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Basic & Clinical Pharmacology &... Jan 2022We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult...
We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1. Eighty-six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (-0.7-2.4), -5.9 (-11.8 to -0.03) and -1.1 (-2.5-0.4) h/L*10 , respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUC )/(AUC ) and (AUC )/(AUC ) ratio was reduced, -1.8 (-3.2 to -0.4) and -0.4 (-0.7 to -0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre-emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.
Topics: Aged; Analgesics, Opioid; Area Under Curve; Female; Genetic Variation; Genotype; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Octamer Transcription Factor-1; Pain, Postoperative; Time Factors
PubMed: 34599645
DOI: 10.1111/bcpt.13667 -
Drug and Alcohol Dependence Nov 2019One emerging strategy to address the opioid crisis includes opioid-targeted immunopharmacotherapies. This study compared effectiveness of a heroin-tetanus toxoid (TT)...
BACKGROUND
One emerging strategy to address the opioid crisis includes opioid-targeted immunopharmacotherapies. This study compared effectiveness of a heroin-tetanus toxoid (TT) conjugate vaccine to antagonize heroin, 6-acetylmorphine (6-AM), morphine, and fentanyl antinociception in rats.
METHODS
Adult male and female Sprague Dawley rats received three doses of active or control vaccine at weeks 0, 2, and 4. Vaccine pharmacological selectivity was assessed by comparing opioid dose-effect curves in 50 °C warm-water tail-withdrawal procedure before and after active or control heroin-TT vaccine. Route of heroin administration [subcutaneous (SC) vs. intravenous [IV)] was also examined as a determinant of vaccine effectiveness. Continuous naltrexone treatment (0.0032-0.032 mg/kg/h) effects on heroin, 6-AM, and morphine antinociceptive potency were also determined as a benchmark for minimal vaccine effectiveness.
RESULTS
The heroin-TT vaccine decreased potency of SC heroin (5-fold), IV heroin (3-fold), and IV 6-AM (3-fold) for several weeks without affecting IV morphine or SC and IV fentanyl potency. The control vaccine did not alter potency of any opioid. Naltrexone dose-dependently decreased antinociceptive potency of SC heroin, and treatment with 0.01 mg/kg/h naltrexone produced similar, approximate 8-fold decreases in potencies of SC and IV heroin, IV 6-AM, and IV morphine. The combination of naltrexone and active vaccine was more effective than naltrexone alone to antagonize SC heroin but not IV heroin.
CONCLUSIONS
The heroin-TT vaccine formulation examined is less effective, but more selective, than chronic naltrexone to attenuate heroin antinociception in rats. Furthermore, these results provide an empirical framework for future preclinical opioid vaccine research to benchmark effectiveness against naltrexone.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Administration Routes; Female; Fentanyl; Heroin; Male; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Rats; Tetanus Toxoid; Vaccination
PubMed: 31479865
DOI: 10.1016/j.drugalcdep.2019.06.006 -
Basic & Clinical Pharmacology &... Jan 2017Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid... (Comparative Study)
Comparative Study
Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co-administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)- and morphine (3 mg/kg, s.c.)-induced antinociception using tail-flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system.
Topics: Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Brain; Chlorothiazide; Disease Models, Animal; Diuretics; Drug Interactions; Drug Therapy, Combination; Eplerenone; Furosemide; Male; Morphine; Neurons; Oxycodone; Pain; Rats, Sprague-Dawley; Spironolactone; Tissue Distribution
PubMed: 27312359
DOI: 10.1111/bcpt.12634 -
Anaesthesia Dec 2002The active metabolite of morphine, morphine-6-glucuronide (M6G), may have fewer unwanted effects than morphine. We randomly allocated 144 women to receive either M6G or... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The active metabolite of morphine, morphine-6-glucuronide (M6G), may have fewer unwanted effects than morphine. We randomly allocated 144 women to receive either M6G or morphine as part of general anaesthesia for day case gynaecological laparoscopy. The incidence of nausea, vomiting, pain, sedation and skin rash, and severity of nausea, pain and sedation after surgery were recorded by direct observation in hospital, and by questionnaire until the next morning. Compared with the M6G group, patients who received morphine were more likely to report nausea in the first 2 h after surgery (odds ratio 2.9, CI 1.31-6.21) and to suffer it with greater severity. During the same time period, they were more likely to vomit and feel sleepy, but the intensity of pain and use of rescue analgesics were similar in both groups. The incidences of nausea, vomiting and the feeling of sleepiness continued to be greater in the morphine group during and after the journey home. The next morning, patients in the morphine group remained sleepier, but the incidence of nausea was similar for the two groups. M6G appears to have a better toxicity profile than morphine. More efficacy studies are needed to define accurately the analgesic potency of systemically administered M6G.
