Murphy Siofra, Hayes Ellis
Department of Oral and Maxillofacial Surgery, University Hospital Crosshouse, Kilmarnock Rd, Crosshouse, Kilmarnock, KA2 0BE, Scotland.
Evid Based Dent. 2024 Jun;25(2):100-101. doi: 10.1038/s41432-024-01007-5. Epub 2024 Apr 22.
The study by Chrepa et al. is a randomised, placebo-controlled, triple-arm, phase IIA clinical trial with double masking which investigates the effectiveness and safety of Cannabidiol (CBD) as an analgesic for acute dental pain. The intervention drug, Epidiolex is an FDA-approved CBD oral solution (100 mg/ml) derived from the cannabis plant. The psychoactive ingredient tetrahydrocannabinol (THC) is not included. The maximum recommended daily dose of Epidiolex is 20 mg/kg. 64 patients with moderate-severe odontogenic pain participated in the study and REDCap software was utilised to randomly assign participants into groups: CBD10 (10 mg/kg), CBD20 (20 mg/kg) and placebo. A single dose of the respective oral solution was administered, and participants monitored for 3 h. Patients remained blinded to group assignment, as did the outcome assessor. The provider was not blinded. The primary outcome measure was VAS (visual analogue scale) pain difference, compared to baseline and recorded at 7 subsequent marked times following administration (15, 30, 45, 60, 90, 120, 180 min). Additional outcome measures were also recorded: changes in bite force, pain intensity differences, the onset of significant pain relief, the maximum pain relief, psychoactive effects, mood changes and adverse events.
40 female and 21 male patients with moderate-severe odontogenic pain (defined as ≥30 on a 100 mm VAS) with a diagnosis of irreversible pulpitis or pulp necrosis and symptomatic apical periodontitis were included. Participation required a negative test for recent drug and alcohol use, a negative pregnancy test and no use of analgesics within 6 h of the trial. Pregnancy, breastfeeding, hepatic impairment, recreational cannabis users and patients taking CBD metabolising drugs were excluded along with those with an ASA classification above III. Patient characteristics recorded included: age, gender, race, tooth type affected, weight and BMI.
Mixed model analysis was used to compare numerical variables among the cohorts at the marked time intervals. VAS, bite force, Bowdle and Bond/Lader questionnaires were recorded. Inter-group analysis was completed using parametric and non-parametric post-hoc tests, including Holm-Bonferroni adjustment and the Shapiro-Wilk test, to evaluate data normality. NNTs were calculated for both CBD doses- the number of patients needing treatment before one patient experiences a minimum of 50% pain relief. X² tests were used to analyse categorical variables: pain intensity and adverse events. JMP software was used for the statistical analysis.
64 participants had originally enroled in the study, but three were excluded from data analysis due to 'unrealistic results', reporting complete pain relief within the first 15 min. 20 participants were given CBD10, 20 were given CBD20 and 21 placebo. 68% of the participants were Hispanic/Latino whilst 11% were white. The average age was 44 +/- 13.7. There was equal distribution of age, sex, race, tooth type, weight and body mass index (p > 0.05). No subject required rescue pain relief during the 3-h observation period. Compared to baseline VAS, significant pain relief was seen 30 min after drug administration for CBD10, versus after 15 min for CBD20 (p < 0.05). Pain reduction reached 50% at 60 min for CBD10 and at 120 min for CBD20. Both reported maximum pain reduction of 73% of baseline at 180 min. 33% pain reduction from baseline was seen in the placebo group, with a median VAS pain of 67% at 180 min. 45.4% of CBD10 and 46.6% of CBD20 required pain relief after 1-6 h, versus 37.5% of placebo (p > 0.05). Bite force increase was seen in both CBD10 and CBD20 groups at 90 and 180 min, versus no significant differences between time points in the placebo group. On assessing pain intensity, pain reduction was significantly associated with increasing time in the CBD groups (p < 0.001), versus no significant association with the placebo group (p = 0.0521). No statistically significant differences were seen between and within the groups for Bowdle or Bond/Lader questions (p > 0.05). In the 3 h observation period, CBD10 experienced 14 times more sedation symptoms versus placebo (p < 0.05), whilst CBD20 experienced this 8 times more (p < 0.05). Within the 3 h, CBD20 were 10-fold more likely to have diarrhoea and abdominal pain (p < 0.05), with some experiencing pain beyond the 3 h but resolving within the day.
