibits no pharmacodynamic activity when administered in recommended doses. However, when opioids are present, naloxone prevents or reverses their effects. In opioiddependent individuals, naloxone precipitates withdrawal. The mechanism of action of naloxone is not fully understood. [30] In vitro studies suggest that, in the presence of opioid agonists, naloxone exerts opioid antagonist effects by competing for the m-, k- and d-opioid receptors in the CNS. Naloxone has the greatest affinity for the m-opioid site. When administered intravenously, opioid antagonist effects of naloxone generally become apparent within 2 minutes. [30] Intranasal administration of naloxone also appears to produce substantial opioid antagonist effects. [31] However, in patients experiencing opioid withdrawal who are given naloxone orally or sublingually in recommended doses, naloxone does not exhibit antagonistic effects owing to its very limited absorption and almost complete first-pass metabolism (sections 2.3 and 3). [23] 2.3 Buprenorphine/Naloxone As with methadone, intravenous misuse and abuse of buprenorphine have been reported. [32,33] However, the addition of naloxone to buprenorphine is expected to decrease the intravenous abuse liability of the partial opioid agonist. [34] The rationale is that when the combination is taken sublingually as prescribed, absorption of naloxone should be minimal and the opioid agonist effects of buprenorphine should predominate. However, when buprenorphine/naloxone tablets are crushed and injected, naloxone would precipitate withdrawal and/or antagonize the opioid agonist effects of buprenorphine [34] in individuals dependent on full opioid agonists. Several different dose ratios of buprenorphine/ naloxone have been investigated to determine the

7 Buprenorphine/Naloxone: A Review 583 optimal ratio in a full agonist opioid-dependent population. [35-41] In a key trial, buprenorphine 2 mg intravenously coadministered with naloxone in a 2 : 1, 4 : 1or8: 1 ratio produced significant (p = 0.02) increases in some measures of opioid withdrawal effects in opioid-dependent volunteers compared with administration of buprenorphine 2 mg alone; however, only the 2 : 1 and 4 : 1 ratios significantly increased all measures of opioid withdrawal relative to buprenorphine alone. [39] The contrasting pharmacodynamic properties of the buprenorphine/naloxone 4 : 1 formulation when taken via the prescribed sublingual route versus parenteral administration were demonstrated in opioid-dependent volunteers in whom intramuscular injection of buprenorphine/naloxone 1 mg/0.25 mg to 16 mg/4mg produced dose-related increases in measures of opioid antagonism in hydromorphone-maintained, opioid-dependent volunteers. [42] However, when administered sublingually, neither opioid antagonist nor agonist effects were reported. [42] Following acute sublingual administration at equivalent dose levels of buprenorphine, the physiological and subjective effects of buprenorphine/naloxone and buprenorphine were similar. [43] Like buprenorphine alone, buprenorphine/naloxone blocks or attenuates the effects of other opioid agonists in opioid-dependent individuals in a dose-related manner. [44] In six opioid-dependent patients who were maintained on sublingual buprenorphine/naloxone 4 mg/ 1 mg, 8 mg/2 mg, 16 mg/4 mg and 32 mg/8 mg for 6 days each, and who were challenged with parenteral doses of hydromorphone 12 mg during each condition, the blockade efficacy of buprenorphine/naloxone was dose related. All buprenorphine/naloxone doses produced a partial but stable blockade of agonist effects for at least 25 hours. [44] Buprenorphine/naloxone was not found to have any significant additional antagonistic effects beyond those of buprenorphine alone. Evidence suggests that the dose of sublingual buprenorphine/naloxone optimal for reducing the agonist effects of heroin may be above 2mg/0.5 mg and below 32 mg/8 mg. [45] Two weeks treatment with buprenorphine/naloxone 8mg/2 mg and 32 mg/8 mg significantly (p < 0.05) reduced the reinforcing and subjective effects of heroin relative to buprenorphine/naloxone 2 mg/ 0.5 mg in seven heroin-dependent patients. There were no significant differences between the buprenorphine/naloxone 8 mg/2 mg and 32 mg/8mg conditions. The effects of buprenorphine in the buprenorphine/naloxone combination