OPRM1 influence on and effectiveness of an individualized treatment plan for prescription opioid use disorder patients

Screening for opioid use disorder should be considered in chronic non-cancer pain (CNCP) patients with long-term use of opioids. The aim of our study was to assess the effectiveness of an individualized treatment plan (ITP) for prescription opioid dependence that included screening of pharmacogenetic markers. An observational prospective study was performed using prescription opioid-dependent CNCP outpatients (n = 88). Patients were divided into nonresponders, responders, or high responders according to their response to the ITP. Genotyping of OPRM1 (A118G), OPRD1 (T921C), COMT (G472A), ABCB1 (C3435T), and ARRB2 (C8622T) was performed by real-time PCR. Our ITP achieved a significant reduction of the morphine equivalent daily dose (MEDD) in 64% of responders, including 33% of high responders. Nonopioid medication or buprenorphine use was significantly higher at final versus basal visit. 118-AA OPRM1 patients required significantly lower MEDD at basal and final visits. Our ITP showed effectiveness and security in reducing MEDD in opioid-dependent patients, with good conversion to buprenorphine that was more pronounced in 118-AA OPRM1 patients

Neuroprotection by the novel calcium antagonist PCA50938, nimodipine and flunarizine, in gerbil global brain ischemia

Calcium is involved in the physiopathology of cerebral ischemia. Calcium antagonists might prevent the calcium overload and death of cells from ischemically compromised tissue. We compare the neuroprotective effect of various doses (0.2, 0.5 and 1 mg/kg) of two dihydropyridines, nimodipine and the novel 1,4-dihydropyridine derivative PCA50938, and flunarizine in the gerbil model of global ischemia. Improvements in morbidity were observed 2 h after the end of carotid occlusion (McGraw's scale) with 0.5 mg/kg of flunarizine, all doses of PCA50938 and 0.2 mg/kg nimodipine. Neuronal loss in the CA1 sector of the hippocampus was examined. The animals treated with 0.5 mg/kg flunarizine and those treated with 1 mg/kg PCA50938 showed a significant reduction in the percentage of damaged neurons in the hippocampal CA1 area, 72 h after transient ischemia. None of the animals treated with 0.5 mg/kg flunarizine had more than 80% of the evaluated neurons altered. We conclude that PCA50938 and flunarizine may act as neuroprotective drugs with different patterns of dose–response and neuroprotective-morbidity-mortality relationships, in the model of global cerebral ischemia in the gerbil. Flunarizine has a narrow therapeutic range.Supported in part by an agreement between the University of Alicante and Laboratories Alter (year 1991).Peer reviewe

Morphine-3-glucuronide prevents tolerance to morphine-6-glucuronide in mice

Daily subcutaneous (s.c.) pretreatment with morphine-3-glucuronide (6 mg/kg) was found to reduce morphine-6-glucuronide (4 mg/kg s.c.)-induced antinociception, with no decrease in the effect over 5 days. Morphine-6-glucuronide administration (4 mg/kg s.c.) on Day 6, without morphine-3-glucorinide pretreatment, results in a significant increase in antinociception (from 24% on Day 5 to 70%; p≤0.05). Morphine-3-glucuronide may prevent tolerance to morphine-6-glucuronide by reducing morphine-6-glucuronide-induced antinociception.Peer reviewe

Anticonvulsant effects of nimodipine and two novel dihydropyridines (PCA 50922 and PCA 50941) against seizures elicited by pentylenetetrazole and electroconvulsive shock in mice

In animal models of epilepsy, calcium entry blockers have shown anticonvulsant properties. We studied the antiepileptic effects of nimodipine and two novel dihydropyridines, a calcium antagonist (PCA 50922) and a calcium agonist (PCA 50941), on pentylenetetrazole seizure and maximal electroshock seizure (MES) in mice. Anticonvulsant profile of nimodipine and PCA 50922 was similar to that of clonazepam, but markedly different from that of phenytoin. None of the doses of the PCA 50941 showed anticonvulsant effect.Alter.Peer reviewe

Pharmacogenetics and prediction of adverse events in prescription opioid use disorder patients

