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. Medically-supervised 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 μ-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 μ-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®), as well as its clinical efficacy and tolerability relevant to its use as a maintenance treatment and medically-supervised withdrawal agent for opioid-dependent adults.

2. Pharmacodynamic Properties

The pharmacodynamic properties of buprenorphine alone and naloxone alone relevant to opioid-dependent 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 μ-opioid receptor agonist and an antagonist at the κ-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 μ-opioid receptors is 166 minutes with buprenorphine vs 7 minutes with fentanyl).[12] The high binding affinity of buprenorphine for the μ-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 μ-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 μ-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 μ-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 μ-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 buprenorphine-maintained patients (e.g. naloxone dose was ≈10-fold higher than that previously shown to precipitate withdrawal in morphine- or methadone-maintained volunteers).[24] However, because buprenorphine has a high binding affinity for the μ-opioid receptor, these results should be interpreted with caution.

Opioid-dependent men receiving maintenance therapy with buprenorphine had higher testosterone 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 < 0.0001) and a significantly (p < 0.0001) 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 75–115 mg or methadone 20–100 mg than those receiving buprenorphine 16–32 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 0.140 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 opioid-dependent 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 μ-, κ- and δ-opioid receptors in the CNS. Naloxone has the greatest affinity for the μ-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 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 : 1 or 8 : 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/4 mg 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 2 mg/0.5 mg and below 32 mg/8 mg.[45] Two weeks’ treatment with buprenorphine/naloxone 8 mg/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/8 mg 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 opioid-dependent 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 4 mg/1 mg, 8 mg/2 mg, 16 mg/4 mg or 32 mg/8 mg. 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 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/long-term 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 HIV-negative 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/1 mg (two tablets), 8 mg/2 mg (one tablet) and 16 mg/4 mg (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/4 mg at 1-week intervals, absorption of naloxone was too low to accurately determine bioavailability.[56] Naloxone is barely detectable in plasma following oral administration.[11]

Table I
figure Tab1

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

Full size image

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 α and β 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 μ-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]

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 medically-supervised 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 placebo-controlled 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]

4.1.1 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 18–59 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 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).

Table II
figure Tab2

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

Full size image

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]

4.1.2 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, single-centre 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]

Patients in the 17-week trial were randomized to receive daily doses of buprenorphine/naloxone 8 mg/2 mg (n = 82) or 16 mg/4 mg (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 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; self-reported insufficient blockade of craving, self-reported 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 (all-negative urine tests), they were permitted take-away 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 hour-long, 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/2 mg or 16 mg/4 mg 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 stepped-care 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 111.0 mg). In the group initially randomized to methadone, the mean final methadone dose was 110.0 mg.

In the 17-week trial, there were no significant differences between the buprenorphine/naloxone 8 mg/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), non-opioid 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]

4.1.3 Different Counselling and/or Medication-Dispensing Regimens

The efficacy of buprenorphine/naloxone with different counselling and/or medication-dispensing regimens has been assessed in four studies.[77–80]

In a randomized, parallel-group, 24-week trial[77] evaluating different levels of counselling and frequency of dispensing, eligible patients (n = 166) were opioid-dependent as defined by DSM-IV[83] criteria. Across study arms, 42–55% of included patients were in full-time employment, the duration of opioid dependence was 7.5–8.6 years, 64–71% of patients had previously attempted medically-supervised withdrawal and 59–71% had previously participated in a methadone maintenance programme. Mean age was ≈36 years.[77]

The trial commenced with a 2-week induction and stabilization phase.[77] In the main treatment phase, buprenorphine/naloxone was taken daily and was dispensed in an office-based treatment setting either once (n = 54) or thrice (n = 56) weekly, accompanied by standard medical management, or thrice weekly accompanied by enhanced medical management (n = 56).[77] Standard and enhanced medical management differed according to the weekly, manual-guided counselling sessions by a trained primary-care nurse. Each session of standard medical management lasted 20 minutes. Enhanced medical management sessions were ≈45 minutes long and covered the same issues as standard medical management sessions, but in more depth. While the standard daily dosage of buprenorphine/naloxone was 16 mg/4 mg, increases up to 24 mg/6 mg per day were permitted. Take-away doses were provided for the days that patients did not receive medication in the office.

Primary endpoints were the percentage of opioid-negative urine samples (samples were provided weekly and results are based on 60% of the 3984 total possible urine samples had all patients remained in treatment and provided all planned urine samples), the self-reported frequency of illicit opioid use and the self-reported maximum number of consecutive weeks abstinence from illicit opioids (verified by urinalysis).[77] The percentage of patients completing the study, the percentage of cocaine-negative urine samples, and patient satisfaction were among secondary endpoints included. Patient satisfaction was measured at week 12 using a questionnaire in which 19 items were rated on a 5-point scale. A higher score corresponded to greater satisfaction and 95 was the highest possible score.[77]

A subsequent exploratory analysis of this trial[77] examined the effect of treatment on HIV risk behaviours (155, 91 and 75 patients were evaluable at baseline and 12 and 24 weeks, respectively).[84] In addition, 53 patients who had achieved ≥9 weeks of abstinence at any point during the trial[77] subsequently entered an extension phase during which buprenorphine/naloxone was dispensed thrice weekly, weekly or every 2 weeks; patients also received monthly counselling sessions.[85] Primary endpoints in this analysis were retention in treatment and the percentage of opioid-negative urine samples; patients were followed for 2–5 years.[85]

A randomized, multicentre, 13-week trial evaluated the efficacy of observed versus unobserved administration of buprenorphine/naloxone; eligible patients (n = 119) were aged >18 years and were opioid dependent with a history of ≥12 months’ opioid use (all but four patients were dependent on heroin).[80] All baseline demographics were similar across the two groups except for patient-reported mean days of opioid use in the previous month which was significantly (p = 0.004) longer in the observed than the unobserved group (25.5 vs 22.9 days). Patients had been opioid dependent for a mean 8.8 years, 75% were male, 38% were employed and 81% had previous opioid treatment experience. Mean age was 34.7 years.

Initial induction was with buprenorphine alone for 7 days. In the main phase of the study, patients received observed (n = 61) or unobserved (n = 58) treatment with buprenorphine/naloxone. Depending on their stability, patients randomized to receive observed administration attended a clinic daily, every second day or thrice weekly. Patients randomized to unobserved administration were given take-away doses, which were dispensed weekly.[80] All patients had weekly meetings with a nurse case manager during which they were interviewed regarding drug use and were asked to submit a urine sample.

