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Objective: To investigate the relationship between metamizol pharmacokinetics and the antinociceptive effect produced after subcutaneous administration of metamizol (177.8 mg/kg) alone or in combination with morphine (3.2 mg/kg), under acute and chronic treatments., Methods: Antinociception was assessed using the pain-induced functional impairment model in rat (PIFIR). Serial blood samples were collected from the same animals to study the pharmacokinetics of metamizol., Key Findings: The co-administration of the drugs in single dose, confirmed the potentiation of their individual antinociceptive effects. When the drugs were administered alone following the chronic schedule, a pronounced tolerance development to their antinociceptive effects was found, whereas it was significantly attenuated when they were administered together. Metamizol pharmacokinetics was unaltered by the presence of morphine. Plasma concentrations of 4-methylaminoantipyrine, an active metabolite markedly decreased under chronic administration., Conclusions: The mechanism involved in the potentiation of the antinociceptive effect produced by the combination, cannot be explained by the interaction of morphine on metamizol pharmacokinetics. Other pharmacokinetic interactions along with known pharmacodynamic interactions in which metamizol active metabolites contribute, should be considered. The frequency of administration enhances tolerance development and induces metamizol elimination process., (© 2017 Royal Pharmaceutical Society.)

In order to detect an anti-nociceptive interaction between morphine and gabapentin, the anti-allodynic and anti-hyperalgesic effects of these drugs, administered either separately or in combination, were determined using the von Frey and acetone tests in a rat model of neuropathic pain (Bennett model). Morphine and gabapentin individually induced moderate attenuation of mechanical hyperalgesia, whereas the morphine and gabapentin combination completely decreased hyperalgesia. Morphine showed its maximal effect at 30 min post-injection in the acetone test; however, this effect gradually returned to the baseline value. Gabapentin did not produce an anti-allodynic effect, whereas the morphine and gabapentin combination completely decreased allodynia behavior at 30 min post-injection, an effect that persisted until 120 min. The area under the curve (AUC) of the anti-allodynic or anti-hyperalgesic effects produced by the combinations were significantly greater than the theoretical sum of effects produced by each drug alone or similar to the theoretical sum. The analysis of the effect, expressed as the AUC of the time course, supports the hypothesis that the combination of these drugs is useful in neuropathic pain therapy.

Background: Neuropathic pain is associated with disease or injury to the peripheral or central nervous system, which is considered particularly difficult to treat due to its diverse etiology and underlying physiopathological mechanisms. Recent experimental and clinical data support the potential of pharmacotherapy using a combination of drugs for neuropathic pain., Methods: In order to assess a possible synergistic anti-hyperalgesic interaction, the anti-hyperalgesic effects of morphine and gabapentin, single-dose administered either separately or in combination, were determined using the von Frey test in a rat model of neuropathic pain (Bennett model)., Results: Time course analysis showed that morphine (3.2 mg/kg s.c.) and gabapentin (17.8 mg/kg s.c.) individually reached their maximum effect at 60 min after treatment, producing an anti-hyperalgesic effect of 51.7+/-10.5% and 55.0+/-11.7%, respectively, whereas the combination morphine + gabapentin (3.2+17.8 mg/kg s.c.) produced an almost total anti-hyperalgesic effect at 30 min (96.7+/-2.1%) and at 60 min showed 100% anti-hyperalgesia. This anti-hyperalgesic effect remained during 180 min of observation. Analysis of global effects as area under the curve of time course showed that the nature of the anti-hyperalgesic interaction of the analyzed dose had an additive effect. There was no significant difference observed in the theoretical sum of anti-hyperalgesic effect produced by each drug alone (225.4+/-29.1 area units, au) compared with the corresponding effects produced by the combination of drugs (263.33+/-3.3 au)., Conclusions: These findings are useful in determining the type of interaction that these drugs produce using this combination ratio in neuropathic pain.