Biotransformation of Morphinone and Its Glutathione Adduct Derived from Morphine by Anaerobic Gut Microbes in Guinea Pigs.

Morphinone (MO) and its glutathione adduct (MO-GSH) are excreted into bile of guinea pigs after subcutaneous administration of morphine (M). In the present study, we examined metabolites of M in guinea pig feces. Surprisingly, minimal amounts of MO and MO-GSH were excreted into the feces, whereas dihydromorphine (DHM) and dihydromorphinone (DHMO), which are not found in bile of guinea pigs administered M, were detected in the feces. Incubation of MO and MO-GSH with the contents of the large intestine under anaerobic conditions resulted in their conversion into DHMO. These results suggest that MO-GSH undergoes C-S cleavage by gut microbes to form MO, which is anaerobically reduced to DHMO excreted into feces.

Rifampin Reduces the Plasma Concentrations of Oral and Intravenous Hydromorphone in Healthy Volunteers.

BACKGROUND: Several opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin. METHODS: In this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuronide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration-time curve (AUC0-last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes. RESULTS: Rifampin reduced the AUC0-last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters. CONCLUSIONS: Rifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5'-diphospho- glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.

Glutathione and Glutathione-Like Sequences of Opioid and Aminergic Receptors Bind Ascorbic Acid, Adrenergic and Opioid Drugs Mediating Antioxidant Function: Relevance for Anesthesia and Abuse.

Opioids and their antagonists alter vitamin C metabolism. Morphine binds to glutathione (l-γ-glutamyl-l-cysteinyl-glycine), an intracellular ascorbic acid recycling molecule with a wide range of additional activities. The morphine metabolite morphinone reacts with glutathione to form a covalent adduct that is then excreted in urine. Morphine also binds to adrenergic and histaminergic receptors in their extracellular loop regions, enhancing aminergic agonist activity. The first and second extracellular loops of adrenergic and histaminergic receptors are, like glutathione, characterized by the presence of cysteines and/or methionines, and recycle ascorbic acid with similar efficiency. Conversely, adrenergic drugs bind to extracellular loops of opioid receptors, enhancing their activity. These observations suggest functional interactions among opioids and amines, their receptors, and glutathione. We therefore explored the relative binding affinities of ascorbic acid, dehydroascorbic acid, opioid and adrenergic compounds, as well as various control compounds, to glutathione and glutathione-like peptides derived from the extracellular loop regions of the human beta 2-adrenergic, dopamine D1, histamine H1, and mu opioid receptors, as well as controls. Some cysteine-containing peptides derived from these receptors do bind ascorbic acid and/or dehydroascorbic acid and the same peptides generally bind opioid compounds. Glutathione binds not only morphine but also naloxone, methadone, and methionine enkephalin. Some adrenergic drugs also bind to glutathione and glutathione-like receptor regions. These sets of interactions provide a novel basis for understanding some ways that adrenergic, opioid and antioxidant systems interact during anesthesia and drug abuse and may have utility for understanding drug interactions.

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments.

(-)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated ß-arrestin recruitment assays). "Body" and "tail" interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address" can be considered the "body" of the hydromorphone molecule and the "message" delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/µ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

Detection and quantification of codeine-6-glucuronide, hydromorphone-3-glucuronide, oxymorphone-3-glucuronide, morphine 3-glucuronide and morphine-6-glucuronide in human hair from opioid users by LC-MS-MS.

Current hair testing methods that rely solely on quantification of parent drug compounds are unable to definitively distinguish between drug use and external contamination. One possible solution to this problem is to confirm the presence of unique drug metabolites that cannot be present through contamination, such as phase II glucuronide conjugates. This work demonstrates for the first time that codeine-6-glucuronide, hydromorphone-3-glucuronide, oxymorphone-3-glucuronide, morphine-3-glucuronide and morphine-6-glucuronide are present at sufficient concentrations to be quantifiable in hair of opioid users and that their concentrations generally increase as the concentrations of the corresponding parent compounds increase. Here, we present a validated liquid chromatography tandem mass spectrometry method to quantify codeine-6-glucuronide, dihydrocodeine-6-glucuronide, hydromorphone-3-glucuronide, morphine-3-glucuronide, morphine-6-glucuronide, oxymorphone-3-glucuronide, codeine, dihydrocodeine, dihydromorphine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone and 6-acetylmorphine in human hair. The method was used to analyze 46 human hair samples from known drug users that were confirmed positive for opioids by an independent laboratory. Glucuronide concentrations in samples positive for parent analytes ranged from ~1 to 25 pg/mg, and most samples had glucuronide concentrations in the range of ~1 to 5 pg/mg. Relative to the parent concentrations, the average concentrations of the four detected glucuronides were as follows: codeine-6-glucuronide, 2.33%; hydromorphone-3-glucuronide, 0.94%; oxymorphone-3-glucuronide, 0.77%; morphine 3-glucuronide, 0.59%; and morphine-6-glucuronide, 0.93%.

