Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar, Pakistan.
Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan.
BMC Pharmacol Toxicol. 2019 Aug 28;20(1):51. doi: 10.1186/s40360-019-0329-3.
Chemotherapy induced peripheral neuropathy (CIPN) has been attributed to chemotherapeutic agents such as cisplatin which adversely affect disease outcome leading to increased cancer related morbidity. The clinical efficacy of systemic gabapentin in neuropathic pain management is limited by central side-effects in addition to a scarceness of conclusive evidence of its efficacy in CIPN management. The topical route therefore may provide a relatively safe alternative for neuropathic pain treatment in general and CIPN in particular.
Cisplatin induced neuropathic nociception was established in rats after a single weekly cisplatin injection (3.0 mg/kg, intraperitoneally) for 4 weeks. The evoked neuropathic sensation of allodynia was assessed by plantar application of von Frey monofilaments as the paw withdrawal threshold (PWT), whereas the expression of heat-hypoalgesia was determined on a hot-plate as paw withdrawal latency (PWL). Gabapentin gel (10% w/w) was applied three-times daily on the hind paws while in a concurrent systemic study, gabapentin was administered daily (75 mg/kg, intraperitoneally) for 4 weeks. To assess any evidence of neurological adverse symptoms of cisplatin and the central side-effect propensity of systemic or topical gabapentin, evaluation of motor coordination (rotarod test) and gait (footprint analysis) were performed.
Cisplatin invoked a progressive development of neuropathic hind paw allodynia (decreased PWT, days 7-28) and heat hypoalgesia (increased PWL, days 21-28). Topical gabapentin significantly delayed the expression of both allodynia on protocol days 21 and 28 and heat-hypoalgesia (day 28). Systemic gabapentin displayed a comparative anti-neuropathic predisposition through a sustained suppression of tactile allodynia on days 14 and 21-28 as well as thermal hypoalgesia (days 21 and 28). Systemic gabapentin also impaired motor coordination and gait thus affirming its clinically documented central side effects, but these outcomes were not evident after topical treatment.
Both topical and systemic gabapentin exhibit a propensity to attenuate CIPN in a cisplatin paradigm. Gabapentin applied topically may therefore provide an adjunctive or alternative route for CIPN management upon cessation of systemic medications due to intolerable side-effects.
化疗引起的周围神经病变（CIPN）归因于顺铂等化疗药物，这些药物会对疾病结局产生不利影响，导致癌症相关发病率增加。加巴喷丁的系统疗效在治疗神经病理性疼痛方面有限，这不仅是由于其中枢副作用，还因为其在 CIPN 管理方面的疗效缺乏确凿证据。因此，局部途径可能为一般神经病理性疼痛治疗，特别是 CIPN 提供相对安全的替代方案。
在每周一次（3.0mg/kg，腹腔内）连续 4 周注射顺铂后，建立大鼠顺铂诱导的神经病理性疼痛。通过足底应用冯弗雷单丝评估伤害性感觉的神经病理性感觉，即足底撤回阈值（PWT），而热痛觉减退则通过热板确定为足底撤回潜伏期（PWL）。加巴喷丁凝胶（10%w/w）每天应用于后爪 3 次，同时在平行的系统研究中，每天腹腔内给予加巴喷丁（75mg/kg），持续 4 周。为评估顺铂的任何神经毒性症状和系统或局部加巴喷丁的中枢副作用倾向，进行了运动协调（转棒试验）和步态（足迹分析）评估。
顺铂引起了神经病理性后爪感觉过敏（PWT 降低，第 7-28 天）和热痛觉减退（PWL 增加，第 21-28 天）的进展性发展。局部加巴喷丁显著延迟了第 21 天和第 28 天的所有感觉过敏和热痛觉减退的表达（第 28 天）。系统加巴喷丁通过持续抑制触觉感觉过敏（第 14 天和第 21-28 天）和热痛觉减退（第 21 天和第 28 天）显示出类似的抗神经病变倾向。系统加巴喷丁还损害了运动协调和步态，从而证实了其临床记录的中枢副作用，但在局部治疗后没有出现这些结果。
局部和系统加巴喷丁在顺铂范式中均表现出减轻 CIPN 的倾向。由于不耐受的副作用而停止全身药物治疗时，局部应用加巴喷丁可能为 CIPN 管理提供辅助或替代途径。