The threats involved in the long-term opioid treatment of chronic non-cancer pain (CNCP) have increased notably. Strategies to identify at-risk patients are important because there is no clear evidence showing which screening or deprescription programmes are appropriate. Our aim was to evaluate the evidence provided by pharmacogenetics applied to predict an analgesic toxicity profile in prescription opioid use disorder (POUD) patients participating in an opioid deprescription programme. Pharmacogenetic markers were analysed in an observational, prospective deprescription programme for POUD patients (n = 88) treated for CNCP. It consisted of monitoring visits (baseline, follow-up and final), opioid rotation or discontinuation and the recording of adverse events and suspected adverse drug reactions (ADRs). Variants in OPRM1 (A118G), ABCB1 (C3435T), COMT (G472A), OPRD1 (T921C) and ARRB2 (C8622T) genes were tested by real-time PCR. Ethics committee approved the study. Wild-type OPRM1-AA genotype carriers reported a significantly higher number of adverse events than OPRM1-AG/GG (median [p25-75], 7 [5-11] vs 5 [3-9]), particularly gastrointestinal system events (90% vs 63%) such as nausea (33% vs 0%). Suspected ADRs (affecting 17% of the patients) were three times higher in males than in females (30% vs 11%). The deprescription programme was effective and safe, and it achieved a significant progressive reduction in the morphine equivalent daily dose, strong opioids and other analgesics' use, without causing any changes in pain intensity or opiate abstinence syndrome. OPRM1 gene polymorphisms could identify the risk of gastrointestinal adverse events in POUD patients. Deprescription programmes including pharmacogenetic analysis should be considered during the follow-up of this population

Lack of morphine-6-glucuronide antinociception after morphine treatment. Is morphine-3-glucuronide involved?

Morphine, morphine-6-glucuronide (M6G) tolerance and cross-tolerance between morphine and M6G have been evaluated in mice. Daily administration of equipotent doses of M6G and morphine induced similar declines in antinociception over 9 days of treatment. However, a higher dose of M6G than morphine is required in tolerant animals to recover the initial response. In studies where daily morphine doses were substituted by M6G administration, on specific days, there was a significant fall in M6G antinociception on those days immediately following morphine administration, relative to the response to continued morphine (a decrease of 53.7% on day 2, P < 0.001 and a decrease of 62.5% on day 11, P < 0.05) and M6G (a decrease of 45.4% on day 2, P < 0.05) exposure. The decrease was independent of treatment duration and dosage. This decrease in the antinociceptive effect of M6G after morphine was avoided after clofibrate treatment, an inhibitor of (-)morphine metabolism. Determination of morphine and its metabolites in plasma revealed that morphine-3-glucuronide (M3G) concentration was significantly lower (P < 0.001) in animals treated with clofibrate (8.3 +/- 8.3 ng/ml) than in controls (422 +/- 80 ng/ml). The dose-response curve for M6G was shifted to the right by prior administration of M3G. These results suggest that during morphine treatment the antinociceptive effect of M6G may be antagonized by the other metabolite, M3G.Peer reviewe

Genetic variability in morphine sensitivity and tolerance between different strains of rats

The development of tolerance, the sensitivity to morphine and the effective morphine plasma concentrations have been studied in Sprague–Dawley (SD-U) and Wistar (W) rats. Daily administration of morphine (10 mg/kg/12 h for 9 days) in W rats produced a reduction in morphine antinociception from day 1 (12±0 s) to day 9 (6.7±1.9 s). Morphine antinociception in the SD-U rats did not change over the period of treatment. Naloxone abolished the antinociception of morphine in both opiate naive and chronically treated SD-U rats. The pharmacokinetic parameters of morphine and morphine-3-glucuronide did not differ significantly between strains. Both naive and chronically treated SD-U rats required smaller doses of morphine than W rats to obtain a maximum antinociceptive effect. Plasma concentrations following administration of the same dose of morphine, did not differ between strains or days of treatment. The range of morphine concentrations required to obtain a maximum effect were lower in SD-U rats, both on day 1 and day 8 when compared to W rats. These results show differences between the two strains with regard to both morphine sensitivity and development of tolerance, whilst also suggesting that the differences do not have a kinetic basis.The study was supported by a project grant (SAF 96-0183) from CICYT, Spain.Peer reviewe