Single-dose evaluation of safety, tolerability and pharmacokinetics of newly formulated hydromorphone immediate-release and hydrophilic matrix extended-release tablets in healthy Japanese subjects without co-administration of an opioid antagonist.

This single dose, open-label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate-release (IR) and hydrophilic matrix extended-release (ER) hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquid-chromatography tandem mass-spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0-inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0-inf and Cmax increased with food for both IR and ER tablets. The AUC0-inf of hydromorphone-3-glucoside was one-tenth of that of hydromorphone-3-glucuronide. A single oral administration of the hydromorphone tablets would be well-tolerated in healthy Japanese subjects despite a lack of co-administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once-daily dosing.

The effect of UGT2B7*2 polymorphism on the pharmacokinetics of OROS® hydromorphone in Taiwanese subjects.

This open-label, single-center, phase I study (NCT1487564) investigated the effect of uridine diphosphate-glucuronosyltransferase2B7 (UGT2B7*2) genetic polymorphism (H268Y) on the pharmacokinetics (PK) and safety of a single, oral, 16-mg dose of OROS® hydromorphone and its metabolite in healthy Taiwanese subjects. Plasma concentrations of hydromorphone and hydromorphone-3-glucuronide were determined in 28 subjects. PK parameters calculated included maximum plasma concentration (Cmax); time to reach maximum plasma concentration (tmax); area under plasma concentration-time curve from 0-48 hours (AUC0-48 h) and 0-infinite time (AUC∞); and hydromorphone-3-glucuronide:hydromorphone metabolic ratio (RM). Mean plasma concentrations of hydromorphone and hydromorphone-3-glucuronide reached a maximum between 12-18 hours and 18-21 hours, respectively. No clear trend in PK parameters and no clinically significant differences in the incidence of treatment-emergent adverse events (TEAEs) were observed among different UGT2B7 genotypes. Our study found UGT2B7 polymorphism had no apparent effect on PK of OROS® hydromorphone; hydromorphone was well tolerated in pain-free volunteers when coadministered with naltrexone.

In vivo activity of norhydrocodone: an active metabolite of hydrocodone.

Hydrocodone is primarily metabolized to hydromorphone and norhydrocodone. Although hydromorphone is a known active metabolite of hydrocodone, the in vivo activity of norhydrocodone is not well documented. In the current study, the pharmacodynamics of norhydrocodone were evaluated and compared with hydrocodone and hydromorphone. Binding studies established that norhydrocodone, similar to hydrocodone and hydromorphone, is a µ-selective opioid ligand. In vivo analgesia studies (tail flick) demonstrated that, following subcutaneous, intrathecal, and intracerebroventricular administration, norhydrocodone produced analgesia. Following subcutaneous administration, norhydrocodone was ∼70-fold less potent, and hydromorphone was ∼5.4-fold more potent than hydrocodone in producing analgesia. Following intrathecal administration, norhydrocodone produced a shallow analgesia dose-response curve and maximal effect of 15-45%, whereas hydrocodone and hydromorphone produced dose-dependent analgesia. Intrathecal hydromorphone was ∼174-fold more potent than intrathecal hydrocodone. Following intracerebroventricular administration, norhydrocodone had similar potency to hydrocodone in producing analgesia, while hydromorphone was ∼96-fold more potent than hydrocodone. Analgesia induced by the three drugs following subcutaneous, intrathecal, and intracerebroventricular administration was antagonized by subcutaneous naltrexone, confirming that it is opioid receptor-mediated. Subcutaneous norhydrocodone-induced analgesia was completely blocked by intracerebroventricular naltrexone, indicating that norhydrocodone-induced analgesia is likely a supraspinal effect. Seizure activity was observed following intrathecal administration of all three drugs. Norhydrocodone and hydromorphone were ∼3.7 to 4.6-fold more potent than hydrocodone in inducing seizure activity. Naltrexone did not antagonize opioid-induced seizure activity, suggesting that seizures were not opioid receptor-mediated. Taken together, norhydrocodone is an active metabolite of hydrocodone and may contribute to therapeutic and toxic effects following hydrocodone administration.

