morphinans and Opioid-Related-Disorders

Pain remains a global health challenge. For decades, clinicians have been primarily relying on μ-opioid receptor (MOR) agonists and nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management. MOR agonists remain the most efficacious analgesics available; however, adverse effects related to MOR agonists use are severe which often lead to forced drug discontinuation and inadequate pain relief. The recent opioid overdose epidemic urges the development of safer analgesics. Combination therapy is a well-established clinical pharmacotherapeutic strategy for the treatment of various clinical disorders. The combination of MOR agonists with non-MOR agonists may increase the analgesic potency of MOR agonists, reduce the development of tolerance and dependence, reduce the diversion and abuse, overdose, and reduce other clinically significant side effects associated with prolonged opioid use such as constipation. Overall, the combination therapy approach could substantially improve the therapeutic profile of MOR agonists. This review summarizes some recent developments in this field. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.

Topics: Abuse-Deterrent Formulations; Analgesics, Non-Narcotic; Analgesics, Opioid; Drug Combinations; Drug Synergism; Drug Therapy, Combination; Drug Tolerance; Humans; Imidazoline Receptors; Morphinans; Narcotic Antagonists; Opioid-Related Disorders; Pain Management; Polyethylene Glycols; Prescription Drug Diversion; Receptors, Opioid, mu

The opioid pain market is a lucrative one, but is experiencing significant challenges in the U.S. as the country grapples with prescription opioid addiction, overdose and fatalities. The situation has been declared a national Public Health Emergency and the Food and Drug Administration (FDA) has introduced several measures intended to reduce opioid abuse. The development of abuse-deterrent prescription opioids is one such measure, but although abuse-deterrent formulations of opioids reduce drug liking and abuse, concerns have been highlighted by an Institute of Clinical and Economic Review (ICER) report regarding the insufficiency of currently available data to determine the effects of these formulations at the population level. However, the low abuse liability but effective analgesic efficacy reported for drugs such as NKTR-181 and difelikefalin highlight the potential of novel abuse-deterrent opioids.

Topics: Abuse-Deterrent Formulations; Analgesics, Opioid; Drug Combinations; Drug Compounding; Humans; Inappropriate Prescribing; Morphinans; Opioid-Related Disorders; Pain; Prescription Drug Misuse

Topics: Analgesics; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Drug Tolerance; Humans; Morphinans; Morphine; Narcotics; Neoplasms; Opioid-Related Disorders; Pain; Parasympatholytics; Psychotropic Drugs; Substance-Related Disorders

The reinforcing properties of drugs can be evaluated pre-clinically using self-administration procedures in laboratory animals. This paper reviews self-administration studies of the four opioid agonist/antagonist analgesics pentazocine, butorphanol, nalbuphine and buprenorphine, and compares these results to those from studies of morphine and cyclazocine. All four agonist/antagonists possess reinforcing properties under at least some test conditions. In this respect they more resemble morphine than cyclazocine. These results suggest that they all may have some potential for recreational use. On the other hand, some data point to a lower reinforcing efficacy for these agonist/antagonists than for the pure agonists such as morphine. Studies comparing the reinforcing efficacy among the agonist/antagonists are also reviewed, however more data are needed before definitive conclusions can be drawn within the class.

Topics: Animals; Buprenorphine; Butorphanol; Cyclazocine; Humans; Macaca mulatta; Morphinans; Morphine; Nalbuphine; Opioid-Related Disorders; Papio; Pentazocine; Rats; Reinforcement, Psychology; Self Administration

Buprenorphine is an opioid mixed agonist-antagonist that has potential usefulness as a pharmacotherapy for opiate addiction. Buprenorphine significantly suppressed opiate self-administration by heroin addicts. Buprenorphine also suppressed opiate self-administration in a primate model. Although buprenorphine is a positive reinforcer in rhesus monkey, it is less reinforcing than other opioids and some opioid mixed agonist-antagonists as evaluated in progressive ratio and drug substitution procedures. These data suggest that the abuse liability of buprenorphine should be less than that of other opioid drugs. The safety and potential therapeutic benefits of buprenorphine relative to other currently available pharmacotherapies probably overweigh the possible risks of abuse.

