Initiation of injectable opioid agonist treatment in hospital: A case report

Uncontrolled opioid withdrawal and pain often drive inpatients with opioid use disorder to leave hospital against medical advice, resulting in suboptimal medical and addiction treatment. When oral opioid agonist treatments such as methadone and buprenorphine/naloxone fail for management of craving and withdrawal, injectable opioid agonist treatment may serve to retain patients in care and link them to addiction services. We describe the case of a 47‐year‐old man with a severe, active opioid use disorder and daily use of illicitly manufactured fentanyl, who was re‐admitted to hospital for post‐operative management after leaving against medical advice due to uncontrolled opioid withdrawal. Intravenous hydromorphone was used to retain him in care, allowing for completion of his antibiotics and enrolment in ongoing community injectable opioid agonist treatment.     

Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers

Sublingual buprenorphine is a promising new treatment for opiate dependence, but its opioid agonist effects pose a risk for parenteral abuse. A formulation combining buprenorphine with the opiate antagonist naloxone could discourage such abuse. The effects of three intravenous (IV) buprenorphine and naloxone combinations on agonist effects and withdrawal signs and symptoms were examined in 12 opiate-dependent subjects. Following stabilization on a daily dose of 60 mg morphine intramuscularly, subjects were challenged with IV doses of buprenorphine alone (2 mg) or in combination with naloxone in ratios of 2:1, 4:1, and 8:1 (1, 0.5, or 0.25 mg naloxone), morphine alone (15 mg) or placebo. Buprenorphine alone did not precipitate withdrawal and had agonist effects similar to morphine. A naloxone dose-dependent increase in opiate withdrawal signs and symptoms and a decrease in opioid agonist effects occurred after all drug combinations. Buprenorphine with naloxone in ratios of 2:1 and 4:1 produced moderate to high increases in global opiate withdrawal, bad drug effect, and sickness. These dose ratios also decreased the pleasurable effects and estimated street value of buprenorphine, thereby suggesting a low abuse liability. The dose ratio of 8:1 produced only mild withdrawal symptoms. Dose combinations at 2:1 and 4:1 ratios may be useful in treating opiate dependence. Received: 9 February 1998/Final version: 8 May 1998     

Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine

RATIONALE: Buprenorphine is an opioid agonist-antagonist used in the treatment of opioid dependence. Naloxone has been combined with buprenorphine to decrease the parenteral abuse potential of buprenorphine. This addition of naloxone may also confer further opioid blockade efficacy. OBJECTIVES: To test the opioid blockade efficacy of sublingual buprenorphine/naloxone versus buprenorphine alone and determine whether: (1) the blockade efficacy of buprenorphine/naloxone varies between the time of expected maximal and minimal effects of naloxone, (2) the blockade efficacy of buprenorphine/naloxone and buprenorphine varies as a function of maintenance dose level, and (3) there are adaptive changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine. METHODS: Residential subjects ( n=6) were maintained on different double-blind dose levels of buprenorphine/naloxone (4/1, 8/2, 16/4, 32/8 mg) and buprenorphine (32 mg) for 6-day periods and challenged with parenteral doses of hydromorphone (12 mg) in laboratory sessions. RESULTS: There was no evidence of additional opioid blockade efficacy conferred by combining naloxone with buprenorphine. Higher doses of buprenorphine/naloxone provided greater blockade of hydromorphone effects. Changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine were minimal. CONCLUSIONS: The addition of naloxone to buprenorphine may deter the parenteral abuse of buprenorphine/naloxone, but it does not enhance the therapeutic efficacy of buprenorphine. The blockade efficacy of buprenorphine/naloxone is dose related; however, doses up to 32/8 mg buprenorphine/naloxone provide only partial blockade when subjects receive a high dose of an opioid agonist.     