All patients were advised that, after remaining in treatment for 3 months, they would be eligible for unobserved dosing if they were considered stable.[80] If patients were absent for 8 days or missed successive scheduled clinical reviews, they were removed from the trial.

Primary endpoints were retention in treatment at 3 months and heroin use at 3 months.[80] The latter was assessed by the change in the number of self-reported days of heroin use from baseline and drug use based on the Opiate Treatment Index Drug Use Scale. Secondary analyses included changes in quality of life (QOL) and psychological symptoms at 3 months.

Finally, two randomized, crossover studies (n = 26[79] or n = 24[78]) with 3-week treatment periods investigated the efficacy of different medication dispensing and administration regimens. Patients were opioid-dependent (DSM-IV criteria[83]) and aged ≥18 years.[78,79] Mean age was 42.4[79] or 45.5[78] years and patients had used opioids for an average of 16.5[79] or 15.9[78] years.

Following a 2-day induction phase, all patients received buprenorphine/naloxone 8 mg/2 mg per day for 14 days prior to the main treatment phase.[78,79] In the main treatment phase of one trial, patients received buprenorphine/naloxone 8 mg/2 mg either daily or on alternate days, or buprenorphine/naloxone 16 mg/4 mg on alternate days.[79] During the alternate-day administration schedules, placebo was administered on the intervening days. In the other trial, patients received buprenorphine/naloxone 8 mg/2 mg per day at a clinic, or buprenorphine/naloxone 16 mg/4 mg at a clinic on Mondays and Wednesdays as a ‘double dose’ and 24 mg/6 mg at a clinic on Fridays as a ‘triple dose’, or patients received daily doses of buprenorphine/naloxone 8 mg/2 mg thrice weekly at a clinic and were given take-away doses for the intervening days.[78]

In both crossover trials, patients received individual counselling sessions with a trained therapist on alternate weeks.[78,79] Patients also had the option to participate in weekly group counselling sessions.

Primary endpoints were not specified.[78,79] Endpoints included treatment retention and illicit drug use (based on urinalysis of samples provided thrice weekly),[78,79] patient assessment of how much they ‘liked’ the dosing schedule based on a VAS where 0 corresponded to ‘not at all’ and 100 to ‘extremely’,[78] and opioid antagonist and agonist effect measures.[79] Across-group analyses, other than treatment retention, were based on the treatment-completer population.[78,79]

Different counselling and/or medication-dispensing regimens were not shown to have a significant effect on the efficacy of buprenorphine/naloxone as a maintenance therapy for opioid dependence in any of the studies (table III).[77–80]

Table III
figure Tab3

Efficacy of buprenorphine/naloxone (BUP/NAL) as maintenance therapy with different counselling or medication-dispensing regimens in opioid dependence.[77–80]] See main text for treatment regimen details

Full size image

Once-daily buprenorphine/naloxone had similar efficacy when dispensed in an office-based treatment setting either once or thrice weekly accompanied by standard medical management or thrice weekly accompanied by enhanced medical management.[77] There were no significant between-group differences in the percentage of opioid-negative urine samples (table III), the maximum duration of continuous abstinence from illicit opioids (table III) or the self-reported frequency of opioid use over time in the parallel-group trial (between-group data not shown).[77] Across treatment arms, the mean self-reported frequency of opioid use significantly decreased from 5.3 days per week at baseline to 1.1 days during induction and 0.4 days during maintenance (p < 0.001 for the induction and maintenance periods vs baseline). There were also no significant between-group differences in the percentages of cocaine-negative urine samples, retention or compliance (table III).[77]

However, patients were shown to prefer administration schedules in which they were less frequently required to attend a clinic or office for medication dispensing.[77] Patient satisfaction with standard medical management and once-weekly medication dispensing was significantly greater than with standard medical management and thrice-weekly dispensing (patient satisfaction scores of 85.2 vs 80.3; p = 0.04). The mean satisfaction score for enhanced medical management with thrice-weekly dispensing was 82.6.

Reductions in certain HIV risk behaviours were seen in patients receiving buprenorphine/naloxone.[84] For example, the proportion of patients who had injected drugs in the previous 3 months (12% and 7% vs 37%) or had sex with a steady partner while ‘high’ on alcohol or drugs in the previous 3 months (13% and 15% vs 64%) was significantly (p < 0.001) lower at weeks 12 and 24 than at baseline. However, there was no significant change in inconsistent condom use over the course of the study, with 84–87% of patients reporting condom use for <50% of the time with a steady partner in the 3 months prior to each timepoint.[84] The prevalence of other HIV risk behaviours (e.g. having unprotected sex in the previous 3 months with someone other than their partner) tended to be low at baseline (<10%) and did not significantly alter over time.

In the extension phase of this trial,[77] 28 of 53 (53%) patients had remained in treatment for ≥1 year, 20 (38%) for ≥2 years, 13 (25%) for ≥3 years, 6 (11%) for ≥4 years and 3 (6%) for ≥5 years at the time of analysis.[85] Of the 53 patients who entered the study, 20 (38%) dropped out, 8 (15%) had persistent drug use, 6 (11%) transferred to an outpatient treatment programme, 3 (6%) tapered off buprenorphine/naloxone, 2 (4%) remained on treatment but declined ongoing assessment and 1 (2%) transferred to an inpatient treatment programme. Of 1106 urine specimens collected, 1005 (91%) were negative for opioids.[85]

In the trial comparing observed with unobserved treatment, there was no significant difference between the observed and unobserved treatment groups in treatment retention (table III) or in the mean reduction from baseline in the number of days of self-reported heroin use (−22.0 vs −18.5 days).[80] Improvements in QOL and psychological symptoms at 3 months did not significantly differ between treatment groups.[80]

These findings are supported by the results of the two small crossover studies. Where compliance was assessed by the number of days adherent to treatment, it did not significantly differ between study arms (table III).[79] Where it was evaluated by the number of doses taken, significantly more doses were taken during the 3 days/week at clinic schedule and the 3 days/week with take-aways schedule than with the daily dosing schedule (19.6 and 19.9 vs 17.1; p = 0.007).[78]

In the crossover study that compared daily buprenorphine/naloxone dispensing with two 3 days/week dispensing schedules,[78] VAS scores for how much patients ‘liked’ the dispensing and administration schedules were significantly (p < 0.05) higher for both 3 days/week schedules than for the daily schedule (VAS scores: 3 days/week at clinic = 62; 3 days/week with take-aways = 80; daily = 40 [values estimated from a graph]).[78]

In the crossover trial comparing a daily dosing schedule with two alternate-day dosing schedules,[79] all measures of agonist and antagonist effects were similar across the dosing schedules with the exception of pupil diameter. Mean pupil diameter was significantly smaller in the buprenorphine/naloxone 16 mg/4 mg on alternate days group than the 8 mg/2 mg on alternate days group (3.8 vs 4.1 mm; p = 0.01). The mean pupil diameter in the buprenorphine/naloxone 8 mg/2 mg per day group was 3.9 mm.