are long-acting, supporting a potential for less than daily dosing. [46] In eight opioid-dependent patients, sublingual buprenorphine/naloxone 8 mg/2 mg, 16 mg/4 mg and 32 mg/8 mg, each administered for 2 weeks, induced substantial but incomplete antagonism of opioid agonist effects; antagonist effects lasted for up to 98 hours and declined at a steady rate over a 4-day period. [46] As seen with buprenorphine alone (section 2.1), administration of buprenorphine/naloxone may precipitate withdrawal in full agonist opioiddependent patients if it is administered before the agonist effects of full opioid agonists such as heroin, morphine or methadone have worn off. [43] However, individuals vary in the extent to which they experience withdrawal, and the administration of split doses may attenuate the subjective experience of withdrawal. [47] Three of ten volunteers maintained on methadone 100 mg/ day did not experience withdrawal after single doses of sublingual buprenorphine/naloxone 4mg/1mg, 8 mg/2 mg, 16 mg/4mgor32mg/8mg. In seven patients who experienced withdrawal, use of a split dose separated by a 2-hour interval resulted in significantly fewer subjective reports of sick or bad withdrawal effects, although observer-rated and physiological measures of withdrawal remained similar. In non-opioid dependent individuals, the addition of naloxone to buprenorphine may attenuate the opioid agonist effects of buprenorphine. [48] In seven non-physically dependent, opioid-abusing volunteers, concomitant administration of buprenorphine and naloxone each at 0.8 mg/70 kg significantly lessened the percentage of patients who identified the administered drug as an opioid compared with when buprenorphine 0.8 mg/70 kg was administered alone (p = 0.043). With the addition of naloxone 0.8 mg/70 kg to buprenorphine 0.8 mg/70 kg, there were also

8 584 Orman & Keating significant decreases in constriction of pupillary diameter (p = 0.009) and depression of respiratory rate (p = 0.011) compared with buprenorphine 0.8 mg/70 kg alone. A preliminary study suggests that increasing doses of buprenorphine/naloxone (from 8 mg/ 2 mg through to 32 mg/8 mg) does not result in escalating impairment of most measures of psychomotor and cognitive performance, including the digit symbol substitution test, computerized trail-making tests, time estimation, short-term/ working memory, recognition memory and free recall. [49] The exception was episodic/longterm memory, which was significantly lower with buprenorphine/naloxone 32 mg/8 mg than with buprenorphine/naloxone 16 mg/4 mg and buprenorphine/naloxone 8 mg/2 mg (p-value not stated). Moreover, buprenorphine/naloxone may preserve cognitive function to a greater extent than methadone, according to the results of a study that included opioid-dependent patients who were starting opioid substitution therapy with buprenorphine/naloxone (n = 17; mean dose 15.8 mg/3.9 mg) or methadone (n = 16; mean dose 53.4 mg) and healthy controls (n = 17). [50] Healthy controls performed significantly (p < 0.05) better than buprenorphine/naloxone or methadone recipients in tests of working memory and verbal list learning. However, simple reaction times were significantly (p < 0.05) faster in buprenorphine/ naloxone than in methadone recipients. [50] Coadministration of buprenorphine/naloxone and antiretroviral agents (delavirdine, efavirenz, lopinavir/ritonavir, nelfinavir, ritonavir) was associated with a statistically significant increase from baseline in the QTc interval (from 409 to 417 msec; p = 0.005) in opioid-dependent HIVnegative patients (n = 50), although this increase was not deemed clinically significant. [51] 3. Pharmacokinetic Properties This section focuses on the pharmacokinetic properties of the buprenorphine/naloxone 4 : 1 fixed combination. Where data are lacking for the fixed combination, the section is supplemented by information pertaining to the separate drugs. 