Incidence of hydromorphone-induced neuroexcitation in hospice patients.

BACKGROUND AND OBJECTIVE: To date, there are no known published studies that prospectively followed hospice patients receiving hydromorphone to evaluate the development of hydromorphone-induced neuroexcitation (HINE). The first objective of this study was to determine the incidence of HINE. The second objective was to identify factors influencing the presence or absence of HINE symptoms in hospice patients. METHODS: This was a noninterventional, prospective study. This study population included hospice patients 18 years of age or older who were admitted to one of two Nathan Adelson Hospice inpatient units in Las Vegas, Nevada, and were initiated on a scheduled regimen of hydromorphone. A total of 156 patients were enrolled and analyzed in this study. Data collection was performed by the study investigators using a standard data tracking form, including hospice diagnosis, gender, renal function, hydromorphone regimen, and whether or not the patient experienced neuroexcitatory symptoms. Data collection occurred from November 2010 to March 2011. RESULTS AND CONCLUSIONS: Based on the data collected in this study, it appears that the likelihood of HINE does increase with larger doses, increasing age, increasing serum creatinine, and the presence of malignant neoplasm. However, after adjusting for the variables in the logistic regression model, diagnosis of malignant neoplasm was not a significant predictor of HINE. Future studies may focus on evaluating metabolite levels, such as hydromorphone-3-glucuronide (H3G), in patients developing HINE symptoms. This may help to determine if the metabolites of opioids, such as H3G, are involved in the development of the neurotoxic symptoms.

Accidental death from hydromorphone ingestion.

A 15-year-old male orally consumed an unknown but fatal amount of sustained release hydromorphone. He was naïve to opioid use. No other drugs or alcohol were involved. The cause of death was acute aspiration-related bronchopneumonia, secondary to hydromorphone ingestion; the manner of death was accidental. Hydromorphone and hydromorphone-3-glucuronide were quantified in postmortem fluids by tandem liquid chromatography-mass spectrometry. The hydromorphone concentrations in the peripheral blood, urine, and vitreous humor were 57, 4460, and 31 ng/mL, respectively. The hydromorphone-3-glucuronide concentrations in the corresponding three fluids were 459, 36,400, and 40 ng/mL. Hydromorphone-3-glucuronide accumulation probably did not contribute significantly to the opiate toxicity. The proposed minimum lethal hydromorphone blood concentration in the nontolerant user is in the vicinity of 60 ng/mL.

Correlation between myoclonus and the 3-glucuronide metabolites in patients treated with morphine or hydromorphone: a pilot study.

BACKGROUND: The 3-glucuronide metabolites of morphine and hydromorphone have been implicated as a causative factor for patients exhibiting myoclonus. OBJECTIVE: The primary goal of this study was to determine plasma levels of morphine-3-glucuronide (M3G) or hydromorphone-3-glucuronide (H3G) in patients demonstrating myoclonus and identify any trends or associations between the two. SETTING: Patients were recruited from San Diego Hospice and the Institute for Palliative Medicine's inpatient unit. DESIGN: A prospective convenience sample comprised of 17 subjects, 12 with myoclonus and 5 without myoclonus. Analysis included demographic, metabolic and clinical variables. Plasma was assayed via high performance liquid chromatography for morphine, M3G, and morphine-6-glucuronide or hydromorphone and hydromorphone-3-glucuronide. RESULTS: No trends or associations were identified between plasma levels of M3G or H3G and myoclonus. Ratio levels of 3-glucuronide metabolite to their corresponding parent opioid were dramatically lower than anticipated. CONCLUSION: In this small pilot study, it appears that the serum levels of metabolites M3G and H3G do not correlate with myoclonus.

Pain management in chronic kidney disease: the pharmacokinetics and pharmacodynamics of hydromorphone and hydromorphone-3-glucuronide in hemodialysis patients.

