Comparative analgesic efficacy of pregabalin administered according to either a prevention protocol or an intervention protocol in rats with cisplatin‐induced peripheral neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of peripheral neuropathic pain that may be dose-limiting in patients administered potentially curative cancer chemotherapy dosing regimens. In cancer survivors, persistent CIPN adversely affects patient quality of life and so adjuvant drugs (anticonvulsants eg pregabalin or antidepressants eg amitriptyline) are recommended for the relief of CIPN. However, most studies in rodent models of CIPN involve administration of single bolus doses of adjuvant drugs to assess pain-relieving efficacy. Hence this study was designed to assess the efficacy of pregabalin administered to CIPN-rats according to either a prevention or an intervention protocol. Groups of male Sprague-Dawley rats received four single intraperitoneal bolus doses of cisplatin at 3 mg/kg at once-weekly intervals to induce CIPN. For the prevention protocol, oral pregabalin (or vehicle) was administered to CIPN-rats once-daily for 21 consecutive days from day 0 to day 20 inclusive. For the intervention protocol, oral pregabalin was administered once-daily for 21 consecutive days from day 28 to day 48, inclusive. Mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws were assessed just prior to each dose of cisplatin and at least once weekly until study completion (day 27, prevention protocol; or day 48, intervention protocol). Mechanical allodynia and mechanical hyperalgesia were also determined at the time of peak effect at about 2 hours post pregabalin/vehicle administration, once weekly until study completion. For the prevention protocol in CIPN-rats, pregabalin alleviated mechanical hyperalgesia but not mechanical allodynia. For the intervention protocol, pregabalin alleviated both mechanical allodynia and mechanical hyperalgesia in the hindpaws.

Pregabalin protected cisplatin-induced oxidative neurotoxicity in neuronal cell line

“…Similarly, it was reported that the CSP-induced excessive mitochondria activation and ROS production was inhibited in the peripheral neurons by the antioxidant properties of PGAB, suggesting inhibition of excessive Ca 2+ entry through membrane channel (TRPV1) (Sasaki et al 2014;Marwaha et al 2016). Decrease of CSP-induced neuropathy and neurotoxicity in the DRG neurons of rats was recently reported (Seto et al, 2017;Han et al 2018) and the reports confirmed results of current study.…”

Searching for analgesic drug candidates alleviating oxaliplatin‐induced cold hypersensitivity in mice

“…The results of the present experiment confirmed that in mice, similarly to humans, oxaliplatin induced cold allodynia-a core symptom of neuropathic pain caused by this cytotoxic drug. After a single dose of oxaliplatin, cold allodynia was persistent and it was maintained for at least 7 days, which is consistent with the previous reports (Furgała, Fijałkowski, Nowaczyk, Sałat, & Sałat, 2018;Han, Kuo, Nicholson, Corradinni, & Smith, 2018;Kono et al, 2013;Nakagawa & Kaneko, 2017;Sałat, Furgała, & Sałat, 2019;Sałat et al, 2017).…”

Somatosensory predictors of response to pregabalin in painful chemotherapy-induced peripheral neuropathy: a randomized, placebo-controlled, crossover study

“…For example, rodent CIPN models consistently show mechanical hypersensitivity of the paw. 10,15,19 By contrast, only 5 of the 24 participants we tested (21%) reported static mechanical allodynia. This decreased mechanosensitivity is concordant with prior research in humans with CIPN.…”