3.1 Absorption and Distribution Buprenorphine is rapidly absorbed into the oral mucosa. [52,53] When buprenorphine is sublingually administered in solution, uptake is usually complete within 2 4 minutes. [52] However, when administered via sublingual tablets, uptake is variable and affected by the rate at which the tablets dissolve in saliva. [52] Complete dissolution of sublingual buprenorphine/naloxone tablets was reported to occur»4, 7 and 8 minutes following administration of 4 mg/1mg (two tablets), 8 mg/2 mg (one tablet) and 16 mg/4mg (two tablets), respectively. [52] However, instances where the 8 mg/2 mg and 16 mg/4 mg doses had not completely dissolved within 10 minutes were also reported. Buprenorphine/naloxone tablets should be dissolved under the tongue, rather than swallowed, as swallowing reduces the bioavailability of the drug. [43] While sublingual uptake of buprenorphine into the oral mucosa is rapid, absorption into the systemic circulation is slower. [53] Peak plasma concentrations of buprenorphine are achieved 90 minutes after sublingual administration. [23] The mean bioavailability of buprenorphine sublingual solution is 28 51%. [53] The plasma bioavailability of sublingual buprenorphine tablets has been estimated at 49 63% of that of the sublingual solution, [53] and the manufacturer s prescribing information indicates that the tablets have»66% bioavailability of the solution (e.g. 8 mg solution roughly equivalent to 12 mg tablet and 16 mg solution roughly equivalent to 24 mg tablet). [43] However, recent data suggests that under longer term dosing conditions (beyond 28 days), tablet and liquid formulations are equally bioavailable. [54] Studies suggest that the addition of naloxone does not affect the pharmacokinetics of buprenorphine. [43,53,55] Sublingual absorption of naloxone is low (table I), [55] as is its bioavailability (»10% with naloxone solution). [40] In a study in which eight non-opioid-dependent volunteers received single doses of buprenorphine/naloxone sublingual tablets 4 mg/1 mg, 8 mg/2 mg and 16 mg/4mg at 1-week intervals, absorption of naloxone was too low to accurately determine bioavailability. [56]

9 Buprenorphine/Naloxone: A Review 585 Table I. Pharmacokinetics of a single dose of sublingual buprenorphine (BUP)/naloxone (NAL) 4 mg/1 mg, 8 mg/2 mg and 16 mg/ 4 mg. BUP/NAL tablets were administered to eight healthy volunteers. [55] Mean values are reported BUP/NAL BUP NAL Dose C max AUC 48 C max AUC 48 (ng/ml) (ng h/ml) (ng/ml) (mg h/ml) 4mg/1mg a 8mg/2mg mg/4 mg a In one patient. AUC 48 = area under the plasma concentration-time curve from 0 to 48 hours; C max = maximum plasma concentration. Naloxone is barely detectable in plasma following oral administration. [11] Interpatient variability in sublingual absorption of buprenorphine and naloxone is wide. [43] However, across sublingual doses given to the same patient at different times, variability in buprenorphine and naloxone absorption is low. Plasma concentrations of buprenorphine increased with increasing buprenorphine/naloxone dose, [43] although the increases were not directly dose proportional (table I). [55] The concentrations of naloxone were too low to assess dose proportionality, although they tended to increase with increasing dose (table I). [55] Evidence also suggests that plasma concentrations of buprenorphine are time and dose related. [57] In 60 opioid-dependent patients randomized to receive buprenorphine 8 mg once daily, or a double or triple dose of buprenorphine thrice weekly (16 mg on Mondays and Wednesdays, and 24 mg on Fridays), there were no significant differences in plasma buprenorphine concentrations between the once-daily group 24 hours after receipt of an 8 mg dose and the thrice-weekly group 72 hours after receipt of a 24 mg dose. Distribution of buprenorphine is rapid (distribution half-life is 2 5 hours). [23] Buprenorphine is highly bound to protein (»96%), primarily to a and b globulin. [43] Naloxone is»45% protein bound, mostly to albumin. [43] 3.2 Metabolism and Elimination Both buprenorphine and naloxone undergo extensive hepatic metabolism. Buprenorphine is metabolized by N-dealkylation and glucuronidation. [43] Cytochrome P450 (CYP) 3A4 mediates N-dealkylation of buprenorphine to norbuprenorphine, a m-opioid agonist with only weak intrinsic activity at this site. [23,43] Naloxone is directly glucuronidated to naloxone-3-glucuronide as well as undergoing N-dealkylation and reduction of the 6-oxo group. [43] Following administration of radiolabelled buprenorphine, there was complete recovery of radioactivity in urine (»30%) and faeces (»69%) with collection up to 11 days after administration. [43] Naloxone is primarily excreted in urine. [23] The mean elimination