Rapid detoxification of heroin dependence by buprenorphine.
AIM: To evaluate the clinical efficacy of buprenorphine (Bup) in treatment of acute heroin withdrawal. METHODS: Bup was given sublingually daily to 60 cases of heroin addicts in 3 groups: low, medium, and high doses. Withdrawal signs and symptoms of heroin were rated by Clinical Institute Narcotic Assessment. Craving for heroin during detoxification was assessed by Visual Analogue Scale. The side effects of Bup was assessed by Treatment Emergent Symptom Scale. RESULTS: The mean daily consumption of Bup in low, medium, and high group was 2.0, 2.9, and 3.6 mg, respectively. Bup not only suppressed objective signs and withdrawal symptoms for heroin withdrawal, but also reduced the duration for heroin detoxification over 7-8 d. CONCLUSION: Bup is an effective and rapid detoxification agent with fewer side effects for treatment of acute heroin withdrawal. (+info)
Nonselective coupling of the human mu-opioid receptor to multiple inhibitory G-protein isoforms.
The human mu-opioid receptor was expressed in Saccharomyces cerevisiae. Binding of [3H]diprenorphine to yeast spheroplasts was specific and saturable (Kd = 1 nm, Bmax = 0.2-1 pmol x mg-1 of membrane proteins). Inhibition of [3H]diprenorphine binding by antagonists and agonists with varying opioid selectivities (mu, delta and kappa) occurred with the same order of potency as in mammalian tissues. Affinities of antagonists were the same with yeast spheroplasts as in reference tissues whereas those of agonists, except etorphine and buprenorphine, were 10-fold to 100-fold lower. Addition of heterotrimeric Gi,o-proteins purified from bovine brain shifted the mu-opioid receptor into a high-affinity state for agonists. Using individually purified Galpha-subunits re-associated with betagamma-dimers, we showed that alphao1, alphao2, alphai1, alphai2 and alphai3 reconstituted high-affinity agonist binding with equal efficiency. This suggests that the structural determinants of the mu-opioid receptor responsible for G-protein coupling are not able to confer a high degree of specificity towards any member of the Gi,o family. The selective effects of opioid observed in specialized tissues upon opioid stimulation may be a result of regulation of G-protein activity by cell-specific factors which should conveniently be analysed using the reconstitution assay described here. (+info)
Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure.
The discriminative stimulus and subjective effects of opioid mixed agonist-antagonists were assessed in volunteer nondependent heroin users trained in a three-choice drug discrimination procedure to discriminate among the effects of i.m. administration of 2 ml of saline, 1 mg of hydromorphone, and 4 mg of hydromorphone (a morphine-like mu agonist). Other subjective, behavioral, and physiological measures were concurrently collected. The discrimination was readily learned by six of the eight subjects. After training, generalization curves were determined for the following i.m. drug conditions: hydromorphone (0.375-4.0 mg), pentazocine (7.5-60 mg), butorphanol (0.75-6 mg), nalbuphine (3-24 mg), and buprenorphine (0.075-0.6 mg). All five of the test drugs were discriminated significantly or showed trends toward being discriminated as hydromorphone 1 mg-like at one or more dose levels. Hydromorphone showed an inverted U-shaped dose-effect function on the hydromorphone 1 mg-like discrimination. Subjective effect measures produced clearer differentiation among the test drugs than did drug discrimination performance. The present results differ from those of a previous study that observed a close relationship between the results of the discrimination measure and subjective effect measures. The previous study used similar methods and test drugs but different training drugs (e.g., 3 mg of hydromorphone versus 6 mg of butorphanol versus saline). It appears that both the sensitivity of drug discrimination performance to between-drug differences and the relationship between discriminative and subjective effects depends upon the specific discrimination that is trained (e.g., two-choice or three-choice). The present high dose-low dose-saline discrimination procedure appears useful for assessing partial agonist activity. The present data are consistent with partial agonist activity for pentazocine, butorphanol, nalbuphine, and buprenorphine. (+info)
Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter gene assay.
