Design: This study 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.
Case selection: 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.
Data analysis: 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.
Results: 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.
Conclusions: Based on this randomised clinical trial, pure CBD drug Epidiolex demonstrates effective analgesia against acute toothache.
© 2024. The Author(s), under exclusive licence to British Dental Association.