OBJECTIVE: To describe the pharmacokinetics of hydromorphone (HM) and its primary metabolite hydromorphone-3-glucuronide (H3G) both on and off dialysis in relation to the pharmacodynamic measurements of pain. DESIGN: Prospective, open-label, observational study. SETTING: Canadian, university-based renal program. PARTICIPANTS: Twelve anuric hemodialysis patients with chronic pain, established on immediate-release HM. MAIN OUTCOME MEASURES: HM and H3G plasma concentrations were measured during and between hemodialysis treatments using a reverse-phase high-performance liquid chromatography assay with liquid chromatography/mass spectrometer/mass spectrometer detection. The McGill Pain Questionnaire (MPQ) and a Visual Analogue Scale (VAS) were used to measure pain. Noncompartmental analyses were conducted. Adverse effects were recorded. RESULTS: HM did not substantially accumulate (accumulation factor R = 2.7 (1.6)), most likely due to the rapid conversion to H3G. Conversely, H3G accumulated between dialysis treatments (R = 12.5 (12.1)) but appeared to be effectively removed during hemodialysis (1.8 (0.7), p = 0.03). HM resulted in > 65 percent reduction in pain over dosing intervals. Mean MPQ pain scores decreased from 39.8 (18.2) to 12.3 (16.2) on dialysis and from 35.0 (18.5) to 15.5 (13.6) between dialysis treatments. Mean VAS pain scores decreased from 7.5 (2.5) to 3.0 (1.5) on dialysis and from 5.9 (3.2) to 4.4 (1.6) between dialysis treatments. No clinically significant opioid toxicity was observed. The accumulation of H3G between hemodialysis treatments was associated with greater sensory-type pain (r = 0.76, p < 0.0001) and reduced duration of analgesia. CONCLUSIONS: HM may be a safe and effective opioid for use in selected hemodialysis patients.

Induction of non-apoptotic cell death by morphinone in human promyelocytic leukemia HL-60 cells.

As previously suggested, codeinone (oxidation product of codeine) induces non-apoptotic cell death, characterized by marginal caspase activation and the lack of DNA fragmentation in HL-60 human promyelocytic leukemia cells, which was inhibited by N-acetyl-L-cysteine. Whether, morphinone, an oxidative metabolite of morphine, also induced a similar type of cell death in HL-60 cells was investigated. Morphinone showed slightly higher cytotoxic activity against human tumor cell lines (oral squamous cell carcinoma HSC-2, HSC-3, HSC-4, NA, Ca9-22, promyelocytic leukemia HL-60, cervical carcinoma HeLa) than against normal oral human cells (gingival fibroblast HGF, pulp cells HPC, periodontal ligament fibroblast HPLF). Morphinone also induced an almost undetectable level of internucleosomal DNA fragmentation in the HL-60 cells. Morphinone did not activate caspase-8 or -9 in these cells. Morphinone dose-dependently activated caspase-3 in both HL-60 and HSC-2 cell lines, but to a much lesser extent than actinomycin D. Electron microscopy demonstrated that morphinone induced mitochondrial shrinkage, vacuolization and production of autophagosome and the loss of cell surface microvilli, without destruction of cell surface and nuclear membranes in the HL-60 cells. The autophagy inhibitor 3-methyladenine (0.3-10 mM) slightly inhibited the morphinone-induced cytotoxicity, when corrected for its own cytotoxicity. These data suggest that morphinone induces non-apoptotic cell death in HL-60 cells.

Decoration of the aromatic ring of dihydrocodeinone (hydrocodone) and 14-hydroxydihydrocodeinone (oxycodone).

Improved protocols for the preparation of 1-bromodihydrocodeinone (1-bromohydrocodone) and 1-bromo-14-hydroxydihydrocodeinone (1-bromooxycodone) and synthesis of the corresponding 1-chloro and 1-iodo derivatives have been achieved using the corresponding N-halosuccinimides in acidic milieu. The corresponding 1-carboethoxy derivative of 14-hydroxydihydrocodeinone (1-carboethoxyoxycodone) has been prepared by Pd-catalyzed reaction with carbon monoxide in ethanol. The ester was hydrolyzed to the corresponding zwitterionic amino acid.

Bioactivation of morphine in human liver: isolation and identification of morphinone, a toxic metabolite.