Topics: Adult; Animals; Buprenorphine; Conditioning, Operant; Eating; Heroin Dependence; Humans; Macaca; Male; Methadone; Morphinans; Naltrexone; Opioid-Related Disorders; Reinforcement, Psychology; Self Administration

Topics: Adult; Aged; Analgesics, Opioid; Double-Blind Method; Female; Humans; Low Back Pain; Male; Middle Aged; Morphinans; Opioid-Related Disorders; Prospective Studies

Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone.. This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users.. Inpatient clinical research site.. Forty-two randomized subjects (73.8% male, 81% white, mean age = 25 years).. The primary objective was to evaluate single orally administered 100, 200, and 400 mg NKTR-181 doses in solution compared with 40 mg oxycodone and placebo solutions using the Drug Liking visual analog scale. Secondary measures included the Drug Effects Questionnaire, Addiction Research Center Inventory/Morphine Benzedrine Group Subscale, Price Value Assessment Questionnaire, Global Assessment of Overall Drug Liking, and Take Drug Again Assessment. Central nervous system mu-opioid effects were assessed using pupillometry. The study included qualifying and treatment phases. Subjects received each of the five treatments using a crossover design.. NKTR-181 at all dose levels had significantly lower Drug Liking Emax than oxycodone (P < 0.0001). Drug Liking scores for oxycodone increased rapidly within 15 minutes and peaked at approximately one hour postdose, whereas Drug Liking (and most secondary abuse potential measures) for all doses of NKTR-181 were comparable with placebo for at least the first hour. Only the 400 mg Drug Liking scores were minimally differentiated vs placebo from one and a half to four hours, but remained significantly lower than oxycodone (P < 0.003). NKTR-181 treatment-related adverse effects were mild and occurred at a lower rate compared with oxycodone.. NKTR-181 demonstrated delayed onset of CNS effects and significantly lower abuse potential scores compared with oxycodone in recreational opioid users.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Morphinans; Opioid-Related Disorders; Oxycodone; Young Adult

The subjective, physiological and behavioral effects of nalbuphine, an opioid mixed agonist/antagonist analgesic, naloxone and hydromorphone were studied on adult, male, methadone-dependent volunteers living on a clinical research ward. The purpose was to assess nalbuphine's agonist properties vs. antagonist properties relative to a standard agonist (hydromorphone) and a standard antagonist (naloxone) in opioid-dependent subjects. Drug conditions included saline placebo, nalbuphine hydrochloride (0.375, 0.75, 1.5, 3 and 6 mg), naloxone hydrochloride (0.1 and 0.2 mg) and hydromorphone hydrochloride (4 and 8 mg). Drug conditions, given by i.m. injection, were tested in five subjects under double-blind conditions in 2.5 hr experimental sessions. Physiologic measures were monitored continuously before and for 2 hr after drug administration: pupil diameter and subject- and observer-rated behavioral responses were measured intermittently over this same period. Hydromorphone increased ratings significantly on subjective measures typical of morphine-like effects. Naloxone precipitated opioid abstinence which was measurable on several subject- and observer-rated behavioral measures and physiological measures. Nalbuphine produced effects which were qualitatively similar to the effects of naloxone and showed no evidence of opioid agonist effects in these methadone-dependent subjects. The withdrawal syndrome precipitated by nalbuphine was indistinguishable from that produced by naloxone.

Topics: Adult; Dose-Response Relationship, Drug; Humans; Hydromorphone; Male; Methadone; Morphinans; Nalbuphine; Naloxone; Opioid-Related Disorders; Substance Withdrawal Syndrome

The subjective, physiological and behavioral effects of hydromorphone, naloxone and butorphanol, an opioid agonist/antagonist analgesic, were studied in adult, male, methadone-dependent volunteers living on a clinical research ward. Drug conditions included saline placebo, 4 and 8 mg of hydromorphone HCl, 0.375, 0.75, 1.5, 3 and 6 mg of butorphanol tartrate and 0.1 and 0.2 mg of naloxone HCl. Drug conditions, given by i.m. injection, were tested in five subjects under double-blind conditions in 2.5-hr experimental sessions. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 2 hr after drug administration. Hydromorphone decreased pupil diameter, and significantly increased ratings of "Good Effects" on the subjective measures. Naloxone precipitated opioid abstinence which was measurable on several subject- and observer-rated behavioral measures and physiological measures. Butorphanol produced effects which were generally similar to the effects of naloxone, indicating that butorphanol doses precipitate withdrawal signs and symptoms when administered to methadone-dependent humans. There were some differences in the withdrawal syndromes precipitated by naloxone vs. butorphanol, suggesting that multiple mechanisms may be involved in opioid withdrawal precipitation.