Topics: Adolescent; Adult; Aged; Ambulatory Surgical Procedures; Analgesics, Opioid; Anesthesia, General; Double-Blind Method; Female; Humans; Laparoscopy; Middle Aged; Morphine; Morphine Derivatives; Odds Ratio; Pain, Postoperative; Postoperative Nausea and Vomiting
PubMed: 12479189
DOI: 10.1046/j.1365-2044.2002.02624_2.x -
BMC Palliative Care Oct 2015The feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This... (Observational Study)
Observational Study
BACKGROUND
The feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This study aimed to determine what predicts serum concentrations of morphine in cancer patients receiving continuously intravenous morphine, the relationships between serum concentration of morphine/its metabolites and urinary concentrations, and the relation between morphine concentrations and with clinical outcomes.
METHODS
We collected serum and urine samples from 24 patients with advanced cancer undergoing continuously intravenous morphine therapy. Serum samples were obtained at day one. Spot urine samples were collected once daily on three consecutive days. Pain and adverse drug events were assessed using the Korean version of MD Anderson Symptom Inventory.
RESULTS
A total of 96 samples (72 urine and 24 serum samples) were collected. Median dose of morphine was 82.0 mg/24 h. In a multivariate analysis, total daily morphine dose was the most significant predictors of both serum and urine concentration of morphine. Morphine, M6G, and M3G in serum and urine were statistical significantly correlated (correlation coefficient = 0.81, 0.44, 0.56; p values < 0.01, 0.03, 0.01, respectively).
CONCLUSION
Spot urine concentrations of morphine and its metabolites were highly correlated to those of serum. Total dose of daily morphine was related to both serum and urine concentration of morphine and its metabolites.
Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Republic of Korea
PubMed: 26507979
DOI: 10.1186/s12904-015-0052-9 -
British Journal of Pharmacology Sep 2003(1) We investigated the distribution of morphine and morphine-6beta-glucuronide (M6G) in the brain and spinal cord after intracerebroventricular (i.c.v.) injection of...
(1) We investigated the distribution of morphine and morphine-6beta-glucuronide (M6G) in the brain and spinal cord after intracerebroventricular (i.c.v.) injection of each drug in rats. (2) The cerebrospinal fluid (CSF) concentration of M6G was 5-37 times greater than that of morphine 10, 60 and 120 min after the i.c.v. injection. The apparent elimination clearance of M6G from the CSF was 10 times lower than that of morphine. (3) The intrathecal CSF concentration of M6G measured by the microdialysis method was 29-79 times greater than that of morphine, and M6G was rapidly distributed into the intrathecal space after the i.c.v. injection. (4) M6G was detected in the cerebrum, brainstem, cerebellum and spinal cord at concentrations 2-21 times higher than morphine after the i.c.v. injection of each drug. The distribution volume of M6G in rat brain slices was three times lower than that of morphine, and close to the extracellular fluid space in the brain regions corresponding to the vicinity of the opioid receptors. (5) These brain distribution characteristics of M6G, namely, low clearance from the central nervous system, localization in the extracellular fluid and rapid distribution into the intrathecal space, may contribute to the potent analgesic effect of M6G after i.c.v. injection.
Topics: Animals; Brain; Injections, Intraventricular; Male; Morphine; Morphine Derivatives; Rats; Rats, Sprague-Dawley; Spinal Cord
PubMed: 12967951
DOI: 10.1038/sj.bjp.0705418 -
The International Journal of... Dec 2014Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low...
BACKGROUND
Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies.
METHODS
A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed.
RESULTS
After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse.
CONCLUSION
These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin.