4.1.4 In ‘Real World’ Settings

Two studies reported outcomes associated with buprenorphine/naloxone maintenance treatment in ‘real world’ primary care settings.[81,82] Both studies examined the use of induction, stabilization and maintenance treatment with buprenorphine/naloxone in opioid-dependent patients (n = 99[81] and 41[82]). One study involved two primary-care centres and had a primary endpoint of sobriety at 6 months.[81] The other study, a retrospective chart review, involved one primary-care centre.[82]

Maintenance treatment with buprenorphine/naloxone was effective in ‘real world’ primary-care settings.[81,82] At 6 months, 53 of 99 (54%) patients were ‘sober’ in one study (sobriety was determined by the treating physician using questioning of the patient regarding substance use, physical examination and periodic urine tests).[81] At day 90 in the other study, 29 of 41 (71%) patients were retained in treatment.[82] Of the 25 patients who had urine tests performed during treatment, 6 (24%) had at least one opioid-positive urine test and 16 (64%) had at least one urine test positive for any drug (e.g. opioids, benzodiazepines, barbiturates, cocaine, cannabinoids, phencyclidine).[82]

4.2 Medically-Supervised Withdrawal Therapy

4.2.1 Comparisons with Clonidine

The therapeutic efficacy of buprenorphine/naloxone in medically-supervised withdrawal therapy for opioid dependence has been compared with that of the α-adrenergic agonist clonidine in two randomized, open-label, multicentre trials, one in an inpatient setting and one in an outpatient programme.[86,87] Across both studies, 344 patients were randomized 2 : 1 to receive either buprenorphine/naloxone or clonidine (table IV).[87] The treatment setting (inpatient or outpatient) was chosen by the patient or assigned as clinically indicated and was not randomized.[88] Results were obtained during a 13-day, medically-supervised withdrawal regimen. Key results from both trials are reported in a single article,[87] with field experience pertaining to just the buprenorphine/naloxone arm of both trials reported in a further article.[86]

Table IV
figure Tab4

Efficacy of buprenorphine/naloxone (BUP/NAL) in medically-supervised opioid withdrawal. Results from two randomized, open-label, multicentre, 13-day trials comparing BUP/NAL with clonidine (CLO) in inpatient and outpatient settings.[87] See main text for treatment regimen details

Full size image

Treatment-seeking adult patients (aged ≥18 years) in good general health who met DSM-IV[83] criteria for opioid dependence were included in both trials.

There were no significant differences in gender, race/ethnicity, age, employment, education or years of heroin use between patients treated with buprenorphine/naloxone and those treated with clonidine in either the inpatient or outpatient study.[87] There were also no significant differences in other substance dependence, with the exception of cannabis dependence, which was diagnosed in 2.6% of the buprenorphine/naloxone group and 13.9% of the clonidine group (p < 0.05).[87] The patients randomized to receive buprenorphine/naloxone had an average age of ≈37 years.[86] These patients had used opioids for ≈10 years and heroin for ≈9 years prior to study enrolment. On average, the buprenorphine/naloxone-treated patients had approximately three lifetime prior drug treatments and ≈74% were employed full-time or part-time.

In sublingual buprenorphine/naloxone recipients, the 13-day taper regimen was initiated using a 3-day rapid induction schedule.[87] Patients had not used heroin or other opioids for at least 6 hours prior to presentation and were in mild opioid withdrawal. On day 1, patients received buprenorphine/naloxone 8 mg/2 mg (an initial dose of two 2 mg/0.5 mg tablets, and a further two tablets 1–2 hours after the initial dose). Subsequently, daily dosages of buprenorphine/naloxone were increased up to a maximum of 16 mg/4 mg on day 3 and then tapered to 2 mg/0.5 mg by days 12–13.[87] On day 1, clonidine recipients received oral clonidine 0.05–0.1 mg every 4–6 hours for 24 hours (up to a maximum of 0.6 mg).[87] If the oral clonidine dose was well tolerated, a clonidine 0.1 mg transdermal patch was applied. Patches provided medication for 7 days and the number of patches (1–6) applied to each patient was weight-adjusted. Oral clonidine was discontinued on day 3 and patients who tolerated the patch well received no further oral doses of clonidine. Clonidine dosages were adjusted as clinically indicated. Clonidine was discontinued at day 13 and any remaining patches were removed. Symptomatic medications were prescribed as needed to patients in each study arm.[87]

The primary efficacy measure for these studies was the proportion of patients who both successfully completed the medically-supervised withdrawal schedule and provided an illicit opioid-free urine sample on the last day of treatment.[87] Withdrawal and craving were also assessed. Only results for the intent-to-treat (ITT) population are discussed.[87] An additional analysis of this trial[87] examined predictors of treatment outcome.[88]

Sublingual buprenorphine/naloxone was an effective medically-supervised withdrawal therapy for opioid dependence.[87] Buprenorphine/naloxone-treated inpatients and outpatients were significantly more likely than patients receiving clonidine in the same treatment settings to achieve the primary endpoint, completing the study and providing an illicit opioid-free urine sample at study completion (table IV).[87]

Buprenorphine/naloxone treatment was associated with significantly lower mean withdrawal scores and craving ratings (averaged from all observations available) and the mean number of days patients were retained in treatment was significantly higher with buprenorphine/naloxone than with clonidine in both treatment settings (table IV).[87]