half-life from plasma is 37 hours for buprenorphine and 1.1 hours for naloxone. [43] 3.3 Special Patient Populations The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is not known. [43] However, because both drugs are extensively metabolized in the liver, plasma concentrations of buprenorphine and naloxone are expected to be higher in patients with moderate or severe hepatic impairment. The manufacturer s US prescribing information indicates that the buprenorphine/naloxone dosage should be adjusted in patients with hepatic impairment and patients should be closely monitored for symptoms of precipitated opioid withdrawal. [43] In the EU, severe hepatic impairment is a contraindication for buprenorphine/naloxone use. [23] In both the US and the EU, cautious discontinuation of buprenorphine/naloxone is recommended for consideration on a case-by-case basis if acute hepatitis develops. [23,43] While the effects of renal failure on the pharmacokinetics of naloxone are unknown, no differences in buprenorphine pharmacokinetics were found between nine dialysis-dependent patients and six patients without kidney disease who received the drug intravenously. [43] Buprenorphine/naloxone should be administered with caution in patients with severe renal impairment. [23] No pharmacokinetic data for buprenorphine/ naloxone in elderly patients are available. [23] Buprenorphine/naloxone should be administered with caution in these patients. [23]

10 586 Orman & Keating 3.4 Potential Drug Interactions Inhibitors of CYP3A4 (such as azole antifungals, macrolide antibacterials and HIV protease inhibitors) may increase plasma concentrations of buprenorphine, and patients concomitantly receiving these medications should be closely monitored and may require buprenorphine/naloxone dosage reductions. [43] Coadministration of buprenorphine/naloxone and the non-nucleoside reverse-transcriptase inhibitors efavirenz and delavirdine in HIV-negative volunteers significantly (p 0.002) increased the area under the plasma concentration-time curve (AUC) of buprenorphine and norbuprenorphine, although these increases were not thought to be of clinical significance. [58] Concomitant administration of buprenorphine/ naloxone and the protease inhibitor ritonavir in HIV-negative volunteers resulted in significant (p = 0.02) increases in the AUC of buprenorphine, although symptoms of opioid excess were not observed. [59] Coadministration of buprenorphine/naloxone with either nelfinavir or lopinavir/ritonavir did not result in significant changes in buprenorphine exposure. AUC values for ritonavir, nelfinavir and lopinavir/ritonavir were not significantly altered when coadministered with buprenorphine/naloxone. Both atazanavir and atazanavir/ritonavir increased the buprenorphine and norbuprenorphine AUC to a significant (p < 0.05) extent when these protease inhibitors were coadministered with buprenorphine/naloxone in HIV-negative volunteers. [60] Three of ten volunteers receiving buprenorphine/naloxone and atazanavir/ritonavir reported increased sedation, suggesting that buprenorphine dose reduction may be needed in some patients. [60] The pharmacokinetics of atazanavir or atazanavir/ritonavir were not affected to a significant extent by buprenorphine. [60] 4. Therapeutic Efficacy In the treatment of opioid dependence, buprenorphine alone has well established efficacy as a maintenance therapy [61-68] and as a medicallysupervised withdrawal treatment. [69-72] When taken sublingually as prescribed, the opioid agonist and antagonist effects of buprenorphine/naloxone have been shown to be largely indistinguishable from those of buprenorphine alone (see section 2). This section focuses on the trials of the buprenorphine/naloxone sublingual tablet. All studies used a 4 : 1 buprenorphine : naloxone ratio. 