Bortezomib-induced neuropathic pain: evaluation of antinociceptive effect of a new analgesic compound

Bortezomib (Btz) is a highly effective and widely used antineoplastic drug for the treatment of many tumors, primarily multiple myeloma. Despite its effectiveness, the use of this proteasome inhibitor is limited by its toxicity. Among Btz side effects, peripheral neurotoxicity is a major and clinically relevant problem. In fact, since the earliest Phase I and Phase II studies, sensory peripheral neuropathy emerged as a dose-limiting side effect. Moreover, a significant proportion of Btz-treated patients developed severe neuropathic pain. The treatment of Btz-induced neuropathic pain is extremely difficult with the currently available drugs and still remains a major challenge for oncologists and neurologists. Aim of this study was to demonstrate if the new analgesic compound CR4056 could reverse the neuropathic pain induced by a chronic treatment with Btz in the rat. The anti-nociceptive and dose-dependent effect of CR4056 was assessed in a well-established experimental rat model in which Btz was administered to Wistar rats (0.20 mg/kg three times/week for 8 weeks) followed by treatment with CR4056 (6, 20 or 60 mg/kg daily p.o.) or buprenorphine administered 28,8 µg/kg/day p.o. for 2 weeks. Body weight change, hematological and histopathological parameters, nerve conduction velocity (NCV) and sensory behavioral tests were evaluated during the experiment. No remarkable effect of Btz administration or of any dose of CR4056 was observed in the hematological parameters and blood chemistry. After 8 weeks of treatment, Btz induced a severe reduction in NCV; this impairment was not reversed by CR4056 or by buprenorphine. The behavioral assessment showed a significant mechanical allodynia in rats treated with Btz for 8 weeks (delta vs. controls -6 g). Buprenorphine significantly reduced Btz-induced allodynia during the fist day by about 63%. However, this effect was lost during the following days of treatment (i.e 20% reduction on the 3rd day).The mid and high dose of CR4056 (20 and 60 mg/kg) showed a significant (i.e > 80 %) reduction of allodynia till the 3rd day of administration, afterwards a slight reduction in efficacy was recorded. On the contrary, the oral daily administration of 6 mg/kg CR4056 persistently counteracted Btz-induced allodynia, showing an even complete reversion after 2 weeks of treatment. The present study gives evidence for a relevant and persistent anti-allodynic effect of CR4056, suggesting a role for CR4056 in the management of neuropathic pain in patients treated with Btz.