Topics: Analgesics, Opioid; Animals; Antibodies; Behavior, Animal; Chromatography, High Pressure Liquid; Dopamine; Drug-Seeking Behavior; Heroin; Locomotion; Male; Morphine; Morphine Derivatives; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Self Administration; Treatment Outcome; Vaccines, Conjugate
PubMed: 25522425
DOI: 10.1093/ijnp/pyu093 -
The AAPS Journal May 2006The metabolites of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), have been extensively studied for their contribution to clinical effects... (Review)
Review
The metabolites of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), have been extensively studied for their contribution to clinical effects following administration of morphine. Those contributions to both the desired effect (ie, analgesia) and the undesired effects (eg, nausea, respiratory depression) are the subject of clinical controversy. Much attention and effort have been directed at investigating the properties of M6G because of interest in this substance as a possible substitute for morphine. It exhibits increased potency and the possibility of a better side effect profile compared with morphine, although the reported relative benefits vary widely. M3G is not analgesic, but its role in producing side effects, including the development of clinical tolerance, has been proposed. This review is focused on M6G and the factors that contribute to its clinical utility. The formation and distribution of M6G are presented, as are the analgesic effect and the onset of this effect. The impact of genetics, age, and gender on M6G and its effects is also reviewed.
Topics: Aging; Analgesia; Animals; Biotransformation; Female; Glucuronides; Humans; Male; Morphine; Morphine Derivatives
PubMed: 16796385
DOI: 10.1007/BF02854905 -
Anesthesiology Jul 1994In patients with renal failure, morphine may cause prolonged narcosis and respiratory depression. Accumulation of the pharmacologically active metabolite... (Comparative Study)
Comparative Study
BACKGROUND
In patients with renal failure, morphine may cause prolonged narcosis and respiratory depression. Accumulation of the pharmacologically active metabolite morphine-6-glucuronide (M-6G) may explain this effect of morphine in patients with renal failure. After a single oral dose, morphine and its conjugates were measured in the plasma and the cerebrospinal fluid (CSF) in patients with renal failure.
METHODS
Eight patients with normal renal function and six patients with renal failure requiring dialysis were studied after operation under spinal anesthesia. Plasma and CSF concentrations of morphine, morphine-3-glucuronide (M-3G), and M-6G were measured by high-pressure liquid chromatography every 4 h for 24 h after an oral dose of 30 mg morphine.
RESULTS
The area under morphine plasma concentration-time curve from 0 to 24 h increased from 38 +/- 4 ng.ml-1 x h in patients with normal renal function to 110 ng.ml-1 x h in those with renal failure (P < 0.01). In patients with renal failure, plasma concentrations of M-3G and M-6G were higher at 4 h and remained at an increased level until the end of the study. The peak CSF concentration of morphine at 8 h was similar in those with renal failure or normal renal function, 1.8 +/- 0.4 and 2.0 +/- 0.6 ng.ml-1 respectively. M-3G and M-6G in CSF reached a maximum at 12 h in patients with normal renal function, whereas in those with renal failure the concentrations gradually increased so that the highest concentrations were observed at 24 h. At 24 h, CSF M-6G concentration was 15 times greater in patients with renal failure than in those with normal renal function.
CONCLUSIONS
We conclude that M-3G and M-6G readily cross the blood-brain barrier in patients with normal renal function or with renal failure. In patients with renal failure, the retention of plasma M-6G induces a progressive accumulation of this active metabolite in CSF; this accumulation may explain the increased susceptibility to morphine in patients with renal failure.
Topics: Administration, Oral; Aged; Aged, 80 and over; Blood-Brain Barrier; Body Weight; Humans; Kidney; Middle Aged; Morphine; Morphine Derivatives; Renal Insufficiency
PubMed: 8042814
DOI: 10.1097/00000542-199407000-00013 -
Forensic Science International Nov 2023Research on the determination of drugs of abuse in hair has established that drugs can be detected in hair even long after cessation of use. The purpose of this study...
Research on the determination of drugs of abuse in hair has established that drugs can be detected in hair even long after cessation of use. The purpose of this study was to analyze hair samples from chronic opioid users who were beginning a controlled drug cessation program. The study population (n = 15) is involved in a drug rehabilitation program in Santiago de Compostela, Spain. Over a 6-month period, subjects provided hair samples at 2-month intervals, with the first sample collected on the day they began the program. Codeine, morphine, and 6-MAM were analyzed by GC/MS (LOQ = 0.2 ng/mg). Hair tresses were divided into 1 cm segments and analyzed for all analytes 0-1 cm corresponding to the proximal portion to the scalp Following cessation of opioid use, traces of codeine, morphine, and 6-MAM still remained in the newly growing hair segments for a specified period. After 2 months, still 27 % of the users tested positive, and at 4 months, 20 % were positive but only for 6-MAM. However, after 6 months of abstinence, the results were negative for all analytes.
Topics: Humans; Morphine; Codeine; Analgesics, Opioid; Substance Abuse Detection; Morphine Derivatives; Hair
PubMed: 37837845
DOI: 10.1016/j.forsciint.2023.111855