AbstractA high proportion of patients suffering from neuropathic pain do not receive satisfactory pain relief from their current treatment, due to incomplete efficacy and dose-limiting adverse effects. Hence, one strategy to improve treatment outcome is the use of a combination of analgesic drugs. The potential benefits of such approach include improved and prolonged duration of analgesic effect and fewer or milder adverse effects with lower doses of each drug. Gabapentin is recommended as a first-line drug in the treatment of neuropathic pain, and has recently been demonstrated to act on supraspinal structures to stimulate the descending noradrenergic pain inhibitory system. Hypothetically, the analgesic effect of gabapentin may be potentiated if combined with a drug that prolongs the action of noradrenaline.In this study, gabapentin was co-administered with the serotonin and noradrenaline reuptake inhibitor venlafaxine, and subsequently evaluated for its effect on mechanical hypersensitivity in the rat spared nerve injury model of neuropathic pain. In this model, two branches of the sciatic nerve (the tibial and common peroneal nerves) are ligated and cut, leaving the third branch (the sural nerve) intact to innervate the hind paw of the animal. Treatment-induced ataxia was tested in order to exclude biased effect measurements. Finally, the pharmacokinetics of gabapentin was investigated alone and in combination with venlafaxine to elucidate any alterations which may have consequences for the pharmacological effect and safety.The overall effect on nerve injury-induced hypersensitivity of co-administered gabapentin (60 mg/kg s.c.) and venlafaxine (60 mg/kg s.c.), measured as the area under the effect-time curve during the three hour time course of testing, was similar to the highest dose of gabapentin (200 mg/kg s.c.) tested in the study. However, this dose of gabapentin was associated with ataxia and severe somnolence, while the combination was not. Furthermore, when administered alone, an effect delay of approximately one hour was observed for gabapentin (60 mg/kg s.c.) with maximum effect occurring 1.5 to 2.5 h after dosing, while venlafaxine (60 mg/kg s.c.) was characterised by a rapid onset of action (within 30 min) which declined to baseline levels before the end of the three hour time of testing. The effect of co-administered drugs (both 60 mg/kg s.c.), in the doses used here, can be interpreted as additive with prolonged duration in comparison to each drug administered alone. An isobolographic study design, enable to accurately classify the combination effect into additive, antagonistic or synergistic, was not applied. The pharmacokinetics of gabapentin was not altered by co-administered venlafaxine, implying that a pharmacokinetic interaction does not occur. The effect of gabapentin on the pharmacokinetics of venlafaxine was not studied, since any alterations are unlikely to occur on the basis of the pharmacokinetic properties of gabapentin.In conclusion, the results from this preclinical study support the rationale for improved effect and less adverse effects through combination therapy with gabapentin and venlafaxine in the management of neuropathic pain.
Stimulating muscarinic M1 receptors in the anterior cingulate cortex reduces mechanical hypersensitivity via GABAergic transmission in nerve injury rats