Effects of buprenorphine/naloxone in opioid-dependent humans

RATIONALE: Buprenorphine is a partial mu opioid agonist under development as a sublingual (SL) medication for opioid dependence treatment in the United States. Because buprenorphine may be abused, tablets combining buprenorphine with naloxone in a 4:1 ratio have been developed to reduce that risk. Low doses of injected buprenorphine/naloxone have been tested in opioid-dependent subjects, but higher doses (more than 2 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined. OBJECTIVES: To assess and compare the effects of intramuscular (i.m.) versus SL buprenorphine/naloxone in opioid-dependent volunteers. METHODS: Opioid-dependent volunteers were maintained on 40 mg per day of oral hydromorphone while on a residential research ward. After safety testing in two pilot subjects, participants (n = 8) were tested with both i.m. and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); i.m. hydromorphone (10 mg) and naloxone (0.25 mg); both i.m. and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was double-blind. RESULTS: Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxone-precipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual buprenorphine/naloxone produced neither opioid agonist nor antagonist effects. CONCLUSIONS: Intramuscular injection of buprenorphine/naloxone precipitates withdrawal in opioid dependent persons; therefore, the combination has a low abuse potential by the injection route in this population. Sublingual buprenorphine/naloxone by tablet is well tolerated in opioid dependent subjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).     

Opioid antagonist challenges in buprenorphine maintained patients

Following one month of sublingual buprenorphine treatment, 15 patients at either 2 mg (n = 7) or 3 mg (n = 8) were hospitalized and the buprenorphine was abruptly stopped by placebo substitution. On the morning following their last dose of buprenorphine, 10 patients were given 1 mg oral naltrexone and 5 were given 0.5 mg/kg intravenous naloxone in a double blind placebo controlled challenge. The naltrexone challenges produced no increase in opioid withdrawal symptoms, plasma MHPG levels, or blood pressure compared to placebo, while naloxone produced significant symptoms and blood pressure increases compared to placebo challenges.     

The problem of pain: Additive analgesic effect of tramadol and buprenorphine in a patient with opioid use disorder

Background: There is a paucity of published literature on the optimal treatment of pain in patients on buprenorphine treatment (BT) for opioid use disorder. Using this case report, we hope to demonstrate that tramadol may represent an effective treatment option for pain in patients on BT while encouraging future clinical trials. Case: The patient is a 56-year-old Caucasian male with a history of opiate use disorder on treatment with buprenorphine/naloxone 8/2?mg 2 times a day (BID) who was followed in an outpatient general psychiatry clinic that specializes in patients with co-occurring substance use disorders. Although maintaining sobriety from opioids, the patient continued to struggle with acute on chronic pain secondary to osteoarthritis that had left him walking with a cane. The patient was started on tramadol 50?mg 3 times a day (TID) for acute pain by his primary care physician (PCP) while he awaited surgical intervention. He reported analgesic effect with buprenorphine/naloxone but noted that it did not last the full period between his doses. He reported further improvement in his pain along with greater daily functioning with the additional use of tramadol, without side effects or withdrawal symptoms. Discussion: Current recommendations for pain management in patients on BT include discontinuation of BT therapy and/or addition of an adjunctive opioid analgesic (including additional buprenorphine/naloxone) while continuing agonist medication for treatment of opioid use disorder. However, determining which medication to use can be difficult, as there has been no literature examining this issue. In this case, the combination of buprenorphine and tramadol demonstrated an additive analgesic effect. Randomized control studies need to be performed to further understand the changes in pain measurement in patients on BT with tramadol compared with other adjunctive analgesic medications.     

Managing opioid withdrawal precipitated by buprenorphine with buprenorphine

Buprenorphine is a partial opioid agonist commonly used to treat opioid dependence. The pharmacology of buprenorphine increases the risk of a precipitated opioid withdrawal when commencing patients on buprenorphine treatment, particularly when transferring from long acting opioids (e.g. methadone). There is little documented experience regarding the management of precipitated withdrawal. In our case, a patient developed a significant precipitated opioid withdrawal following buprenorphine administration, and was able to be successfully treated in hospital with further buprenorphine. This demonstrates that rapid increases in buprenorphine dose can be used as an effective treatment for buprenorphine-induced precipitated opioid withdrawal. The use of buprenorphine to manage withdrawal then allows the individual to continue on this highly effective treatment.     