Topics: Adult; Butorphanol; Cognition; Double-Blind Method; Humans; Hydromorphone; Injections, Intramuscular; Male; Methadone; Morphinans; Naloxone; Opioid-Related Disorders; Psychomotor Performance; Substance Withdrawal Syndrome

The μ opioid receptor (MOR) has been an intrinsic target to develop treatment of opioid use disorders (OUD). Herein, we report our efforts on developing centrally acting MOR antagonists by structural modifications of 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl) carboxamido] morphinan (NAP), a peripherally acting MOR-selective antagonist. An isosteric replacement concept was applied and incorporated with physiochemical property predictions in the molecular design. Three analogs, namely,

Topics: Analgesics, Opioid; Central Nervous System; Humans; Morphinans; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Receptors, Opioid, mu

Mu-opioid receptor (MOR) agonists are highly efficacious for the treatment of pain but have significant abuse liability. Recently, we reported that nalfurafine, when combined with oxycodone at a certain ratio, reduced the reinforcing effects of oxycodone in rats while producing additive antinociceptive effects. Questions remain, however, including if the combination will function as a reinforcer in drug-naïve rats, and if the combination produces aversive effects that could explain nalfurafine's ability to reduce oxycodone self-administration? In the present study, we investigated nalfurafine's ability to reduce acquisition of oxycodone self-administration when the two were self-administered as a mixture in drug-naïve rats and nalfurafine's ability to attenuate a conditioned place preference (CPP) induced by oxycodone. In the self-administration study, male Sprague-Dawley rats self-administered intravenous injections of oxycodone (0.056 mg/kg/injection), an oxycodone/nalfurafine combination (0.056/0.0032 mg/kg/injection), or saline under fixed-ratio schedules of reinforcement for 20 days to compare rates of acquisition of drug taking. In the CPP assay, male Sprague-Dawley rats received subcutaneous injections of either saline, oxycodone (3.2 mg/kg), nalfurafine (0.18 mg/kg), or an oxycodone/nalfurafine combination at the same ratio used in the self-administration study (3.2 mg/kg/0.18 mg/kg). All subjects self-administering oxycodone alone met acquisition criteria. However, only 13% of subjects self-administering oxycodone/nalfurafine met criteria, and no subjects acquired self-administration of saline. Oxycodone, but not nalfurafine alone or the oxycodone/nalfurafine combination, produced rewarding effects in rats in the CPP test. These findings suggest that the combination of oxycodone and nalfurafine will be less habit forming in opioid-naïve patients than oxycodone alone.

Topics: Analgesics, Opioid; Animals; Conditioning, Classical; Dose-Response Relationship, Drug; Male; Morphinans; Opioid-Related Disorders; Oxycodone; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, kappa; Reinforcement, Psychology; Reward; Self Administration; Spiro Compounds; Substance-Related Disorders

For thousands of years opioids have been the first-line treatment option for pain management. However, the tolerance and addiction potential of opioids limit their applications in clinic. NFP, a MOR/KOR dual-selective opioid antagonist, was identified as a ligand that significantly antagonized the antinociceptive effects of morphine with lesser withdrawal effects than naloxone at similar doses. To validate the potential application of NFP in opioid addiction treatment, a series of in vitro and in vivo assays were conducted to further characterize its pharmacological profile. In calcium mobilization assays and MOR internalization studies, NFP showed the apparent capacity to antagonize DAMGO-induced calcium flux and etorphine-induced MOR internalization. In contrast to the opioid agonists DAMGO and morphine, cells pretreated with NFP did not show apparent desensitization and down regulation of the MOR. Though in vitro bidirectional transport studies showed that NFP might be a P-gp substrate, in warm-water tail-withdrawal assays it was able to antagonize the antinociceptive effects of morphine indicating its potential central nervous system activity. Overall these results suggest that NFP is a promising dual selective opioid antagonist that may have the potential to be used therapeutically in opioid use disorder treatment.

Topics: Analgesics, Opioid; Animals; Biological Transport; Caco-2 Cells; Calcium; Cell Line, Tumor; CHO Cells; Cricetulus; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Humans; Ligands; Male; Mice, Inbred C57BL; Morphinans; Narcotic Antagonists; Opioid-Related Disorders; Receptors, Opioid, kappa; Receptors, Opioid, mu

Here, we described the structural modification of previously identified μ opioid receptor (MOR) antagonist NAN, a 6α-

Topics: Animals; Calcium; Cyclic AMP; Drug Design; Drug Discovery; Ligands; Male; Mice; Morphinans; Narcotic Antagonists; Opioid-Related Disorders; Radioligand Assay; Receptors, Opioid, mu; Signal Transduction; Structure-Activity Relationship