4.1 Maintenance Therapy The efficacy of buprenorphine/naloxone as maintenance therapy for opioid dependence has been evaluated in a 24-week, noncomparative, pilot trial (n = 17) [73] and a larger, well designed, 52-week trial that compared the efficacy of buprenorphine/naloxone with that of placebo over 4 weeks. [74] As results from the pivotal, 52-week trial are available, the pilot trial is not discussed further. This section focuses on the placebocontrolled trial, [74] a trial comparing buprenorphine/naloxone with methadone [75] and a trial comparing stepped buprenorphine/naloxone-based treatment (including crossover to methadone treatment as necessary) with methadone alone. [76] Four trials evaluating buprenorphine/naloxone and different counselling and/or medication dispensing regimens are also included in this section, [77-80] and the results of two studies conducted in a real world setting are also briefly discussed. [81,82] Comparison with Placebo The pivotal, multicentre, 52-week trial of buprenorphine/naloxone comprised a 4-week, randomized, double-blind phase comparing the efficacy of buprenorphine/naloxone with that of placebo, [74] followed by an»48-week, open-label phase assessing safety (section 5). Patients met Diagnostic and Statistical Manual, 4th edition (DSM-IV) [83] criteria for opioid dependence and were aged years (mean age»38 years). [74] In the double-blind phase, patients were randomized to receive once-daily sublingual buprenorphine/naloxone 16 mg/4 mg (n = 110), buprenorphine 16 mg (n = 106) or placebo (n = 110) for 4 weeks. [74] Tablets were administered at a clinic each weekday and take-away doses were

11 Buprenorphine/Naloxone: A Review 587 dispensed for weekend use. Treatment began with an induction phase. No significant between-group differences in baseline characteristics were reported. [74] The median duration of heroin abuse was 84 months. Across groups, 48 55% of patients had at least one past enrolment in a methadone or levacetylmethadol maintenance programme and 45 55% of patients had been in full-time employment within the previous 3 years. Patients received up to 1 hour of individual counselling per week. Emergency counselling sessions (e.g. after a relapse) and referrals (e.g. to community legal aid programmes) were also available. [74] Primary efficacy measures were the percentage of opioid-negative urine samples and the patient s self-reported craving for opioids. [74] Urine samples were collected thrice weekly. Samples not provided at the appropriate time were recorded as missing and were considered not negative for opioids. Craving for opioids was recorded at each clinic visit using a visual analogue scale (VAS). VAS scores ranged from 0 mm ( no craving ) to 100 mm ( the most extreme craving I ve ever had ) and related to peak craving during the previous 24 hours. Secondary endpoints included patients and clinicians impressions of overall status since enrolment in the study, patient retention in treatment and the percentage of urine samples that were negative for other drugs of abuse. [74] The patients analyzed for efficacy had received at least one dose of study medication (109 buprenorphine/naloxone recipients, 105 buprenorphine alone recipients and 109 placebo recipients). [74] Clear efficacy results meant the trial was terminated early and 27 of these patients (8%) were not able to complete the 4-week treatment phase. The primary comparison was between buprenorphine/ naloxone and placebo; the buprenorphine alone group was included as an active control. Sublingual buprenorphine/naloxone therapy was an effective maintenance therapy for opioid dependence. [74] In terms of primary endpoints, the percentage of illicit opioid-negative urine samples was significantly (p < 0.001) higher among buprenorphine/naloxone recipients than placebo recipients (table II). In addition, the mean opioid craving score during each week was significantly lower in the buprenorphine/ naloxone group than in the placebo group (table II). Significant differences favouring active treatment were also seen between patients receiving buprenorphine alone and those receiving placebo (table II). Overall status scores through weeks 1 4, denoting the improvement from baseline in overall health and well-being, were significantly (all p < 0.001) higher at each week with buprenorphine/ naloxone or buprenorphine alone versus placebo as rated by the patient or clinician, thus indicating greater improvement. [74] Clinician-assessed scores were generally lower than the patients self-assessments. The percentage of patients completing the trial was calculated based on the 296 patients not affected by early termination and did not differ significantly between treatment groups (table II). The percentage of cocaine-negative urine samples also did not significantly differ across groups (table II). [74] Comparisons with