Buprenorphine alone and in combination with naloxone in non-dependent humans

This study evaluated the effects of concurrent naloxone on the opioid agonist effects of buprenorphine, a mixed agonistantagonist marketed as an analgesic and under development as a treatment for drug abuse. In a residential laboratory seven non-physically-dependent opioid abuser volunteers received intramuscular buprenorphine (0.4 mg or 0.8 mg/70 kg) alone and in combination with naloxone (0.4 mg or 0.8 mg/70 kg) versus placebo. Buprenorphine produced dose-related opioid agonist effects on physiological and subjective measures. Concurrent naloxone attenuated the opioid agonist effects of buprenorphine. Thus, a combination product of buprenorphine and naloxone may have lower abuse liability than buprenorphine alone.     

Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100mg of daily methadone

RATIONALE: Acute doses of buprenorphine can precipitate withdrawal in opioid dependent persons. The likelihood of this withdrawal increases as a function of the level of physical dependence. OBJECTIVES: To test the acute effects of sublingual buprenorphine/naloxone tablets in volunteers with a higher level of physical dependence. The goal was to identify a dose that would precipitate withdrawal (Phase 1), then determine if withdrawal could be attenuated by splitting this dose (Phase 2). METHODS: Residential laboratory study; subjects (N=16) maintained on 100mg per day of methadone. Phase 1: randomized, double blind, triple dummy, within subject study. Conditions were sublingual buprenorphine/naloxone (4/1, 8/2, 16/4, 32mg/8mg), intramuscular naloxone (0.2mg), oral methadone (100mg), or placebo. Medication conditions were randomized, but buprenorphine/naloxone doses were ascending within the randomization. Phase 2: Conditions were methadone, placebo, naloxone, 100% of the buprenorphine/naloxone dose that precipitated withdrawal in Phase 1 (full dose), and 50% of this dose administered twice in a session (split dose). Analyses covaried by trough methadone serum levels. RESULTS: Six subjects did not complete the study. Of the 10 who completed, 3 tolerated up to 32mg/8mg of buprenorphine/naloxone without evidence of precipitated withdrawal. For the seven completing both phases, split doses generally produced less precipitated withdrawal compared to full doses. CONCLUSIONS: There is considerable between subject variability in sensitivity to buprenorphine's antagonist effects. Low, repeated doses of buprenorphine/naloxone (e.g., 2mg/0.5mg) may be an effective mechanism for safely dosing this medication in persons with higher levels of physical dependence.     

Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts

The present study, conducted as part of the development of a buprenorphine/naloxone combination product, was designed to evaluate the individual and combined effects of intravenously administered buprenorphine and naloxone. This in-patient trial used a randomized, double-blind, crossover design. Ten opioid-dependent male subjects were stabilized and maintained on morphine, 15 mg given intramuscularly four times daily. Then, at 48- to 72-h intervals, subjects received one of the following by intravenous injection: (1) placebo, (2) morphine 15 mg, (3) buprenorphine 2 mg, (4) buprenorphine 2 mg/naloxone 0.5 mg, and (5) naloxone 0.5 mg. Both naloxone and buprenorphine/naloxone produced significant (P<0.005) opioid withdrawal effects compared to placebo as assessed with the CINA scale, an instrument which utilizes subject- and observer-reported, as well as physiological parameters. The combination of buprenorphine with naloxone in a 4:1 ratio produced opioid antagonist-like effects which should limit its potential for intravenous abuse by opioid addicts.     

Consideration of opioid agonist treatment in a pregnant adolescent: A case report and literature review