While results across settings should be interpreted with caution given the non-randomized selection of treatment setting, rates of successful treatment completion among patients receiving buprenorphine/naloxone and clonidine in the outpatient setting were substantially lower than those among patients receiving these treatments in the inpatient setting (table IV).[87] However, among patients treated with buprenorphine/naloxone across treatment settings a high proportion of patients (90.1%) successfully completed induction and received the buprenorphine/naloxone 16 mg/4 mg target dose on day 3, and 52.9% complied perfectly with the treatment regimen.[86] The mean percentage of doses taken was 80.7%. Comparative results were not reported for clonidine. Neither of the studies reported the rate at which patients transitioned to ongoing care.[87]

The strongest predictor of treatment success was medication type; adjusting for treatment setting, buprenorphine/naloxone recipients were 9-fold more likely than clonidine recipients to achieve treatment success (OR 9.50; 95% CI 4.60, 19.61; p < 0.001).[88] In addition, inpatients were more likely than outpatients to achieve treatment success (OR 7.27; 95% CI 4.13, 12.79; p < 0.001); the relationship between medication type and retention in treatment was moderated by the treatment setting. Moreover, patients with higher versus lower early withdrawal scores on the Clinical Opiate Withdrawal Scale (COWS) were more likely to achieve treatment success (OR 4.40; 95% CI 1.61, 12.05; p = 0.004); the reduction from baseline to day 3 in opioid withdrawal severity scores was a moderating factor in treatment outcomes. Treatment success did not seem to be influenced by sociodemographic factors such as age, gender, ethnicity, employment status and years of education.[88]

4.2.2 Shorter Versus Longer Tapering Schedules

Tapering schedules of 4 and 28 days’ duration were compared in opioid-dependent patients aged ≥15 years in a randomized, open-label, multicentre, outpatient trial.[90] Following a 4-week induction/stabilization phase with buprenorphine/naloxone, patients were randomized to receive a 7- (n = 255) or 28-day (n = 261) tapering schedule.[90] Mean age was 35.8 and 36.0 years in patients receiving the 7- and 28-day tapering schedules; the mean duration of life-time heroin use was ≈8 years in both treatment groups.[90]

The 4-week induction/stabilization phase comprised 3 weeks of flexible dosing after which patients received buprenorphine/naloxone 8 mg/2 mg, 16 mg/4 mg or 24 mg/6 mg per day during the fourth week.[90] The buprenorphine/naloxone dosage was then tapered down in 2 mg/0.5 mg or 4 mg/1 mg increments over 7 or 28 days. Patients were also encouraged to participate in the psychosocial treatment programme offered at each treatment site.

The primary endpoint was the proportion of patients with opioid-negative urine samples at the end of the taper.[90] Secondary endpoints included use of all drugs and withdrawal and craving scores (assessed using the Adjective Rating Scale for Withdrawal [ARSW], the COWS and a VAS).[90]

A longer tapering schedule did not improve outcome in opioid-dependent patients.[90] Significantly more patients receiving the 7- than the 28-day tapering schedule had an opioid-negative urine test at the end of the taper period (44.3% vs 29.9%; p = 0.0007). However, there were no significant differences between the 7- and 28-day groups in the proportion of patients with opioid-negative urine tests 1 (17.7% vs 17.6%) and 3 (12.2% vs 13.4%) months post-taper. When all drug use was considered, there was no significant difference between the 7- and 28-day tapers in the proportion of patients with negative urine samples at the end of the taper (24.7% vs 18.8%) or after 1 (11.0% vs 11.5%) or 3 (6.7% vs 9.2%) months of follow-up.[90]

In terms of withdrawal and craving, there were no significant between-group differences in ARSW, COWS or VAS scores at the end of the taper or at 1 or 3 months’ follow-up, apart from a significantly higher mean COWS score (indicating greater withdrawal symptoms) in the 7- versus 28-day taper group after 1 month’s follow-up (1.58 vs 0.98; p = 0.0248).[90]

4.2.3 In Adolescents and Young Adults

Medically-supervised withdrawal therapy with buprenorphine/naloxone for 14 days was compared with a 12-week tapering schedule of buprenorphine/naloxone in opioid-dependent adolescents and young adults in a randomized, open-label, multicentre, outpatient trial.[91] Patients were eligible for inclusion if they were aged 14–21 years and met DSM-IV[83] criteria for opioid dependence.[91] Of the 80 patients randomized to withdrawal therapy and the 74 randomized to 12 weeks’ therapy, 78 and 74 patients entered treatment. In the corresponding treatment groups, mean age was 19.2 and 19.1 years, with 18% and 16% of patients aged <18 years (no 14-year-olds and only one patient aged 15 years was enrolled). Heroin use was the main issue in 53% of withdrawal therapy recipients and 57% of patients receiving 12 weeks’ therapy; the median duration of both heroin and opioid use in both treatment groups was 1 year.[91]

On day 1, patients received buprenorphine/naloxone 2 mg/0.5 mg, with a second dose of 2 mg/0.5 mg to 6 mg/1.5 mg administered 1.5–2 hours later if necessary.[91] On days 2 and 3, patients received the dose from the previous day, adjusted as needed. The maximum dosage in withdrawal therapy recipients was 14 mg/3.5 mg per day; the taper ended by day 14. The maximum dosage in patients receiving the 12-week tapering schedule was 24 mg/6 mg per day; the taper began at week 9 and had ended by week 12. Patients were scheduled to receive at least one individual counselling session and one group counselling session each week.[91]

The primary endpoint was the proportion of patients with opioid-positive urine tests at weeks 4, 8 and 12.[91] Secondary endpoints included dropping out from the assigned treatment, self-reported use, injecting, enrolling in treatment for opioid dependence outside of the assigned condition and other drug use.