Methadone The efficacy of buprenorphine/naloxone was compared with that of methadone for the maintenance treatment of opioid dependence in a 17-week, randomized, double-blind, double-dummy, singlecentre study. [75] In addition, the efficacy of buprenorphine/naloxone-based stepped care, with a transition to methadone if necessary after a maximum dosage of buprenorphine/naloxone was reached, was compared with methadone treatment from the outset as maintenance therapy for opioid dependence in a 6-month, randomized, multicentre trial. [76] The 17-week study included adult patients (aged 18 years) meeting DSM-IV [83] criteria for opioid dependence and US FDA criteria for methadone maintenance who were using heroin or prescription opioids or were already receiving methadone maintenance treatment. [75] Adult patients (aged >20 years) who had been heroin dependent (defined by DSM-IV criteria [83] )for>1 year were included in the stepped-care trial. [76]

12 588 Orman & Keating Table II. Efficacy of buprenorphine/naloxone (BUP/NAL) as maintenance therapy in opioid dependence. Results from trials comparing BUP/NAL with buprenorphine alone (BUP) and placebo (PL) [74] or methadone (MET). [75,76] See main text for treatment regimen details Study [design details] Treatment (mg od) Duration No. of pts Opioidnegative urine samples a (%) Adjusted Retention in mean opioid treatment craving score (% of (VAS score pts [74,76] or at wk 4 b ) mean time [wk] [75] ) Medication compliance (% of days) Cocainenegative urine samples (%) Comparison with placebo Fudala et al. [11,74]c BUP/NAL 16/4 4 wk *d 29.8 *d 84 e 55 [r, db, mc] BUP *d 33.0 *d 85 e 56 PL d 55.1 d 79 e 60 Comparisons with methadone Kakko et al. [76] BUP/NAL-based stepped 6mo 48»78 h»77 d,h [r, db-sb, mc] f care g 16/4 to32/8 MET »86 h»79 d,h Kamien et al. [75] BUP/NAL 8/2 17 wk [r, db, sc] BUP/NAL 16/ MET MET a Opioid-negative sample defined as containing <300 ng/ml of illicit drug or metabolite. b VAS score for peak craving during the previous 24 h; ranged from 0 mm ( no craving ) to 100 mm ( the most extreme craving I ve ever had ). c Data for the week 4 opioid craving scores obtained from the European Medicines Agency scientific discussion document. [11] d Primary endpoint. e Percentages apply to pts not affected by the early termination of the db phase because of clear efficacy findings. f Trial began with a 24-day db induction phase, followed by a flexible, sb treatment period to 6 mo. g All pts start treatment with BUP/NAL 16 mg/4 mg; if clinical response was insufficient at maximum dose, pts transferred to MET. h Value estimated from a figure. db = double-blind; mc = multicentre; od = once daily; pts = patients; r = randomized; sb = single-blind; sc = single-centre; VAS = visual analogue scale; * p < vs PL. Patients in the 17-week trial were randomized to receive daily doses of buprenorphine/naloxone 8mg/2mg (n= 82) or 16 mg/4mg (n= 58) or methadone 45 mg (n = 52) or 90 mg (n = 76) using minimum likelihood allocation and controlling for gender, treatment history and years of regular opioid use. [75] In the stepped-care trial, patients were randomized to initial treatment with buprenorphine/naloxone (n = 48) or methadone (n = 48). [76] Patients were in withdrawal prior to the first dose of medication being given in both studies. [75,76] Both trials commenced with an induction phase. [75,76] In the 17-week trial, the buprenorphine/naloxone groups were inducted on buprenorphine alone for 2 days and began receiving their randomized dosage on day 3. Methadone recipients received 15 mg on day 1 increasing to the target dosage of 45 mg on day 3 or 90 mg on day 6. [75] The stepped-care trial commenced with a 24-day, double-blind induction and dose stabilization phase within each study arm. [76] Patients randomized to buprenorphine/naloxone were stabilized on 16 mg/4 mg per day by day 2 and those receiving methadone were stabilized on 70 mg/day by day 10. Following induction in the stepped-care trial, patients were eligible to transition to a higher dose of medication after completing 2 weeks of the previous dose regimen (maximum dosages of methadone 120 mg/day and buprenorphine/ naloxone 32 mg/8 mg per day). [76] Patients who continued to meet transition criteria following receipt of buprenorphine 32 mg/8 mg per day were