Abstract

Background: Opioid use greatly increases the risk of overdose death, as well as contracting human immunodeficiency virus (HIV) and hepatitis. Opioid agonist treatment is recommended for pregnant women who are dependent on opioids. However, there is a dearth of studies on the use of opioid agonist treatment in pregnant teenagers. Case: Ms. A, a 15?year-old G1PO in foster care, presented to our tertiary women’s hospital requesting opioid agonist treatment for use of pill opioids. She reported nasal inhalation of 5–6 opioid tablets daily, with recent attempts to self-taper using nonprescribed buprenorphine since learning of her pregnancy. Last reported opioid use was >24?hours prior to admission. Urine drug testing was positive only for opioids (negative for buprenorphine and methadone). She did not exhibit significant withdrawal symptoms while hospitalized. The psychiatric treatment team recommended deferring opioid agonist treatment and pursuing outpatient substance use treatment. Unfortunately, Ms. A did not attend outpatient treatment and was lost to follow up. Discussion: Based upon our experience and review of the studies regarding opioid use disorder (OUD) and perinatal and adolescent opioid use, we recommend that pregnant adolescents with OUD be referred to opioid agonist treatment with buprenorphine or methadone. Studies specifically addressing opioid agonist treatment in pregnant teenagers are needed.     

Urine naloxone concentration at different phases of buprenorphine maintenance treatment

In spite of the benefits of buprenorphine‐naloxone co‐formulation (BNX) in opioid maintenance treatment, the naloxone component has not prevented parenteral use of BNX. Current laboratory methods are not sufficient to differentiate between therapeutic and illicit use of buprenorphine, and little is known about urine naloxone concentrations. Measurement of urine naloxone, together with buprenorphine and norbuprenorphine, might help to determine the naloxone source and administration route. A liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method was developed and validated for this purpose. Naloxone, buprenorphine, and norbuprenorphine total concentrations were measured in urine samples from opioid‐dependent patients before and during stable and unstable phases of maintenance treatment with BNX. The limit of quantification in urine was 1.0 µg/L for naloxone, buprenorphine and norbuprenorphine. Before treatment, all samples contained buprenorphine but the median naloxone concentration was 0 µg/L. During the maintenance treatment with BNX all urine samples were positive for naloxone, buprenorphine and norbuprenorphine. The naloxone concentration at a stable phase of treatment (median 60 µg/L, range 5–200 µg/L) was not different from the naloxone concentration at an unstable phase (70 µg/L, 10–1700 µg/L). Applying an upper limit of 200 µg/L to the sample, the median naloxone/buprenorphine ratio was higher in the high than in the low naloxone concentration group (0.9 vs 0.3, respectively). This study suggests that naloxone in urine can act as an indicator of compliance with BNX. Parenteral use of BNX was associated with a high naloxone/buprenorphine ratio. Negative naloxone with positive buprenorphine suggests the use/abuse of buprenorphine alone. Copyright © 2013 John Wiley & Sons, Ltd.     

Efficacy of daily and alternate-day dosing regimens with the combination buprenorphine-naloxone tablet

This study evaluated the efficacy of a combination tablet formulation of buprenorphine containing 8 mg of buprenorphine and 2 mg of naloxone for every other day treatment and whether increasing the daily maintenance dose was essential for maintaining an efficacious alternate-day treatment. Twenty-six opioid-dependent outpatients completing a 16-day baseline entered a double-blind, placebo-controlled, triple crossover trial. Twenty-one days of daily combination tablet administration were compared to two different 21-day periods of alternate-day buprenorphine administration where subjects received either 8 or 16 mg of the combination tablet every other day with placebo on the interposed day. Fifty-four percent (14/26) of subjects completed the study, but only two subjects dropped out during the 16-mg alternate-day condition. Rates of medication compliance, illicit opioid use and subject- and observer-rated measures of opioid effects did not distinguish daily from alternate-day treatments in subjects completing the study. However, pupillary diameter was significantly increased during 8-mg alternate-day compared to the 8-mg daily or 16-mg alternate-day treatment. These data replicate earlier findings describing the acceptability of alternate-day buprenorphine treatment using multiples of the daily maintenance dose and extend these findings by establishing the clinical efficacy of daily and alternate-day dosing regimens with the combination buprenorphine naloxone tablet. This study also suggests slightly improved outcomes during alternate-day treatment using multiples of the daily dose.     