The role of the opioid-like receptor 1 (ORL1) and its endogenous ligand, nociceptin/orphanin FQ (N/OFQ), in nociception, anxiety, and learning remains to be defined. To allow the rapid identification of agonists and antagonists, a reporter gene assay has been established in which the ORL1 receptor is functionally linked to the cyclic AMP-dependent expression of luciferase. N/OFQ and N/OFQ(1-13)NH(2) inhibited the forskolin-induced luciferase gene expression with IC(50) values of 0.81 +/- 0.5 and 0.87 +/- 0.16 nM, respectively. Buprenorphine was identified as a full agonist at the ORL1 receptor with an IC(50) value of 8.4 +/- 2.8 nM. Fentanyl and 7-benzylidenenaltrexone displayed a weak agonistic activity. The ORL1 antagonist [Phe(1)Psi(CH(2)-NH)Gly(2)]N/OFQ((1-13))NH(2) clearly behaved as an agonist in this assay with an IC(50) value of 85 +/- 47 nM. Thus, there is still a need for antagonistic tool compounds that might help to elucidate the neurophysiological role of N/OFQ. (+info)
Determination of buprenorphine and norbuprenorphine in urine and hair by gas chromatography-mass spectrometry.
Buprenorphine, which is used in France as a substitution drug for opioid addiction, is widely abused, and several fatal cases have been reported. In order to confirm a recent intoxication or to establish retrospectively chronic abuse, a simple and reliable gas chromatographic-mass spectrometric method was developed and validated for quantitation of buprenorphine and its active metabolite norbuprenorphine in urine and hair. Two milliliters of urine or 50 mg of pulverized hair was submitted to a pretreatment (enzymatic hydrolysis for urine and decontamination with dichloromethane followed by incubation in 0.1 M HCI for hair). Buprenorphine-d4 was chosen as the internal standard. Selective solid-phase extraction with Bond Elut Certify columns provided recoveries higher than 85% for urine and 43% for hair. By using a mixture of MSTFA/TMSIM/TMCS (100:2:5), buprenorphine and norbuprenorphine produced stable silylated derivatives. The detection was carried out with a quadrupole mass detector working in El selected ion monitoring mode. Ions at m/z 450 and 468 were chosen for the quantitation of buprenorphine and norbuprenorphine, respectively (m/z 454 was used for the internal standard). Limits of quantitation were 0.25 and 0.20 ng/mL, respectively, for buprenorphine and norbuprenorphine in urine and 0.005 ng/mg for the two compounds in hair. Calibration curves were linear from 0 to 50 ng/mL in urine and from 0 to 0.4 ng/mg in hair. Between-day and within-day precisions were less than 8.4% in hair and 6.1% in urine for both molecules in all cases. This method was applied to urine and hair samples collected from patients in a withdrawal treatment program and demonstrated its good applicability in routine analysis and its benefit for clinicians. This technique, which requires instruments already available to many toxicology laboratories, offers an attractive alternative to more sophisticated techniques. (+info)
A retrospective study of buprenorphine and norbuprenorphine in human hair after multiple doses.
The analysis of hair has been proposed as a tool for monitoring drug-treatment compliance. This study was performed to determine if buprenorphine (BPR) and norbuprenorphine (NBPR) could be detected in human hair after controlled administration of drug and to determine if segmental analysis of hair was an accurate record of the dosing history. Subjects with dark hair (six males, six females) received 8 mg sublingual BPR for a maximum of 180 days. Single hair collections were made once after BPR treatment and stored at -20 degrees C until analysis. Hair was aligned scalp-end to tip and then segmented in 3-cm sections. For this study, it was assumed that the mean hair growth rate was 1.0 cm/month. Deuterated internal standard was added to hair segments (2-20 mg of hair) and digested overnight at room temperature with 1 N NaOH. Specimens were extracted with a liquid-liquid procedure and analyzed by liquid chromatography-tandem mass spectrometry. The limits of quantitation for BPR and NBPR were 3 pg/mg and 5 pg/mg, respectively, for 20 mg of hair. BPR and NBPR concentrations were highest for all subjects in hair segments estimated to correspond to the subject's period of drug treatment. With one exception, NBPR was present in higher concentrations in hair than was the parent compound. BPR concentrations in hair segments ranged from 3.1 pg/mg to 123.8 pg/mg. NBPR concentrations ranged from 4.8 pg/mg to 1517.8 pg/mg. In one subject, BPR and NBPR were not detected in any hair segment. In some subjects, BPR and NBPR were detected in hair segments that did not correspond to the period of drug treatment, suggesting that drug movement may have occurred by diffusion in sweat and other mechanisms. The data from this study also indicate that there is a high degree of intersubject variability in measured concentration of BPR and NBPR in hair segments, even when subjects receive the same dose for an equivalent number of treatment days. Future prospective studies involving controlled drug administration will be necessary to evaluate whether hair can serve as an accurate historical record of variations in the pattern of drug use. (+info)
Ring-constrained orvinols as analogs of buprenorphine: differences in opioid activity related to configuration of C(20) hydroxyl group.