Opioid-dependent adolescents and young adults receiving medically-supervised withdrawal therapy with buprenorphine/naloxone were significantly (p ≤ 0.001) more likely than those receiving 12 weeks’ therapy with buprenorphine/naloxone to have opioid-positive urine tests at weeks 4 (61% vs 26%) [OR 7.05; 95% CI 2.87, 17.29] and 8 (54% vs 23%) [OR 5.07; 95% CI 2.02, 12.79], but not at week 12 (51% vs 43%) [OR 1.84; 95% CI 0.75, 4.49].[91]

In terms of secondary endpoints, patients receiving withdrawal therapy with buprenorphine/naloxone were significantly (p < 0.001) less likely than those receiving 12 weeks’ therapy with buprenorphine/naloxone to continue receiving their assigned treatment (OR 0.13; 95% CI 0.07, 0.26) and were significantly (p ≤ 0.01) more likely to report enrolment in non-study treatment (OR 13.09; 95% CI 3.73, 45.89), use of opioids (OR 4.30; 95% CI 2.25, 8.22) or cocaine (OR 16.39; 95% CI 3.07, 87.47) in the past week, and injecting in the past 30 days (OR 3.54; 95% CI 1.27, 9.87).[91]

Longer term follow-up at months 6, 9 and 12 revealed that patients receiving withdrawal therapy were significantly (p ≤ 0.01) more likely than those receiving 12 weeks’ therapy to have opioid-positive urine tests (65–76% vs 41–56%) [OR 2.65; 95% CI 1.28, 5.50] or report cocaine use (OR 3.84; 95% CI 1.47, 10.02), although there were no significant between-group differences in self-reported opioid use (OR 1.34; 95% CI 0.70, 2.57) or injecting (OR 1.60; 95% CI 0.71, 3.60).[91]

4.2.4 Retrospective Trials

The efficacy of buprenorphine/naloxone in medically-supervised withdrawal therapy was also investigated in three retrospective, observational studies conducted in opioid-dependent adults.[92–94] In one study,[92] a group of patients receiving a buprenorphine/naloxone short-term taper treatment (8 mg/2 mg on days 1 and 2, 16 mg/4 mg on day 3, then escalation as necessary to control symptoms before a gradual reduction to no medication; duration of treatment ≤21 days; n = 64) were compared with two groups of patients, both treated with dextropropoxyphene/paracetamol (acetaminophen) [100–650 mg] and clonidine (dose and duration of treatment not specified; one group [n = 157] was treated before and the other [n = 227] after the introduction of buprenorphine/naloxone therapy).[92] In a second study, patients receiving a buprenorphine/naloxone taper (up to 6 mg/1.5 mg on day 1, up to 8 mg/2 mg on day 2, up to 6 mg/1.5 mg on day 3 and up to 4 mg/1 mg on day 4, with 2 mg/0.5 mg administered as needed on days 5–6; n = 85) in addition to clonidine and chlordiazepoxide (doses given as needed) were compared with a control group (n = 85) receiving clonidine and chlordiazepoxide alone.[93] In the third study, a group of patients receiving a 14-day buprenorphine/naloxone taper treatment (8 mg/2 mg on days 1 and 2, 16 mg/4 mg on day 3, then a gradual reduction to no medication by day 14; n = 38) in a drug-free residential treatment programme were compared with a concurrently admitted, demographically matched, control group of patients without impending opioid withdrawal (no details of any treatment given).[94] The primary drug problem of the majority of these control patients was cocaine dependence.

Importantly, these studies provided data regarding the percentage of patients who continued to receive further opioid-dependence treatment following the medically-supervised withdrawal period.[92–94]

The favourable effect of buprenorphine/naloxone on retention in treatment is supported by two retrospective, observational studies.[92,93] Significantly (p < 0.001) more patients in the group receiving buprenorphine/naloxone short-term taper treatment completed the medically-supervised withdrawal programme compared with the two groups of patients treated with clonidine (84% vs 56% and 54%).[92] Importantly, this study also showed that significantly (p < 0.001) more patients in the group receiving buprenorphine/naloxone short-term taper continued treatment (i.e. attended at least 1 day of an inpatient or outpatient treatment programme) following medically-supervised withdrawal compared with the two groups of patients treated with clonidine (83% vs 32% and 31%).[92] For patients treated with buprenorphine/naloxone, clonidine and chlordiazepoxide versus patients treated with clonidine and chlordiazepoxide alone,[93] treatment group was not associated with length of stay on the detoxification unit. However, the percentage of patients transferring to the inpatient unit following medically-supervised withdrawal was significantly (p < 0.001) higher in the group receiving buprenorphine/naloxone treatment (97.6%) than the group treated without this therapy (55.3%). The average total length of stay (including time spent in the detoxification and inpatient units) in the buprenorphine/naloxone group was also significantly (p < 0.001) longer (11.5 days) than in the comparator group (6.5 days).[93]

In a third study, the proportion of patients completing at least 3 months’ residential treatment did not significantly differ between opioid-dependent patients receiving an initial 14-day buprenorphine/naloxone taper and a control group without impending opioid withdrawal (39% vs 57%).[94] However, because opioid withdrawal syndrome has been recognized as a barrier to entry and retention in drug-free programmes, this is considered to be a favourable result.[94]

5. Tolerability

Buprenorphine/naloxone is generally well tolerated. Few differences between the adverse event profiles of buprenorphine/naloxone and buprenorphine alone have been observed.[43] Indeed, many of the trials discussed in section 4 did not examine tolerability. In the 4-week, placebo-controlled phase of the pivotal, 52-week trial of buprenorphine/naloxone in maintenance therapy (see section 4.1.1 for trial details; n = 317), the overall rate of adverse events did not significantly differ between treatment groups; adverse events were reported in 78% of patients receiving buprenorphine/naloxone, 85% of buprenorphine alone recipients and 80% of placebo recipients.[74]

The most commonly reported adverse events in buprenorphine/naloxone recipients included headache, withdrawal syndrome, pain, nausea, insomnia and sweating (figure 1).[74] For the overall comparison between patients receiving buprenorphine/naloxone, buprenorphine alone and placebo, significant differences were seen for withdrawal syndrome, diarrhoea and constipation; withdrawal syndrome and diarrhoea occurred with a higher incidence in the placebo group than the buprenorphine/naloxone and buprenorphine alone groups, and constipation occurred with a higher incidence in the buprenorphine/naloxone and buprenorphine alone groups than in the placebo group (figure 1).

Fig. 1
figure 1

Tolerability of sublingual buprenorphine/naloxone in adult patients receiving maintenance therapy for opioid dependence.[74] Adverse events occurring in ≥5% of patients in any treatment arm during 4 weeks’ randomized, double-blind treatment with buprenorphine/naloxone 16 mg/4 mg once daily (n = 107), buprenorphine 16 mg once daily (n = 103) or placebo (n = 107). * p = 0.03, ** p = 0.008, *** p = 0.005 (p-values are for the overall comparison among the three groups).