Buprenorphine–naloxone buccal soluble film for the treatment of opioid dependence: current update

Introduction: Opioid dependence is a severe medical disorder with a high psychiatric and somatic comorbidity and mortality rate. The opioid agonist methadone, mixed agonist-antagonist buprenorphine and the combination of buprenorphine with the opioid antagonist naloxone are the first-line maintenance treatments for opioid dependence. Risk of diversion and accidental intoxications, especially in children, are of great concern. To lower these risks, a novel buprenorphine–naloxone film has been developed and introduced in the USA and Australia.

Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine–naloxone film for treatment of opioid dependence. Literature was identified through a comprehensive PubMed search. Data sources also included official FDA information and material made public by the manufacturer.

Expert opinion: Few preclinical and clinical data on safety and efficacy have been published. The pharmacological differences between the novel film and the conventional buprenorphine/naloxone are small. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal. The spectrum of adverse events seems to be similar to that of the conventional sublingual tablet. Recent data show that patients prefer the novel film over the conventional sublingual tablet. Emerging surveillance data indicate a lower risk of accidental poisoning in children compared with the conventional formulation. Further clinical and preclinical data are needed to explore additional possible advantages of the new formulation.     

Buprenorphine and buprenorphine/naloxone soluble-film for treatment of opioid dependence

Introduction: Opioid dependence is a chronic relapsing disorder that shows excess mortality and comorbidity with somatic and psychiatric disorders. Methadone and buprenorphine/naloxone are widely accepted and are used as first-line maintenance treatments for opioid dependence. Fatal intoxications with these agents, risk of diversion, and accidental intoxications, especially in children, are apparent risks and are of increasing public concern. Buprenorphine/naloxone sublingual tablet is an established treatment for opioid dependence. A novel buprenorphine/naloxone film has been developed with improved pharmacokinetics and a hopefully lower risk of diversion and accidental intoxications.

Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine/naloxone film for the treatment of opioid dependence. Literature was identified though a comprehensive PubMed search and data sources included official FDA information.

Expert opinion: This is an interesting new formulation of a well-established medication in opioid dependence. However, few data have been published on its safety and efficacy. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal as expected. Results of an unpublished study made public by the FDA suggest a spectrum of adverse events similar to that of the conventional sublingual tablet. Some data show patients may prefer the novel film over the sublingual tablet. The estimated lower risk for diversion and especially for accidental poisoning in children cannot be assessed in clinical studies but requires data from emergency room visits.     

BUPRENORPHINE AND GASTROINTESTINAL TRANSIT IN RATS: EFFECT OF NALOXONE ON THE BIPHASIC DOSE-RESPONSE CURVE

1. Buprenorphine (0.01-10 mg/kg, subcutaneous [s.c.]) slowed the passage of a charcoal meal along the gastrointestinal tract in rats. The dose-response relationship was U-shaped. 2. When rats were pretreated with naloxone (0.30 mg/kg, s.c.), both the descending and ascending components of the buprenorphine dose-response curve were displaced to the right. 3. Buprenorphine-induced delay of transit was maximal at a dose of 0.10 mg/kg. In rats pretreated with naloxone, a 30-fold higher dose of buprenorphine was required for a comparable peak effect. 4. Moderate-high doses of buprenorphine may be acting on a functionally related binding site which non-competitively inhibits the usual buprenorphine-mu opioid receptor interaction.     

Blocking of enhanced sensitivity to behavioral effects of naloxone induced by narcotic agonists in rats

The present experiment evaluated whether prior treatment with naloxone could block the sensitization to opiate antagonist induced by single dose administration of pure agonist (morphine) or mixed agonist (buprenorphine). Food deprived male Wistar rats were trained to respond for food on a multiple-trial, fixed-interval 3 min schedule. Reinforcement was contingent upon a response within a 10-s limited hold period following a fixed-interval of 3 min. A trial consisted of three fixed interval of 3 min separated by a 10 min timeout period during which responses were not reinforced. The rate decreasing effects of the opioid antagonist naloxone was determined by cumulative dosing. Pretreatment with morphine (0.3 mg/ kg, SC) and buprenorphine (0.03 mg/kg, SC) resulted in an increase sensitivity to the rate decreasing effect of naloxone compared to saline pretreatment. Administration of naloxone (0.3 mg/kg) 10 min prior to pretreatment doses of buprenorphine (0.03 mg/kg; 1.0 mg/kg) and morphine (0.3 mg/kg) increased sensitization to naloxone. However, greater sensitization was observed at low dose of buprenorphine. The increased sensitivity was partially blocked at high dose of buprenorphine (1.0 mg/ kg) by naloxone pretreatment. These results suggest that the doses of naloxone used to block opioid induced sensitization might be different from those required in animals with normal sensitivity to opioid antagonists. Further agonist-induced sensitization to behavioral effects of opioid antagonist appears to be opioid receptor specific.     