The relative positions of the C(20) substituents in buprenorphine, particularly the hydroxyl group, have been implicated in its actions as a partial mu-agonist and a kappa-antagonist. This hypothesis has been examined by the synthesis and pharmacological characterization of five orvinols in which the C(20) carbon atom of buprenorphine is constrained in a five-membered ring, fixing the hydroxyl group above (beta) or below (alpha) the plane of the ring. All five compounds were nonselective in binding assays with similar, low nanomolar affinities. The compounds acted as delta-agonists in the mouse vas deferens and kappa-agonists in the myenteric plexus-longitudinal muscle of the guinea pig ileum and in Chinese hamster ovary (CHO) cells expressing the human kappa-opioid receptor (CHO-hkor). All were lower efficacy mu-agonists than buprenorphine as measured by the [(35)S]guanosine-5'-O-(3-thio)triphosphate assay in SH-SY5Y cells. The major difference between the isomers was an 11- to 12-fold higher potency of the beta-OH isomer (BU46) compared with the alpha-OH isomer (BU47) at the kappa-receptor in the guinea pig ileum and CHO-hkor cells and a somewhat higher efficacy of BU46 in CHO-hkor cells. BU46 and BU47 were evaluated in vivo. BU46 was a full agonist in the mouse writhing assay and antinociception was prevented by norbinaltorphimine, showing a kappa-mechanism of action. In contrast, BU47 acted as an antagonist of mu-, delta-, and kappa-mediated antinociception in the writhing assay. The results show that the configuration of the hydroxyl group is not important in binding affinity at mu-, delta-, or kappa-receptors but does influence kappa-potency and kappa-efficacy, particularly in vivo. (+info)
Opiate drugs and delta-receptor-mediated myocardial protection.
BACKGROUND: Hypothermic myocardial arrest is necessary to complete most cardiac surgery, which limits the success of such operations. Similarly, cold, inhospitable environments limit the survival of warm-blooded animals. Animals have successfully adapted to this challenge through hibernation. Hibernation is an energy-conserving state, now known to be governed by cyclical variation in endogenous opiate compounds. It may also be induced in nonhibernators via hibernating animal serum factors or delta-opiate peptides. Furthermore, hibernation-induction triggers extend organ preservation in many models. This study examined whether opiate drugs with an affinity for the delta-opiate receptor confer similar protection. METHODS AND RESULTS: Isolated hearts harvested from New Zealand White rabbits were treated with either cardioplegia alone or delta-opiate drugs (fentanyl, morphine, buprenorphine, pentazocine) followed by 2 hours of 34 degrees C ischemia. Hearts were then reperfused, and functional and metabolic indices of treated groups were compared with untreated controls. Isovolumic developed pressure, coronary flow, and oxygen consumption were compared as a percent of preischemia versus 45 minutes after reflow. Developed pressure and oxygen consumption were better preserved in the morphine, buprenorphine, and pentazocine groups when compared with cardioplegia alone. CONCLUSIONS: Drugs with delta-opiate activity confer myocardial protection, which is additive to cardioplegia. Use of delta-opiate drugs in this context may have important clinical implications. (+info)