Dean Jon G, Reyes Mikaila, Oliva Valeria, Khatib Lora, Riegner Gabriel, Gonzalez Nailea, Posey Grace, Collier Jason, Birenbaum Julia, Chakravarthy Krishnan, Wells Rebecca E, Goodin Burel, Fillingim Roger, Zeidan Fadel
Department of Anesthesiology, University of California San Diego, La Jolla, CA 92013, USA.
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC 27109, USA.
PNAS Nexus. 2024 Oct 14;3(10):pgae453. doi: 10.1093/pnasnexus/pgae453. eCollection 2024 Oct.
Converging lines of preclinical and clinical research indicate that females, in stark contrast to males, display an increased prevalence of chronic pain. Females also demonstrate weaker analgesic efficacy in response to opioid therapies when compared with males. These sex-specific differences may be driven by dimorphic endogenous opioidergic responses. In rodent models, analgesia exhibited in males but not females was reversed by inhibiting endogenous opioidergic reception. In humans, the sex-specific endogenous system(s) supporting the direct attenuation of evoked pain has not been identified. To determine whether opioidergic blockade reverses self-regulated analgesia in males as compared to females, the present study combined two operationally analogous clinical trials ( = 98; 51 females and 47 males). In a double-blinded, counterbalanced study involving healthy ( = 39) and chronic low back pain ( = 59) populations, a high-dose naloxone (μ-, κ-, δ-opioid antagonist) vs. placebo-saline cross-over design (15 mg/kg bolus +0.1 mg/kg/h) tested the hypothesis that endogenous opioids mediate analgesia in males but not females. An 11-point visual analog scale (VAS) (0 = no pain; 10 = worst pain imaginable) evaluated pain ratings in response to noxious heat stimulation (49 °C; calf). After baseline pain testing, participants were randomized to a validated four-session mindfulness meditation or sham mindfulness meditation training intervention. Participants practiced their respective meditation during noxious heat, intravenous high-dose naloxone, and placebo saline, respectively. In males and females, meditation significantly lowered evoked pain during saline infusion. Intravenous naloxone inhibited analgesia in males, but pain relief was well preserved in females. The present findings indicate that endogenous opioids mediate self-regulated analgesia in males but not females and underscore the need to establish sex-specific pain therapeutics.
临床前研究和临床研究的多条证据表明，与男性形成鲜明对比的是，女性慢性疼痛的患病率更高。与男性相比，女性对阿片类药物治疗的镇痛效果也较弱。这些性别特异性差异可能由双态内源性阿片肽反应驱动。在啮齿动物模型中，通过抑制内源性阿片肽受体可逆转雄性而非雌性表现出的镇痛作用。在人类中，尚未确定支持直接减轻诱发性疼痛的性别特异性内源性系统。为了确定与女性相比，阿片肽阻断是否会逆转男性的自我调节镇痛作用，本研究结合了两项操作类似的临床试验（n = 98；51名女性和47名男性）。在一项涉及健康人群（n = 39）和慢性下腰痛人群（n = 59）的双盲、平衡研究中，采用高剂量纳洛酮（μ、κ、δ阿片受体拮抗剂）与安慰剂生理盐水交叉设计（15mg/kg推注 + 0.1mg/kg/h），检验内源性阿片类药物介导男性而非女性镇痛作用的假设。使用一个11点视觉模拟量表（VAS）（0 = 无疼痛；10 = 可想象的最严重疼痛）评估对有害热刺激（49°C；小腿）的疼痛评分。在基线疼痛测试后，参与者被随机分配到经过验证的四节正念冥想或假正念冥想训练干预中。参与者分别在有害热刺激、静脉注射高剂量纳洛酮和安慰剂生理盐水期间进行各自的冥想。在男性和女性中，冥想均显著降低了生理盐水输注期间的诱发性疼痛。静脉注射纳洛酮抑制了男性的镇痛作用，但女性的疼痛缓解效果良好。本研究结果表明，内源性阿片类药物介导男性而非女性的自我调节镇痛作用，并强调了建立性别特异性疼痛治疗方法的必要性。
