A systematic review of the efficacy of ketamine for craniofacial pain

Craniofacial pain (CFP) poses a burden on patients and health care systems. It is hypothesized that ketamine, an <i>N</i>-methyl-d-aspartate (NMDA) receptor antagonist, can reverse central sensitization associated with causation and propagation of CFP. This systematic review aims to assess the role of ketamine for CFP. Databases were searched for studies published up to September 26, 2022, investigating the efficacy of ketamine for adults with CFP. Primary outcome was the change in pain intensity at 60 min postintervention. Two reviewers screened and extracted data. Registration with PROSPERO was performed (CRD42020178649). Twenty papers (six randomized controlled trials [RCTs], 14 observational studies) including 670 patients were identified. Substantial heterogeneity in terms of study design, population, dose, route of administration, treatment duration, and follow-up was noted. Bolus dose ranged from 0.2–0.3 mg/kg (intravenous) to 0.4 mg/kg (intramuscular) to 0.25–0.75 mg/kg (intranasal). Ketamine infusions (0.1–1 mg/kg/h) were given over various durations. Follow-up was short in RCTs (from 60 min to 72 h) but longer in observational studies (up to 18 months). Ketamine by bolus treatment failed to reduce migraine intensity but had an effect by reducing intensity of aura, cluster headache (CH), and trigeminal neuralgia. Prolonged ketamine infusions showed sustainable reduction of migraine intensity and frequency of CH attacks, but the quality of the evidence is low. Current evidence remains conflicting on the efficacy of ketamine for CFP owing to low quality and heterogeneity across studies. Ketamine infusions are suggested to provide sustained improvement, possibly because of prolonged duration and higher dosage of administration. RCTs should focus on the dose–response relationship of prolonged ketamine infusions on CFP.

颅面痛（Craniofacial Pain, CFP）会给患者与医疗保健系统带来沉重负担。有假说认为，作为N-甲基-D-天冬氨酸（N-methyl-d-aspartate, NMDA）受体拮抗剂的氯胺酮，能够逆转与颅面痛发生及传播相关的中枢敏化现象。本系统综述旨在评估氯胺酮在颅面痛治疗中的作用。本研究检索了截至2022年9月26日发表的、探讨氯胺酮对成人颅面痛疗效的相关研究，主要结局指标为干预后60分钟时的疼痛强度变化。由两名研究者独立进行文献筛选与数据提取，本研究已在PROSPERO平台注册（注册号：CRD42020178649）。最终纳入20篇文献，含670例患者，其中随机对照试验（Randomized Controlled Trial, RCTs）6篇、观察性研究14篇。研究在设计类型、研究人群、给药剂量、给药途径、治疗时长及随访周期方面均存在显著异质性。单次推注剂量范围为：静脉给药0.2~0.3 mg/kg、肌内给药0.4 mg/kg、鼻内给药0.25~0.75 mg/kg；氯胺酮静脉输注剂量为0.1~1 mg/kg/h，给药时长各不相同。随机对照试验的随访周期较短（60分钟至72小时），而观察性研究的随访周期更长，最长可达18个月。单次推注氯胺酮未能降低偏头痛的疼痛强度，但可缓解先兆症状、丛集性头痛（Cluster Headache, CH）及三叉神经痛的疼痛程度。长时间氯胺酮输注可使偏头痛疼痛强度及丛集性头痛发作频率持续降低，但相关证据质量较低。由于现有研究证据质量较低且异质性显著，目前关于氯胺酮治疗颅面痛的疗效仍存在争议。有研究提示氯胺酮输注可带来持续的症状改善，这可能与给药时长更长、给药剂量更高有关。未来的随机对照试验应聚焦于长时间氯胺酮输注治疗颅面痛的量效关系。