Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: why the 4:1 ratio for treatment? (original) (raw)
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Drug and Alcohol Dependence, 2000
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 40 and 10%, respectively. Intravenous buprenorphine and naloxone produced subjective effects similar to those of s.l. buprenorphine and did not precipitate opiate withdrawal.
Effects of buprenorphine/naloxone in opioid-dependent humans
Psychopharmacology, 2001
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 (IM) 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 IM and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); IM hydromorphone (10 mg) and naloxone (0.25 mg); both IM and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was doubleblind. Results: Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxoneprecipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual bupre-norphine/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).
Sublingual versus subcutaneous buprenorphine in opiate abusers
Clinical pharmacology and therapeutics, 1989
To compare the pharmacologic profiles of sublingually and subcutaneously administered buprenorphine, 10 healthy male subjects with histories of opiate abuse were given sublingually administered buprenorphine (1, 2, and 4 mg), subcutaneously administered buprenorphine (1 and 2 mg), and placebo in a double-blind, double-dummy, placebo-controlled study. All active buprenorphine dosages produced a significant degree of miosis but no significant changes in body temperature, blood pressure, or respiratory or heart rate. Buprenorphine produced varying degrees of euphoria related to dose and route of administration but little dysphoria and sedation, as assessed by subscales of the Addiction Research Center Inventory. Subject "liking" for buprenorphine was reported by both observers and subjects. The relative potency of sublingually to subcutaneously administered buprenorphine was calculated for both physiologic and behavioral parameters and found to be approximately two thirds. Th...
Journal of Opioid Management, 2012
Objective: Sublingual buprenorphine/naloxone (Bup/Nx) is approved for addiction treatment and may be useful for pain management, particularly in opioid-treated patients with pain with nonadherence behaviors. The transition of opioid-treated patients with pain to buprenorphine carries the risk of precipitated withdrawal and increased pain. This study convened pain and addiction specialists to develop and pilot a clinical protocol for safe transitioning to Bup/Nx.Design: The protocol was revised three times based on outside expert review and pilot study observations. The pilot was conducted with a prospective cohort of 12 patients with moderate to severe chronic pain, who were receiving long-term opioid therapy with any full µ-agonist drug, and had exhibited one or more aberrant drugrelated behaviors. Patients were followed up for 3-6 months with the expectation that they would experience few adverse events (AEs) and report lower pain severity.Results: The three patients on the highes...
Journal of Addiction Medicine, 2017
Objective: To assess the safety of rapidly dissolving buprenorphine/naloxone sublingual tablets (BNX-RDT) in opioid-dependent patients. Methods: This open-label, 24-week extension study enrolled patients who completed primary trials of BNX-RDT. Daily tablet doses ranged from 5.7 to 17.1 mg. The primary endpoint was safety; secondary assessments included opioid cravings, addiction severity, health-related quality of life (QOL), and workplace productivity at screening (final day of the primary trials) through study end, with changes measured from baseline of the primary trials. Results: In all, 665 patients received treatment; 292 (43.9%) completed the study. A total of 258 patients (38.8%) reported 557 treatment-emergent adverse events, most commonly headache (3.2%) and constipation (3.0%). Craving scores showed continued improvement on 100-mm visual analog scale (mean change from primary trial baseline, −52.8 at screening; mean change from extension trial baseline, −60.5 at week 24)...
Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans
Psychopharmacology, 2002
Rationale: Buprenorphine can decrease opioid self-administration by humans and animals, but its ability to decrease drug-seeking behavior and craving (i.e. motivational measures) among outpatient volunteers using clinically relevant dosing schedules has not been extensively studied. Objectives: We investigated whether daily versus alternating-day administration of high versus low buprenorphine doses influenced choice of, and operant responding for, hydromorphone versus money. Methods: Fourteen heroin-dependent outpatients were maintained under four buprenorphine sublingual tablet (double blind) dose conditions using a within-subject, randomized crossover design. All participants received, for 2 weeks each, buprenorphine doses of 2 mg daily, 4 mg/placebo on alternating days, 16 mg daily, and 32 mg/placebo on alternating days. In each laboratory test session, participants chose between money ($2/choice) and drug (1/8 of total hydromorphone, 4 or 24 mg IM in different sessions) alternatives using an eight-trial non-independent progressive ratio schedule (FR 100, 200,...12,800). The drug dose and money amount earned was delivered after the end of the 2.5-h work period. Results: Hydromorphone 24 mg was more reinforcing than 4 mg. Higher versus lower average buprenorphine doses (regardless of daily versus alternateday schedule) significantly decreased hydromorphone 24 mg choice and increased money choice. Baseline heroin craving questionnaire scores predicted drug choice, and craving scores were significantly decreased by highdose buprenorphine. Conclusions: High-dose buprenorphine attenuated opioid drug-seeking behavior, heroin craving self-reports and increased sensitivity to alternative reinforcement. These beneficial effects were retained when high-dose buprenorphine was administered on alternate days.
Buprenorphine and naloxone interactions in methadone maintenance patients
Biological Psychiatry, 1997
Buprenorphine is undergoing clinical trials for the treatment of opiate addiction. Although the abuse liability of sublingual buprenorphine is low, reports of intravenous abuse have appeared. This study describes the physiologic and subjective effects of intravenously administered buprenorphine and naloxone given alone and in combination to methadonemaintained patients (40-60 mg/day). On four separate occasions at least 1 day apart, 6 subjects were administered either 0.2 mg buprenorphine, O. 1 mg naloxone, 0.2 mg buprenorphine and O. 1 mg naloxone in combination, or placebo. One male subject quit the experiment after three sessions because of excessive opiate withdrawal. Buprenorphine produced no significant physiologic or subjective effects. Naloxone produced marked opiate withdrawal symptoms. Buprenorphine in combination with naloxone produced characteristic physiologic and subjective opiate antagonist-like symptoms and signs. The parenteral abuse potential of the buprenorphine and naloxone combination is discussed.
American Journal on Addictions, 2019
Background-Prerequisite opioid withdrawal symptoms prior to buprenorphine induction are unacceptable to many patients. We assessed whether transdermal buprenorphine minimized withdrawal while bridging to sublingual therapy among hospital inpatients. Methods-Retrospective chart review of (n = 23) inpatients with opioid use disorder or opioid dependence due to chronic pain. Results-Of 23 inpatients, 65% transitioned without symptoms, while 35% experienced mild withdrawal. Ninety-six percent completed planned hospitalizations, with 83% engaged in treatment 4 weeks post-discharge. Discussion and Conclusions-Bridging to sublingual therapy with transdermal buprenorphine patches was feasible without withdrawal symptoms.