Full size image

Buprenorphine/naloxone was further evaluated for safety in 472 patients (268 had participated in both the 4-week, placebo-controlled assessment and 48-week, open-label safety continuation, 193 were newly included in the open-label part of the study up to a maximum of 52 weeks and 11 only participated in the double-blind trial).[74] During the open-label part of the study, patients received buprenorphine/naloxone up to a total daily dose of 24 mg/6 mg. Medication was administered at a clinic each week day during the first 2 weeks. Subsequently, up to 10 days’ supply of medication could be provided to patients at the investigators’ discretion. Of the 472 patients included in the safety population, 385 received at least 8 weeks’ treatment with buprenorphine/naloxone and 261 received at least 6 months’ treatment.[74]

Treatment was discontinued in 14 patients because of adverse events, of which withdrawal symptoms such as rhinitis and diarrhoea were most common.[74] Medical conditions considered unrelated to the study medication caused eight treatment discontinuations, and two patients discontinued treatment because of conditions possibly related to buprenorphine/naloxone.

Increases in hepatic ALT, AST or lactate dehydrogenase levels were the most common serious adverse events reported (ten patients) and were considered possibly or probably related to buprenorphine/naloxone treatment in seven patients; there were 81 reports of serious adverse events overall.[74]

ECG recordings and chemical and haematological tests did not reveal any clinically important changes from baseline.[74]

In this trial, treatment-related adverse events with buprenorphine/naloxone were reported for 342 of 472 patients (72.5%) according to the manufacturer’s prescribing information.[23] Treatment-related adverse events that occurred in >10% of patients were insomnia, constipation, nausea, sweating, withdrawal syndrome and headache.

No serious treatment-related adverse events were reported in adolescents and young adults receiving buprenorphine/naloxone as medically-supervised withdrawal therapy or as a 12-week tapering schedule, and no patient discontinued therapy because of adverse events (see section 4.2.3 for study details).[91] The most commonly reported adverse event was headache (reported by 16–21% of patients), with other adverse events such as nausea, insomnia, stomach ache, vomiting and anxiety reported by <10% of patients. Of the 83 patients who were hepatitis C-negative at baseline, two patients in each treatment group were positive for hepatitis C at week 12.

Limited tolerability data are available versus active comparators other than buprenorphine alone. During medically-supervised withdrawal treatment (section 4.2.1), the number of adverse events was significantly lower with buprenorphine/naloxone than clonidine in both the inpatient (1.5 vs 2.4 adverse events per patient per day; p < 0.0001) and outpatient (0.7 vs 1.2 adverse events per patient per day; p < 0.001) settings.[87]

Few serious adverse events were reported in either treatment setting.[87] In the inpatient trial, four serious adverse events, including one death each, occurred in each study arm. The death in the buprenorphine/naloxone group was caused by respiratory failure that was thought unrelated to study medication; other serious adverse events were suicidal behaviour in two patients and severe vomiting in one patient. The death in the clonidine group was caused by bacterial endocarditis and was also thought to be unrelated to study medication; severe vomiting, a motor vehicle accident and cellulitis were the other serious adverse events in this group.

Among the 18 serious adverse events that occurred in patients receiving buprenorphine/naloxone across the two trials, only one (possible oesophageal tear associated with excessive hiccupping) was thought possibly related to buprenorphine/naloxone.[86]

In the trial directly comparing buprenorphine/naloxone and methadone maintenance therapies (section 4.1.2), there were five serious adverse events: three injection drug use-related abscesses, one case of high blood pressure and one lung mass/shoulder infection.[75] None of these serious adverse events were thought related to study medication. Four occurred in patients assigned to methadone and one in a patient receiving buprenorphine/naloxone. No serious treatment-related adverse events were reported in the trial comparing buprenorphine/naloxone-based stepped care maintenance therapy with methadone maintenance therapy (section 4.1.2).[76] One patient randomized to buprenorphine/naloxone was withdrawn from the study because of respiratory difficulties and two methadone recipients were withdrawn because of lower leg oedema. These were classified as nonserious adverse events.

6. Dosage and Administration

Sublingual buprenorphine/naloxone has been approved in the US[43] and the EU[23] for the treatment of opioid dependence.

In the US, the target dosage of buprenorphine/naloxone for maintenance therapy is 16 mg/4 mg per day.[43] However, in some patients, dosages of 12 mg/3 mg per day may be clinically effective and the dosage of buprenorphine/naloxone should be individualized in order to keep the patient in treatment and effectively suppress opioid withdrawal effects. Buprenorphine/naloxone dose adjustments should be progressive and occur in 2 mg/0.5 mg or 4 mg/1 mg increments or decrements. The final maintenance dosage is likely to be in the range of 4 mg/1 mg to 24 mg/6 mg per day, depending on the individual.

In the EU, it is also recommended that the dose of buprenorphine/naloxone be increased progressively according to the clinical effect on the individual patient and should not exceed a maximum single daily dose of 24 mg/6 mg.[23] Dose adjustments should be made in increments between 2 mg/0.5 mg and 8 mg/2 mg. EU prescribing information states that following satisfactory stabilization, buprenorphine/naloxone may be administered on alternate days or thrice weekly in some patients (although the buprenorphine/naloxone dose given on any one day should not exceed 24 mg/6 mg).[23]

EU prescribing information recommends buprenorphine/naloxone for treatment induction.[23] Moreover, current clinical guidelines in the US recommend that buprenorphine/naloxone is used for induction in most patients[1] (although the US manufacturer’s prescribing information still states that buprenorphine alone is preferred for use during induction[43]). In both regions, it is recommended that induction only be initiated in patients with objective and clear signs of withdrawal in order to avoid precipitating withdrawal.[23,43]

The local manufacturer’s prescribing information should be consulted for comprehensive information on dosage, administration, precautions, warnings and contraindications.

