Abstract
Neuropathic pain is a chronic debilitating condition caused by injury or disease of the nerves of the somatosensory system. Although several therapeutic approaches are recommended, none has emerged as an optimal treatment leaving a need for developing more effective therapies. Given the small number of approved drugs and their limited clinical efficacy, combining drugs with different mechanisms of action is frequently used to yield greater efficacy. We demonstrate that the combination of trazodone, a multifunctional drug for the treatment of major depressive disorders, and gabapentin, a GABA analogue approved for neuropathic pain relief, results in a synergistic antinociceptive effect in the mice writhing test. To explore the potential relevance of this finding in chronic neuropathic pain, pharmacodynamic interactions between low doses of trazodone (0.3 mg/kg) and gabapentin (3 mg/kg) were evaluated in the chronic constriction injury (CCI) rat model, measuring the effects of the two drugs both on evoked and spontaneous nociception and on general well being components. Two innate behaviors, burrowing and nest building, were used to assess these aspects. Besides exerting a significant antinociceptive effect on hyperalgesia and on spontaneous pain, combined inactive doses of trazodone and gabapentin restored in CCI rats innate behaviors that are strongly reduced or even abolished during persistent nociception, suggesting that the combination may have an impact also on pain components different from somatosensory perception. Our results support the development of a trazodone and gabapentin low doses combination product for optimal multimodal analgesia treatment.
Highlights
Neuropathic pain is a chronic and debilitating condition caused by injury or disease of the nerves of the somatosensory system [1]
To explore the potential clinical relevance of these findings in chronic neuropathic pain conditions, we examined the effects of the trazodone and gabapentin combination in the constriction injury (CCI) rat model
The results of our study show that the combination of ineffective doses of trazodone and gabapentin can reverse the weight-bearing deficit observed in CCI rats, confirming on spontaneous pain symptoms, the effects assessed on evoked pain behaviors
Summary
Neuropathic pain is a chronic and debilitating condition caused by injury or disease of the nerves of the somatosensory system [1]. Because of the heterogeneity of its aetiologies, symptoms and underlying mechanisms [2], current pharmacological treatments encompass different drug classes. Given the small number of approved drugs and their limited clinical efficacy, at least 45% of patients with neuropathic pain concurrently receive two or more drugs to treat their condition [3]. Trazodone and gabapentin combination in rodent models of neuropathic pain articulated in the “author contributions” section. The funder had a role in the study design, data collection and analysis, decision to publish and preparation of the manuscript through the provision of expert decision-making input from the preclinical and management teams
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