morphine-3-glucuronide and Morphine-Dependence

The aim was to evaluate the clinical effectiveness, pharmacodynamics and pharmacokinetics of a range of Tincture of Opium (TOP) doses in the management of opioid withdrawal.. Forty-five opium-dependent Thai subjects were allocated to three dosing groups (6.66, 13.3 and 20 mg morphine equivalents, twice daily) depending on their self-reported prior opium use. On day 5 of dosing subjects underwent an interdosing interval study where blood, withdrawal scores, heart rate and blood pressure (BP) were collected at 0, 1, 3 and 8 h. Plasma morphine concentrations were quantified by high-performance liquid chromatography, and plasma morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations by LCMS.. Thirty-two subjects completed the study. Withdrawal scores were low for all subjects (range 9-23% of maximum response). There were dose-dependent changes in both systolic and diastolic BP (P = 0.021 and P = 0.01, respectively), but these were not considered clinically significant. There were no effects of dose on respiratory rate. Plasma morphine concentrations changed significantly across the interdosing interval (P = 0.0001), rising to a maximum at 1 h after dosing. Plasma morphine concentrations also differed according to dose (P < 0.05). The mean ratios of the morphine glucuronides were found to be: M3G/M6G = 7.7, M3G/morphine = 35.6 and M6G/morphine = 4.9, values comparable to those previously reported.. The management of opioid withdrawal can be achieved, with minimal adverse effects, by using flexible dosing of TOP.

Topics: Adolescent; Adult; Analysis of Variance; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morphine; Morphine Dependence; Morphine Derivatives; Narcotics; Respiration; Substance Withdrawal Syndrome; Thailand; Treatment Outcome; Young Adult

Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious comorbidities, such as dependence, tolerance, immunosuppression and gastrointestinal disorders limit their long-term use. In the current study, a morphine-murine model was used to investigate the role of the gut microbiome and metabolome as a potential mechanism contributing to the negative consequences associated with opioid use. Results reveal a significant shift in the gut microbiome and metabolome within one day following morphine treatment compared to that observed after placebo. Morphine-induced gut microbial dysbiosis exhibited distinct characteristic signatures, including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance and significant impairment in bile acids and morphine-3-glucuronide/morphine biotransformation in the gut. Moreover, expansion of Enterococcus faecalis was strongly correlated with gut dysbiosis following morphine treatment, and alterations in deoxycholic acid (DCA) and phosphatidylethanolamines (PEs) were associated with opioid-induced metabolomic changes. Collectively, these results indicate that morphine induced distinct alterations in the gut microbiome and metabolome, contributing to negative consequences associated with opioid use. Therapeutics directed at maintaining microbiome homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Deoxycholic Acid; Disease Models, Animal; Drug Tolerance; Dysbiosis; Enterococcus faecalis; Female; Gastrointestinal Microbiome; Metabolome; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Phosphatidylethanolamines; Statistics, Nonparametric

A cation-selective exhaustive injection and sweeping micellar EKC (CSEI-Sweep-MEKC) was established to analyze morphine and its four metabolites, including codeine, normorphine (NM), morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G). After SPE, the urine samples were analyzed by this CE method. The phosphate buffer (75 mM, pH 2.5) containing 30% methanol was first filled into an uncoated fused-silica capillary (40 cm, 50 microm id), then a high-conductivity buffer (120 mM phosphate, 10.3 kPa for 99.9 s) followed. The pretreated urine sample was loaded by electrokinetic injection (10 kV, 600 s). The stacking and separation were performed by using phosphate buffer (25 mM, pH 2.5) containing 22% methanol and 100 mM SDS at -20 kV, and detected at 200 nm. During method validation, calibration plots were linear (r > or = 0.998) over a range of 30-3000 ng/mL for morphine, NM, and codeine, 100-2000 ng/mL for M6G, and 80-3200 ng/mL for M3G. The LODs (S/N = 5, sampling 600 s at 10 kV) were 10 ng/mL for morphine, NM, and codeine, 35 ng/mL for M6G, and 25 ng/mL for M3G. This stacking CE method could increase 2500-fold sensitivity of codeine, when comparing with CZE. Five addicts' urine specimens were analyzed. Their results were compared with those of LC-MS-MS, and showed good coincidence. This method could be feasible for monitoring morphine and its metabolites in forensic interest and pharmacokinetic investigations.

Topics: Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Codeine; Humans; Morphine; Morphine Dependence; Morphine Derivatives; Reproducibility of Results; Solid Phase Extraction; Tandem Mass Spectrometry

A polyclonal antibody raised against morphine-3-glucuronide (M3G, the main metabolite of heroin and morphine) was used in the development of a novel assay format using a surface plasmon resonance (SPR)-based biosensor. Previously developed assays have generated calibration curves based on differences in the quantity of response units binding to the surface of a chip coated with the analyte. The novel assay described here was based on the development of a standard curve using the slope of a series of consecutive binding interactions. Using this format, regeneration between each assay cycle was no longer required. This increased the useable life span of the chip surface and, as a result, decreased the cost associated with the assay. Thus, at least 15 binding interactions could be carried out before the saturation of antibody on the surface of the chip caused the response to deviate significantly from linearity. After 15 nonregenerated binding interactions, the slope still remained within 1.5% of the slope after a single binding event. Analysis time, and the sample volumes required were also markedly decreased while sensitivity was enhanced. The inhibition assay developed had a detection range of 270 to 17,500 pg ml(-1).

Topics: Antibodies; Heroin Dependence; Humans; Microchip Analytical Procedures; Morphine Dependence; Morphine Derivatives; Substance Abuse Detection; Surface Plasmon Resonance

Concentrations of morphine and its 3- and 6-glucuronide metabolites (M3G and M6G) in plasma, brain, and urine of rats exposed to morphine for either 24 or 48 h were measured using high-performance liquid chromatography. In another group of morphine-treated rats, the intensity of naloxone-precipitated withdrawal behaviours was monitored at 24 and 48 h. The behavioural effects of M3G in opiate-naive and opiate-dependent rats were also investigated. Morphine was present in plasma, urine, and brain at 24 and 48 h, whereas M3G was detected in plasma and urine only. M6G was not present in detectable quantities in either plasma, urine, or brain. Although plasma concentrations of M3G were similar in both time groups, rats treated for 48 h had significantly larger quantities of M3G in their urine than did the other treatment groups. The incidence of withdrawal behaviour was significantly higher in animals exposed to morphine for 48 h than in those with only 24 h of exposure, M3G had no behavioural effects in the opiate-naive rats and did not precipitate an opiate-abstinence syndrome in morphine-dependent rats. From these results, it was concluded that although M3G is the major product formed by morphine breakdown in rats, it is unlikely that it is involved in the development of morphine dependence in this species.

Topics: Animals; Body Weight; Brain; Defecation; Female; Morphine; Morphine Dependence; Morphine Derivatives; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Substance Withdrawal Syndrome