7. Place of Buprenorphine/Naloxone in the Treatment of Opioid Dependence

Drug dependence is a complex condition affected by social, psychological and biological factors.[95] Opioid dependence is associated with severe morbidity and an increased risk of death.[95] However, a review of several studies indicates that successful treatment decreases both mortality and morbidity.[96]

Guidelines from the US Department of Health and Human Services indicate that psychosocial therapy and pharmacotherapy are the two main modalities for the treatment of opioid dependence.[1] Psychosocial approaches such as residential therapeutic communities, as well as mutual-help programmes such as Narcotics Anonymous and 12-step- or abstinence-based treatment programmes are important methods of treating opioid dependence and may be used either as stand-alone interventions or in combination with pharmacotherapy.[1]

Pharmacotherapies available for treating opioid dependence can be classified as maintenance therapies and/or medically-supervised withdrawal therapies. Whereas maintenance therapy usually involves the administration of a long-acting synthetic opioid over a prolonged period, medically-supervised withdrawal therapy is a short-term treatment addressing the acute physiological effects of cessation of illicit opioid use.[3] While the most effective maintenance programmes include a psychosocial therapy component, medically-supervised withdrawal therapy does not address the psychological, social and behavioural aspects of opioid dependence and is therefore appropriately considered a precursor to other treatment rather than an independent treatment in itself.[3]

Historically, maintenance therapies for opioid dependence comprised methadone or levacetylmethadol.[5] However, owing to regulatory issues and the linking of levacetylmethadol to QT-interval prolongation, levacetylmethadol is no longer a commonly used treatment[97] and maintenance therapy with methadone has been the treatment of choice.[5]

Buprenorphine is a partial μ-opioid receptor agonist that may be used to expand treatment options for opioid dependence. While some evidence suggests it may be less effective than high-dose methadone in terms of patient retention and suppression of heroin use, buprenorphine has some important pharmacodynamic advantages over methadone (section 2.1).[6] Because opioid agonist effects of buprenorphine are less than those of a full opioid agonist and owing to the ceiling on these effects (section 2.1) buprenorphine is potentially safer in overdose situations.[6] In terms of the potential for overdose, a possible drug interaction between buprenorphine and benzodiazepines leading to increased respiratory depression is of concern with regards to illicit street use.[12] However, some evidence suggests that the effects of any interaction between diazepam and methadone may be greater than any effects of a diazepam and buprenorphine interaction.[21,98] Some evidence also suggests that buprenorphine may produce a lower degree of physical dependence than full opioid agonists such as methadone and morphine (section 2.1). In addition, neither buprenorphine alone nor buprenorphine/naloxone appear to be associated with clinically significant QT-interval prolongation (sections 2.1 and 2.3).

The long duration of action of buprenorphine also supports a potential for less than daily dosing (section 2.1). Indeed, administration of buprenorphine/naloxone on alternate days or thrice weekly are approved options in the EU,[23] although the approved regimen in the US comprises once-daily administration[43] (section 6).

A further important advantage of buprenorphine in the US is that it can be administered in a less controlled office-based setting.[1] This expands the treatment options available for patients with opioid dependence and appears to be associated with different types of patients entering treatment. In an observational analysis of patients entering a buprenorphine/naloxone clinical trial in a primary-care clinic versus patients entering an opioid treatment programme, patients entering the primary-care clinic were significantly more likely to be male, younger, Caucasian, employed full time, have no prior history of methadone treatment, fewer years of opioid dependence and lower rates of injection drug use.[8] Some preliminary evidence also suggests that treatment with buprenorphine could be particularly effective for patients with dual diagnoses of opioid-dependence and depression, perhaps due to κ-opioid receptor antagonism.[99,100]

However, like methadone, buprenorphine is susceptible to illicit diversion and misuse.[2,9] The addition of naloxone to buprenorphine was designed to reduce this problem (section 2.3). When taken sublingually as prescribed, the naloxone component of the buprenorphine/naloxone formulation has no clinically significant effect (section 2.3). Following acute sublingual administration at equivalent dose levels of buprenorphine, the physiological and subjective effects of buprenorphine/naloxone and buprenorphine alone have been shown to be similar (section 2.3). This is associated with the different sublingual bioavailabilities of the two components of the drugs as well as their different mean elimination half-lives from plasma (section 3). Further data evaluating the extent to which this theoretical advantage results in a reduced incidence of abuse and diversion will be of great interest. Results currently available from a Finnish study suggest that while buprenorphine/naloxone has been abused by many street users, the majority had a ‘bad’ experience with the drug combination and the street value of buprenorphine/naloxone is less than than of buprenorphine alone.[9] In addition, in a retrospective study, all five patients who misused buprenorphine/naloxone intravenously described it like injecting ‘nothing’ or reported it as a ‘bad’ experience.[101]

Sublingual buprenorphine/naloxone in a 4 : 1 ratio is approved in the US[43] and the EU[23] for the treatment of opioid dependence. EU prescribing information recommends buprenorphine/naloxone for treatment induction.[23] Current clinical guidelines in the US also recommend that buprenorphine/naloxone is used for induction in most patients[1] (although the US manufacturer’s prescribing information still states that buprenorphine alone is preferred for use during induction[43]). In both regions, it is recommended that induction only be initiated in patients with objective and clear signs of withdrawal in order to avoid precipitating withdrawal.[23,43] Recommended dosages of buprenorphine/naloxone during maintenance therapy are outlined in section 6.

In a well designed maintenance therapy trial, buprenorphine/naloxone was shown to have superior efficacy to placebo (section 4.1.1). Based on surrogate endpoints (the number of opioid-negative urine samples and subjectively evaluated opioid craving scores), buprenorphine/naloxone recipients used illicit opioids less than placebo recipients and also craved illicit opioids less during the 4-week placebo-controlled part of this pivotal, 52-week study (section 4.1.1).

Maintenance therapy with buprenorphine/naloxone had generally similar efficacy to that of methadone, according to the results of a randomized, double-blind, single-centre study (section 4.1.2). While the results of additional direct comparisons of buprenorphine/naloxone with methadone are awaited with interest, a comparison of buprenorphine/naloxone-based stepped care, with transition to methadone therapy if necessary, versus methadone-alone treatment also suggests similar efficacy (section 4.1.2). Initial treatment with buprenorphine/naloxone was noninferior to methadone in terms of retention in treatment, suggesting that all patients can be treated with buprenorphine/naloxone as an initial therapy without loss of retention if transition to methadone is permitted for those who do not respond adequately to buprenorphine/naloxone treatment (section 4.1.2).

Guidelines suggest that pharmacotherapy for opioid dependence is most often effective when part of a comprehensive regimen including drug abuse counselling and participation in self-help programmes.[1] It is also believed that many opioid-dependent individuals are resistant to the strict regimen and lack of anonymity that characterize administration of medication in highly regulated opioid treatment programmes.[14] Several trials examined the efficacy of buprenorphine/naloxone maintenance therapy with different counselling and/or medication-dispensing regimens (section 4.1.3). In these trials, buprenorphine/naloxone was not significantly less effective at reducing illicit opioid use (as assessed by surrogate and/or self-reported measures) when medication was dispensed or administered at less frequent intervals. Neither were there significant differences in efficacy across groups receiving different levels of counselling (standard vs enhanced medical management) or observed versus unobserved dosing. However, patients preferred dosing schedules in which they were less frequently required to attend a clinic or office for medication dispensing or administration (section 4.1.3).