Based on this randomised clinical trial, pure CBD drug Epidiolex demonstrates effective analgesia against acute toothache.
Chrepa等人的这项研究是一项随机、安慰剂对照、三臂、IIA期双盲临床试验，旨在研究大麻二酚（CBD）作为急性牙痛镇痛药的有效性和安全性。干预药物Epidiolex是一种经美国食品药品监督管理局（FDA）批准的源自大麻植物的CBD口服溶液（100毫克/毫升）。不包含精神活性成分四氢大麻酚（THC）。Epidiolex的最大推荐日剂量为20毫克/千克。64名中重度牙源性疼痛患者参与了该研究，并使用REDCap软件将参与者随机分为几组：CBD10（10毫克/千克）、CBD20（20毫克/千克）和安慰剂组。给予各口服溶液单剂量，并对参与者进行3小时监测。患者对分组情况不知情，结果评估者也不知情。提供治疗者不设盲。主要结局指标是视觉模拟量表（VAS）疼痛差值，与基线相比，并在给药后的7个后续标记时间点（15、30、45、60、90、120、180分钟）记录。还记录了其他结局指标：咬合力变化、疼痛强度差值、显著疼痛缓解的开始时间、最大疼痛缓解程度、精神活性效应、情绪变化和不良事件。
纳入40名女性和21名男性中重度牙源性疼痛患者（定义为在100毫米VAS上≥30），诊断为不可逆性牙髓炎或牙髓坏死以及有症状的根尖周炎。参与研究要求近期药物和酒精使用检测呈阴性、妊娠试验呈阴性且在试验前6小时内未使用镇痛药。排除妊娠、哺乳期、肝功能损害、娱乐性大麻使用者以及服用CBD代谢药物的患者，以及ASA分级高于III级的患者。记录的患者特征包括：年龄、性别、种族、受影响牙齿类型、体重和体重指数。
采用混合模型分析在标记时间间隔内比较各队列中的数值变量。记录VAS、咬合力、Bowdle和Bond/Lader问卷。使用参数和非参数事后检验（包括Holm - Bonferroni校正和Shapiro - Wilk检验）完成组间分析，以评估数据正态性。计算两种CBD剂量的需治数（NNT）——在一名患者至少经历50%疼痛缓解之前需要治疗的患者数量。使用卡方检验分析分类变量：疼痛强度和不良事件。使用JMP软件进行统计分析。
最初有64名参与者登记参加该研究，但由于“结果不切实际”（报告在最初15分钟内疼痛完全缓解），3名被排除在数据分析之外。20名参与者给予CBD10，20名给予CBD20，21名给予安慰剂。68%的参与者为西班牙裔/拉丁裔，11%为白人。平均年龄为44±13.7岁。年龄、性别、种族、牙齿类型、体重和体重指数分布均衡（p>0.05）。在3小时观察期内，没有受试者需要急救止痛。与基线VAS相比，CBD10给药后30分钟出现显著疼痛缓解，而CBD20在15分钟后出现（p<0.05）。CBD10在60分钟时疼痛减轻达到50%，CBD20在120分钟时达到。两者均报告在180分钟时最大疼痛减轻为基线的73%。安慰剂组从基线减轻33%的疼痛，在180分钟时VAS疼痛中位数为67%。CBD10组45.4%和CBD20组46.6%在1 - 6小时后需要止痛，而安慰剂组为37.5%（p>0.05）。CBD10组和CBD20组在90分钟和180分钟时咬合力增加，而安慰剂组各时间点之间无显著差异。在评估疼痛强度时，CBD组疼痛减轻与时间增加显著相关（p<0.001），而安慰剂组无显著相关性（p = 0.0521）。对于Bowdle或Bond/Lader问题，组间和组内均未观察到统计学显著差异（p>0.05）。在3小时观察期内，CBD10出现镇静症状的次数是安慰剂组的14倍（p<0.05），而CBD20出现的次数是8倍（p<0.05）。在3小时内，CBD20出现腹泻和腹痛的可能性是安慰剂组的10倍（p<0.05），一些患者疼痛持续超过3小时但在当天内缓解。
基于这项随机临床试验，纯CBD药物Epidiolex对急性牙痛显示出有效的镇痛作用。