Morphinone, identified in the bile of guinea pigs and rats given morphine, is a reactive electrophile and has the ability to bind to glutathione (GSH) and tissue macromolecules, leading to GSH depletion and cell damage. We previously demonstrated that the livers of various animal species are capable of forming morphinone from morphine. In this study, we examined whether the human liver can produce morphinone from morphine. HPLC analysis revealed that the incubation of morphine with the 9000xg supernatant of human liver in the presence of NAD(P) and 2-mercaptoethanol (ME) gave a peak corresponding to the synthetic morphinone-ME adduct (MO-ME), which is readily formed by a nonenzymatic reaction of morphinone with ME. The reaction product was isolated and was unambiguously identified as MO-ME using FAB-MS and NMR analyses in comparison with synthetic MO-ME. The conversion of morphine to morphinone required NAD(P), and NAD was a preferred cofactor over NADP. All the 9000xg supernatants from six human livers could produce morphinone at different rates, ranging from 30 to 120 nmol/g liver/30 min with NAD at pH 7.4. The enzyme activity responsible for the formation of morphinone from morphine was mainly localized in the microsomes. The microsomal enzyme activity was inhibited by steroids, lithocholic acid and indomethacin. Among these compounds, steroids with a 17beta-hydroxyl group almost completely depressed morphinone formation. In conclusion, the metabolic pathway of morphine to morphinone, a toxic metabolite, in human was shown for the first time in in vitro experiments.

Identification and synthesis of norhydromorphone, and determination of antinociceptive activities in the rat formalin test.

The main objective of this paper is to report the identification and synthesis of norhydromorphone, a novel metabolite of hydromorphone, and its antinociceptive activities when tested in the formalin test as compared to other known analgesics. In addition, we are reporting for the first time the lack of antinociceptive activities of hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide in the rat formalin test. Norhydromorphone was isolated and identified as a metabolite of hydromorphone in a cancer patient's urine. An authentic standard of norhydromorphone was synthesized. The identity of norhydromorphone in the urine sample was confirmed by comparing the LC retention time and MS ion fragmentation with the synthetic standard using a liquid chromatographic-mass spectrometric-mass spectrometric (LC-MS-MS) assay. Norhydromorphone was found to be a minor metabolite of hydromorphone in the urine. Additionally, the antinociceptive activities of norhydromorphone, hydromorphone, morphine, dihydromorphine, dihydroisomorphine, hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide were determined in the rat formalin test following intraperitoneal (i.p.) administration. Only limited antinociception was observed and no significant increase in antinociception was detected at the three doses tested. The increased polarity of norhydromorphone as compared to hydromorphone due to the primary piperidine nitrogen may make it less favorable to cross the blood-brain-barrier (BBB), which may be partly responsible. In addition, lower intrinsic antinociceptive activity, which remains to be determined, could also contribute to the low antinociception. Our results also show that hydromorphone was five times as potent as morphine in the formalin test, while dihydromorphine and dihydroisomorphine were equipotent to and 36% as potent as morphine, respectively. Hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide did not exhibit any antinociceptive effect at the doses tested. The results further underscore the importance of a free C3-OH to the analgesic effect of morphine alkaloids.

[Combined use of intrathecal morphine and diclofenac suppository for postoperative analgesia after caesarean section].

BACKGROUND: Intrathecal morphine for postoperative analgesia after caesarean section has been used in Europe and North America, but its use is not common in Japan. METHODS: We randomized 40 parturients to two groups, given either intrathecal saline (control group) or intrathecal morphine 0.05 mg (morphine group) for caesarean section. To both groups, we gave a diclofenac suppository 50 mg every 8 hours after surgery. RESULTS: The area under curve for the visual analogue scale for pain during 24 hours after operation was significantly lower (P < 0.01) in the morphine group than the control group. In addition, the parturients who required pentazocine as a rescue analgesia was significantly fewer in the morphine group (5 parturients) than the control group (11 parturients). There was no significant difference between the two groups in the Apgar score of infants, pH in umbilical cord arterial and venous blood and the incidence of postoperative nausea and vomiting. The incidence of pruritus was significantly higher in the morphine group (11 parturients) than the control group (no parturient). CONCLUSIONS: Intrathecal morphine 0.05 mg and diclofenac suppository 50 mg given every 8 hours produced effective postoperative analgesia with minimum side effects after caesarean section.

Opioid ligands having delayed long-term antagonist activity: potential pharmacotherapies for opioid abuse.

Buprenorphine is a partial agonist at the micro -opioid receptor with long duration of action and also exhibits delayed antagonist activity. Buprenorphine is finding increasing use as a treatment agent for opioid abuse, though its low efficacy is not well tolerated by all addicts. There is interest in developing a higher efficacy version of buprenorphine and in this mini-review some of the ligands recently discovered, that share with buprenorphine a profile of agonism followed by delayed antagonism, are discussed.