13 Buprenorphine/Naloxone: A Review 589 transferred to methadone on the day after the final buprenorphine/naloxone dose was received. To be eligible for transition, patients must have met the following criteria within the preceding 2 weeks: fewer than three missed visits; selfreported insufficient blockade of craving, selfreported withdrawal symptoms or nadir, or any urine sample positive for illicit opioids; and no signs of overdosing. Daily medication was administered under supervision at a clinic in the 17-week trial. [75] In the stepped-care study, daily medication administration was supervised initially. [76] However, if, after 3 months, patients had achieved 4 weeks continuous stability in treatment (allnegative urine tests), they were permitted takeaway doses for weekends. Following a further 4 weeks stability, take-away doses were dispensed twice weekly. Subsequently, if stability was demonstrated for a further 4 weeks, doses were dispensed once weekly. Daily supervision of medication administration was resumed if patients relapsed. In the 17-week trial, patients received hourlong, once-fortnightly counselling sessions with a trained therapist. [75] In the stepped-care trial, counselling sessions with case managers took place at least once weekly. [76] The frequency of these sessions was increased if patients displayed indicators of relapse despite dose increases, or if the maximum dose had been reached. Counselling sessions were augmented by group relapse prevention therapy. In the 17-week study, the primary endpoint was the percentage of opioid-negative urine samples for each week a participant was active in the study. [75] Urine samples were collected under observation thrice weekly. Secondary endpoints included the percentage of patients achieving 12 consecutive opioid-negative samples, the percentage of successful inductions, medication compliance, non-opioid illicit drug use, treatment retention and changes in overall functioning. The primary endpoint of the stepped-care trial examined the noninferiority of buprenorphine/ naloxone-based stepped care versus methadone alone with regard to retention in treatment. [76] Secondary endpoints included the proportion of urine samples negative for illicit opioids and the Addiction Severity Index (ASI) severity rating. Analyses of secondary endpoints were based on the population of patients who completed treatment. Between 48 and 54 urine samples were collected per patient completing treatment. Missing samples were treated as positive. Over time, the percentage of opioid-negative urine samples did not significantly differ between patients receiving buprenorphine/naloxone 8 mg/ 2mg or 16mg/4mg per day and those receiving methadone 45 or 90 mg/day in the 17-week study (quantitative data not reported). [75] In terms of 6-month retention rates in the steppedcare trial, starting patients on buprenorphine/ naloxone with transition to methadone if necessary was noninferior to methadone alone (table II), with an adjusted odds ratio (OR) of 1.02 (95% CI 0.65, 1.60) [noninferiority threshold 0.15; p < 0.05]. [76] Of the 37 patients randomized to stepped buprenorphine/naloxone-based treatment who completed the trial, 17 (46%) were treated with buprenorphine/naloxone throughout (mean final buprenorphine/naloxone dose 29.6 mg). The remainder completed the trial after switching to methadone (mean final methadone dose mg). In the group initially randomized to methadone, the mean final methadone dose was mg. In the 17-week trial, there were no significant differences between the buprenorphine/naloxone 8mg/2 mg, buprenorphine/naloxone 16 mg/4 mg, methadone 45 mg and methadone 90 mg groups in the percentage of patients with 12 consecutive opioid-negative urine samples (10%, 17%, 12% and 16%, respectively), the percentage of patients successfully inducted (80.5%, 81.0%, 82.7% and 82.9%), medication compliance (table II), nonopioid drug use, mean retention time (table II) or ASI opiate composite scores at weeks 8 or 16. [75] At study end, 94%, 79%, 94% and 91% of patients in the corresponding treatment groups elected to continue treatment in a compassionate extension programme. [75] In the stepped-care trial, there were no significant between-group differences in the percentages of urine samples free of illicit opioids (table II) or the ASI severity ratings (data not shown). [76]