The opioid crisis is a significant public health issue with more than 115 people dying from opioid overdose per day in the United States. The aim of the present study was to characterize the in vitro and in vivo pharmacological effects of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN), a μ opioid receptor (MOR) ligand that may be a potential candidate for opioid use disorder treatment that produces less withdrawal signs than naltrexone. The efficacy of NAN was compared to varying efficacy ligands at the MOR, and determined at the δ opioid receptor (DOR) and κ opioid receptor (KOR). NAN was identified as a low efficacy partial agonist for G-protein activation at the MOR and DOR, but had relatively high efficacy at the KOR. In contrast to high efficacy MOR agonists, NAN did not induce MOR internalization, downregulation, or desensitization, but it antagonized agonist-induced MOR internalization and stimulation of intracellular Ca

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Mice; Morphinans; Narcotic Antagonists; Opioid-Related Disorders; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Thalamus

Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects.. The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats.. To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared.. Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression.. These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone.

Topics: Analgesics; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Male; Models, Animal; Morphinans; Nociception; Opioid-Related Disorders; Oxycodone; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Reinforcement, Psychology; Respiration; Self Administration; Spiro Compounds

Mu opioid receptor (MOR) selective antagonists and partial agonists have been used for the treatment of opioid abuse and addiction. Our recent efforts on the identification of MOR antagonists have provided several novel leads displaying interesting pharmacological profiles. Among them, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamido]morphinan (NAQ) showed sub-nanomolar binding affinity to the MOR with significant selectivity over the delta opioid receptor (DOR) and the kappa opioid receptor (KOR). Its central nervous system penetration capacity together with marginal agonism in the MOR-GTPγS binding assay made it a very interesting molecule for developing novel opioid abuse and addiction therapeutic agents. Therefore, further pharmacological characterization was conducted to fully understand its biological profile. At the molecular and cellular level, NAQ not only induced no translocation of β-arrestin2 to the MOR, but also efficaciously antagonized the effect of DAMGO in MOR-βarr2eGFP-U2OS cells in the β-arrestin2 recruitment assay. At the in vivo level, NAQ displayed a potent inhibition of the analgesic effect of morphine in the tail-flick assay (ID50=1.19 mg/kg). NAQ (10 mg/kg) also significantly decreased the hyper-locomotion induced by acute morphine without inducing any vertical jumps. Meanwhile NAQ precipitated lesser withdrawal symptoms in morphine dependent mice than naloxone. In conclusion, NAQ may represent a new chemical entity for opioid abuse and addiction treatment.

Topics: Analgesics; Animals; Arrestins; Behavior, Animal; beta-Arrestins; Cell Line, Tumor; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Humans; Isoquinolines; Ligands; Male; Mice, Inbred ICR; Morphinans; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Receptors, Opioid, mu

In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.

Topics: Analgesics, Opioid; Animals; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Drug Tolerance; Humans; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Opioid-Related Disorders; Pyridines; Radioligand Assay; Receptors, Opioid, mu; Receptors, sigma; Structure-Activity Relationship

Butorphanol has been known to act on mu-, delta-, and kappa-opioid receptors, mu- and possibly delta-receptors are thought to mediate morphine dependence. Relative to morphine, butorphanol has a higher affinity for mu- and delta-receptors. In the present study, beta-funaltrexamine (beta-FNA) and naltrindole (NTI) (nonequilibrium mu- and delta-antagonist, respectively) were used to precipitate withdrawal in butorphanol-dependent rats. It was found that beta-FNA (12, 24, 48, and 100 nM) did not elicit significant withdrawal behaviors, while NTI caused teeth-chattering (100 nM), wet shakes (100 nM), forepaw tremors (24 nM), yawning (48 and 100 nM), ejaculation (24 nM), and urination (100 nM). The present results indicate that delta-opioid receptors may be involved in mediating butorphanol dependence, while the involvement of mu-opioid receptors needs to be further investigated.

Topics: Animals; Behavior, Animal; Butorphanol; Indoles; Injections, Intraventricular; Male; Morphinans; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome

The threshold lowering effects of the coadministration of tripelennamine plus nalbuphine or tripelennamine plus pentazocine on the threshold for rewarding electrical intracranial stimulation, a model of drug-induced euphoria, was determined in rats physically dependent to morphine. Although tripelennamine plus nalbuphine had threshold-lowering effects similar to tripelennamine plus pentazocine in non-opiate-dependent subjects, tripelennamine plus nalbuphine failed to lower the threshold for rewarding stimulation in morphine-dependent animals. To the extent that these data may be applied to human addicts, it suggests that opiate-dependent addicts are unlikely to use the combination of tripelennamine plus nalbuphine but are likely to use tripelennamine plus pentazocine.

