From the Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Global Neuromodulation Research, Medtronic, Inc, Minneapolis, Minnesota.
Anesth Analg. 2020 Apr;130(4):1077-1084. doi: 10.1213/ANE.0000000000004396.
Neuromodulation, as a therapeutic modality for pain treatment, is an alternative to opioid therapies and therefore receiving increased interest and use. Neuromodulation at a peripheral nerve target, in the form of bilateral electrical pudendal nerve stimulation (bPNS), has been shown to reduce bladder hypersensitivity in rats and anecdotally reduces pain in humans with pelvic pain of urological origin. Recent studies have identified a role for spinal γ-aminobutyric acid (GABA) receptors in this effect. Concomitant medication use, such as benzodiazepines, could alter responses to neuromodulation, and so before the development of a clinical trial to confirm translation of this potential therapy, the potential interactions between acute and chronic use of benzodiazepines and bPNS were examined in a preclinical model.
Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Diazepam (1-5 mg/kg intraperitoneal [i.p.]) or vehicle was administered acutely (with or without bPNS) and chronically (5 mg/kg subcutaneous [s.c.] daily for 2 weeks before the final experiment). bPNS was delivered as bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMRs; abdominal muscle contractile responses to urinary bladder distension [UBD]) were used as nociceptive end points. Due to the profound effects of diazepam, the effect of midazolam (0.5-1.0 mg/kg i.p.) on VMRs and bPNS effects was also studied.
Diazepam and midazolam both produced a dose-dependent, flumazenil-reversible inhibition of VMRs to UBD. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that had received vehicle injections. Select doses of diazepam and midazolam suppressed the inhibitory effect of bPNS on VMRs.
This study suggests that inhibitory effects of bPNS on bladder pain could be suppressed in subjects receiving benzodiazepine therapy, suggesting that potential clinical testing of pudendal nerve stimulation for the treatment of painful bladder syndromes may be confounded by the use of benzodiazepines. Clinical assessment of other forms of neuromodulation should also be screened for impacts of benzodiazepines.
神经调节作为一种治疗疼痛的方法，是阿片类药物治疗的替代方法，因此越来越受到关注和应用。以双侧阴部神经电刺激（bPNS）形式作用于周围神经靶点的神经调节已被证明可降低大鼠的膀胱过敏反应，并在患有泌尿系统来源的骨盆疼痛的患者中减轻疼痛。最近的研究表明，脊髓 γ-氨基丁酸（GABA）受体在这种作用中起作用。伴随药物的使用，如苯二氮䓬类药物，可能会改变对神经调节的反应，因此，在开发临床试验以确认这种潜在治疗方法的转化之前，在临床前模型中研究了急性和慢性使用苯二氮䓬类药物和 bPNS 之间的潜在相互作用。
通过新生大鼠膀胱炎症和成年时的第二次炎症刺激来产生膀胱过敏反应。地西泮（1-5mg/kg 腹腔内[ip.]) 或载体被急性给药（有无 bPNS）和慢性给药（5mg/kg 皮下[sc.] 每天一次，共 2 周，然后进行最后一次实验）。bPNS 通过双侧阴部混合运动/感觉神经的双相电刺激来传递。内脏运动反应（VMR；膀胱扩张[UBD]引起的腹部肌肉收缩反应）用作伤害性终点。由于地西泮的影响深远，还研究了咪达唑仑（0.5-1.0mg/kg ip.）对 VMR 和 bPNS 效果的影响。
地西泮和咪达唑仑均对 UBD 的 VMR 产生剂量依赖性、氟马西尼可逆转的抑制作用。bPNS 导致接受载体注射的过敏反应大鼠的 UBD VMR 统计学显著抑制。选择剂量的地西泮和咪达唑仑抑制了 bPNS 对 VMR 的抑制作用。
本研究表明，接受苯二氮䓬类药物治疗的患者，bPNS 对膀胱疼痛的抑制作用可能受到抑制，这表明阴部神经刺激治疗疼痛性膀胱综合征的潜在临床测试可能会因苯二氮䓬类药物的使用而受到影响。还应筛选其他形式的神经调节的临床评估，以确定苯二氮䓬类药物的影响。