Limits to buprenorphine dosing: a comparison between quintuple and sextuple the maintenance dose every 5 days

The relative efficacy of quintuple and sextuple buprenorphine dosing in abating withdrawal symptoms for 120 h was compared in opioid-dependent outpatients. Fourteen subjects received buprenorphine in a double-blind, placebo-controlled, cross-over design. Daily sublingual maintenance doses were 4 mg/70 kg (n=4) and 8 mg/70 kg (n=10). After a stabilization period of daily maintenance administration, subjects received quintuple (5x daily maintenance dose) and sextuple (6x daily maintenance dose) doses every 120 h. Measures of opioid agonist and withdrawal effects were assessed daily. Subjective ratings of withdrawal were significantly greater than baseline ratings beyond 96-h post dosing under both regimens. There was no evidence, however, that those subjective ratings of withdrawal differed between the two regimens. Thus, these data suggest that sextuple buprenorphine dosing, administered every 5 days, does not abate opioid-withdrawal beyond 96 hours.     

Cessation of methadone maintenance treatment using buprenorphine: transfer from methadone to buprenorphine and subsequent buprenorphine reductions

BACKGROUND: Buprenorphine is used in the treatment of opioid dependence. Due to its pharmacology, the transfer from methadone to buprenorphine may precipitate withdrawal symptoms. METHODS: Methadone maintained patients with clinical indicators of stability who were seeking withdrawal from methadone were recruited from three Australian states. Patients on methadone doses between 30 and 40 mg were randomised to transfer to buprenorphine by a fixed dose (transfer at 30 mg methadone) or by a variable dose induction (transfer when 'uncomfortable'). A third group of patients with methadone doses less than 30 mg were transferred to buprenorphine at their entry methadone dose. Fifty-one patients were inducted onto buprenorphine using the same dosing protocol with the first dose of 4 mg buprenorphine. Following stabilisation on buprenorphine, patients gradually reduced the buprenorphine dose to 0 mg. Withdrawal severity and drug use was monitored. RESULTS: There were no significant difference between the transfer at 30 mg and transfer when 'uncomfortable' dosing protocols in severity of withdrawal on transfer from methadone to buprenorphine. Those on doses less than 30 mg reported significantly less withdrawal discomfort at transfer. All but one patient stabilised on buprenorphine. Thirty-eight of the 51 patients inducted onto buprenorphine reached 0 mg. CONCLUSIONS: Transfer from methadone to buprenorphine can safely occur from doses of around 30 mg of methadone. Buprenorphine dose reductions were well tolerated. Thirty-one percent of patients were not using heroin or methadone at 1-month follow-up.     

Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine

Buprenorphine and naloxone sublingual (s.l.) dose formulations may decrease parenteral buprenorphine abuse. We evaluated pharmacologic interactions between 8 mg s.l. buprenorphine combined with 0, 4, or 8 mg of naloxone in nine opiate-dependent volunteers stabilized on 8 mg s.l. buprenorphine for 7 days. Combined naloxone and buprenorphine did not diminish buprenorphine's effects on opiate withdrawal nor alter buprenorphine bioavailability. Opiate addicts stabilized on buprenorphine showed no evidence of precipitated opiate withdrawal after s.l. buprenorphine-naloxone combinations. Buprenorphine and naloxone bioavailability was approximately 40 and 10%, respectively. Intravenous buprenorphine and naloxone produced subjective effects similar to those of s.l. buprenorphine and did not precipitate opiate withdrawal.