Topics: Animals; Brain; Electric Stimulation; Electrodes, Implanted; Male; Morphinans; Nalbuphine; Opioid-Related Disorders; Pentazocine; Rats; Rats, Inbred F344; Reward; Tripelennamine

Topics: Butorphanol; Heart Rate; Humans; Hydromorphone; Male; Methadone; Morphinans; Naloxone; Opioid-Related Disorders; Pupil; Respiration; Skin Temperature; Substance Withdrawal Syndrome; Surveys and Questionnaires

Male subjects on methadone maintenance who were residing in a research ward were switched to buprenorphine for 45 days. Physiologic measures, behavioral and subjective ratings of mood states, and an electroencephalogram (EEG) were obtained daily. Distinct changes in EEG activity paralleled physiologic and behavioral effects during the transition to buprenorphine. Similar physiologic effects and a reversal of EEG effects occurred when saline solution was substituted for buprenorphine. It is concluded that, consistent with its classification as a partial opiate agonist, buprenorphine may not substitute fully for methadone.

Topics: Adult; Behavior; Buprenorphine; Double-Blind Method; Drug Evaluation; Electroencephalography; Humans; Male; Methadone; Morphinans; Opioid-Related Disorders

The effects of ascending and descending doses of buprenorphine (0.014-0.789 mg/kg/day) and methadone (0.179-11.86 mg/kg/day) on opiate and food intake were studied in Macaque monkeys over 195 to 245 days. Food (1-g banana pellets) and i.v. drug self-administration (heroin 0.01 or 0.02 mg/kg/injection or Dilaudid 0.02 mg/kg/injection) were maintained on a second-order schedule of reinforcement [FR 4 (VR 16:S)]. Buprenorphine (0.282-0.789 mg/kg/day) produced a significant suppression of opiate self-administration at 2.5 to 7 times the dose shown to be effective in human opiate abusers (P less than .05-.001). Methadone (1.43-11.86 mg/kg/day) did not suppress opiate self-administration in four of five monkeys across a dose range equivalent to 100 to 800 mg/day in man. The distribution of opiate self-administration across drug sessions did not account for the absence of methadone suppression as monkeys took 43% of the total daily opiate injections during the first daily drug session, 2.5 hr after methadone administration. During buprenorphine maintenance, food intake remained stable or increased significantly above base-line levels. Methadone maintenance was associated with significant decrements in food intake in four of five monkeys. Buprenorphine appeared to be significantly more effective in suppressing opiate self-administration than methadone across the dose range studied. Buprenorphine had none of the toxic side effects (seizures, respiratory depression, profound psychomotor retardation) associated with high doses of methadone over 6 to 8 months of daily drug treatment. These data are consistent with clinical studies of buprenorphine effects on heroin self-administration in human opiate addicts.

Topics: Animals; Buprenorphine; Depression, Chemical; Disease Models, Animal; Feeding Behavior; Heroin; Humans; Hydromorphone; Macaca mulatta; Macaca nemestrina; Methadone; Morphinans; Opioid-Related Disorders; Self Administration

Topics: Animals; Buprenorphine; Codeine; Humans; Male; Morphinans; Narcotics; Opioid-Related Disorders; Papio; Self Administration; Time Factors

Topics: Buprenorphine; Germany, West; Humans; Morphinans; Opioid-Related Disorders

Topics: Adult; Buprenorphine; Female; Germany, West; Humans; Male; Middle Aged; Morphinans; Opioid-Related Disorders; Risk

Topics: Animals; Buprenorphine; Dose-Response Relationship, Drug; Eating; Heroin Dependence; Humans; Hydromorphone; Macaca mulatta; Macaca nemestrina; Male; Methadone; Morphinans; Opioid-Related Disorders; Self Administration

Topics: Analgesics; Animals; Etorphine; Female; Humans; Macaca mulatta; Male; Mice; Morphinans; Morphine Dependence; Opioid-Related Disorders; Substance Withdrawal Syndrome

Topics: Animals; Drug and Narcotic Control; Drug Evaluation, Preclinical; Humans; Morphinans; Narcotics; Opioid-Related Disorders; Risk

Topics: Analgesics; Animals; Brain; Drug Tolerance; Etorphine; Humans; Male; Morphinans; Morphine Dependence; Opioid-Related Disorders; Rats; Sulfobromophthalein; Time Factors; Tissue Distribution