Pharmacotherapies other than buprenorphine/naloxone used as medically-supervised withdrawal agents include methadone, buprenorphine alone, and the α-adrenergic agonist clonidine.[1] A Cochrane review of trials of buprenorphine alone for the management of opioid withdrawal showed buprenorphine to be more effective than clonidine and of similar efficacy to methadone.[102]

In two prospective, randomized studies, buprenorphine/naloxone was also found to be more effective than clonidine as a medically-supervised withdrawal therapy. Buprenorphine/naloxone-treated inpatients and outpatients were significantly more likely to complete the study and provide an illicit-opioid-free urine sample at study completion than patients treated with clonidine in the same treatment settings (section 4.2). No data are currently available comparing the efficacy of buprenorphine/naloxone with methadone for medically-supervised withdrawal therapy.

Two other studies found that using longer buprenorphine/naloxone taper schedules did not improve outcomes in opioid-dependent patients (sections 4.2.2 and 4.2.3), including in adolescents and young adults. Indeed, opioid dependence is a growing problem in adolescents.[103] Following medically-supervised withdrawal therapy, opioid-dependent adolescents usually receive nonpharmacological treatment options, because of concerns over administering longer term opioid-based medication to patients in this age group.[103] Buprenorphine/naloxone is indicated for use in both adults and adolescents aged over 15 years in the EU,[23] although it is not currently approved for use in paediatric patients in the US.[43] The results of the study in adolescents and young adults demonstrated that in the shorter term, outcomes were generally better with a 12-week tapering schedule of buprenorphine/naloxone therapy than with medically-supervised withdrawal therapy alone (section 4.2.3). However, in the longer term, there were no significant between-treatment differences in self-reported opioid use or injecting. Strategies to help prevent relapse include offering supportive counselling and close monitoring for relapse following the tapering of buprenorphine/naloxone; naltrexone may also be an option following taper in some patients.[103] More data are needed concerning the potential of long-term maintenance therapy with buprenorphine/naloxone in adolescents.

The relatively high relapse rates seen in opioid-dependent patients completing medically-supervised withdrawal therapy have raised questions concerning the adequacy of this approach as a treatment strategy.[87] Although comparisons across studies should be made with caution, comparing the findings of the buprenorphine/naloxone maintenance therapy trials (section 4.1) with those of the buprenorphine/naloxone medically-supervised withdrawal therapy trials (section 4.2) supports the contention that better outcomes are generally seen with longer-term maintenance therapy than with brief tapering schedules.[103,104] Maintenance therapy with buprenorphine or methadone has also been reported to reduce the risk of fatal overdose and HIV infection in opioid-dependent patients.[91] Barriers to greater uptake of maintenance therapy include government regulations, cost and availability.[104]

Where reported, buprenorphine/naloxone was generally well tolerated in the trials described above. In the open-label portion of the pivotal, 52-week trial, which evaluated the safety of buprenorphine/naloxone maintenance therapy, treatment-related adverse events occurring in >10% of patients included insomnia, constipation, nausea, sweating, withdrawal syndrome and headache (section 5).

Given the wide-ranging direct and indirect costs associated with opioid dependence, pharmacoeconomic data pertaining to the use of buprenorphine/naloxone is of great interest. In a pharmacoeconomic analysis of methadone versus low-dose buprenorphine, the cost effectiveness of buprenorphine/naloxone was not found to be significantly different to that of methadone.[105] In terms of the dispensing regimen, the mean cost of observed treatment over 3 months with buprenorphine/naloxone was $A2138 versus $A1663 with unobserved treatment (2005 values), with no between-group difference in efficacy (section 4.1.3).[80] Considering all costs and outcomes, achieving an equivalent change in heroin-free days was associated with an average additional cost of $A1477 with observed versus unobserved treatment.[80] However, further robust pharmacoeconomic evaluations of the long-term benefits of primary care use of buprenorphine/naloxone would expand understanding of the cost effectiveness of this drug combination. Well designed studies investigating the transitioning of patients from methadone to buprenorphine/naloxone at therapeutic dose ranges as well as dose-response studies of buprenorphine/naloxone at the higher end of the therapeutic dose range would also be useful.

Further information regarding the adoption of buprenorphine/naloxone in different treatment settings and the willingness of treatment providers to prescribe, dispense and administer this medication would also be of significant interest. However, evidence suggests that the majority of pharmacists and technicians are willing to dispense buprenorphine/naloxone and buprenorphine alone to opioid-dependent patients and do not believe that dispensing these medications compromises safety at their pharmacies.[106] In a survey returned by 40 pharmacists and pharmacy technicians from 27 pharmacies located in seven US states, 77.5% of study respondents did not express greater concern about theft or break-ins, 70% of respondents indicated they were prepared to provide opioid-dependence medication in the future and 85% reported that patients receiving these medications did not cause problems in their pharmacy.[106] Furthermore, a retrospective review of a family practitioner’s first 2 years’ prescribing buprenorphine/naloxone for opioid dependence in private practice in the US also suggests easy integration of opioid dependence treatment with buprenorphine/naloxone in an office-based setting.[107]

In conclusion, the sublingual tablet formulation of the partial μ-opioid receptor agonist buprenorphine in combination with the opioid antagonist naloxone in a 4 : 1 ratio is an effective and generally well tolerated medically-supervised withdrawal and maintenance treatment for opioid-dependent patients with some pharmacodynamic advantages and lower abuse potential compared with the current standard-of-care maintenance pharmacotherapy, methadone. Buprenorphine/naloxone is an effective maintenance therapy for opioid dependence and appears to have generally similar efficacy to methadone, although more data are needed. Less frequent dispensing of buprenorphine/naloxone does not appear to compromise efficacy and improves patient satisfaction. Buprenorphine/naloxone is more effective than clonidine as a medically-supervised withdrawal therapy. Thus, buprenorphine/naloxone is a valuable pharmacotherapy for the treatment of opioid dependence.

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.