Cannabidiol - an effective analgesic for toothache?

DESIGN: 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. 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.

What e-cigarette factors determine oral epithelial DNA damage in consumers?

DESIGN: Study participants were divided equally into three groups being exclusive vapers (never smokers), current exclusive smokers and non-users. Brush biopsy samples of oral epithelial cells were collected. DNA damage quantification was assessed using LA-QPCR, and analysis interrogated a 12.2 kb region of the DNA polymerase beta gene (POLB). An additional gene, hypoxanthine phosphoribosyltransferase 1 (HPRT), was also interrogated for validity. Enzyme-linked immunosorbent assay (ELISA) was used to measure plasma cotinine levels. Breath monitoring was measured using Bedfont Micro Smokerlyzer in order to quantify exhaled CO and %COHb levels in participants. CASE SELECTION: 72 subjects, consisting of both males and females of diverse ages, races and ethnicities, were recruited. Comprehensive interviews alongside biochemical studies were used to verify smoking and vaping status. Participants classified as vapers reported a minimum use of e-cigarettes three times weekly for 6 months, with no use of cigarettes or tobacco products in their lifetime. Smokers reported cigarette consumption for a minimum of three times weekly for at least 12 months, less than five vaping sessions ever and no use of other tobacco products in the previous 6 months. Participants reporting no or less than five uses of e-cigarettes or tobacco products were classified as non-users. Former smokers, vapers and those who were dual or poly users of e-cigarettes, cigarettes or tobacco products were excluded. DATA ANALYSIS: R environment for statistical computing (RStudio), was used for data analysis. The Shapiro-Wilk test was used to evaluate the distribution of data. Student's t test allowed comparison of all variables between two groups (vapers and nonusers, smokers and nonusers, or vapers and smokers), specifically DNA damage levels. A one-way Analysis of Variance (ANOVA) followed by a post hoc Tukey HSD test allowed comparison of damage in three or more groups (heavy vapers, light vapers, and nonusers, as well as heavy smokers, light smokers, and nonusers). DNA damage was also analysed in this manner when assessing e-cigarette device type, liquid type or in non-users. Pearson correlation coefficient analysis allowed examination of relationships between different variables. RESULTS: Mean levels of DNA damage in the POLB gene was 2.6-fold higher in vapers (p = 0.005) and 2.2-fold higher in smokers (p = 0.020), when compared to non-users. On comparing POLB gene DNA damage in vapers versus smokers, the results were not statistically significant (p = 0.522). Comparing DNA damage in the HPRT gene, levels were much higher in vapers (p = 0.029) and smokers (p = 0.033) versus non-users. Similarly to the POLB gene, DNA damage levels in the HPRT gene in vapers versus smokers were not statistically significant (p = 0.578). When assessing volume of e-cigarette liquid or smoking pack years, levels of DNA damage in increased in the POLB gene in a dose-dependent manner between 'light' and 'heavy' users versus non-users (F = 4.571, p = 0.0156 | Tukey's HSD p = 0.0195 in vapers, F = 4.368, p = 0.0185 | Tukey's HSD p = 0.0135 in smokers). Vaping device type was investigated showing mean level of DNA damage in the oral cells of pod device users was 3.3-fold higher compared to non-users (F = 3.886, p = 0.0152 | Tukey's HSD p = 0.0216). This was followed by a 2.6-fold increase in oral cell DNA damage in Mod device users, and a 1.6-fold increase in multiple device users. Levels of DNA damage was higher in those who consume sweet-flavoured e-liquid (F = 3.238, p = 0.0146 | Tukey's HSD p < 0.05), followed by vapers of multiple flavours, mint or menthol and tobacco, and fruit flavours. No correlation was found between DNA damage of oral cells and cumulative nicotine consumption in vapers (r = 0.3189, p = 0.1288). Plasma cotinine levels, a validated maker of tobacco in cigarettes and e-cigarettes, were not significantly different between vapers and smokers (p = 0.607), but were significantly higher compared to non-users (p < 0.0001). Whist compared to non-users, vapers had similar levels of CO and %COHb, smokers showed significantly increased levels (p = 0.0005 and p = 0.0002, respectively). CONCLUSIONS: Based on the results of this study, there is evidence to support a dose-dependent formation of DNA damage in oral cells in those vapers who have never smoked cigarettes, and in those exclusive cigarette smokers. Additionally, e-cigarette device type and flavour, may also determine levels of DNA damage.

Is there an association between periodontitis and breast cancer?

DESIGN: This study uses bidirectional, two-sample Mendelian randomization (MR) analysis through genome-wide association studies (GWAS) statistics to assess the causal association between periodontitis and breast cancer. Periodontitis data from the FinnGen project and breast cancer data from OpenGWAS was used, with all data subjects being of European ancestry. Periodontitis cases were categorized by probing depths or self-reporting according to the Centers for Disease Control and Prevention (CDC)/American Academy of Periodontology definition. CASE SELECTION: 3046 periodontitis cases and 195,395 control cases along with 76,192 cases of breast cancer and 63,082 control cases were obtained from GWAS data. DATA ANALYSIS: R (version 4.2.1) through TwoSampleMR and MRPRESSO were used for data analysis. Primary analysis was conducted using the inverse-variance weighted method. Horizontal pleiotrophy was corrected and causal effects were examined through detection methods of the weighted median method, weighted mode method, simple mode, MR-Egger regression method, and MR-pleiosis residual and outlier method (MR-PRESSO). A heterogeneity test was adopted for the inverse-variance weighted (IVW) analysis method and MR-Egger regression (P > 0.05). Pleiotropy was evaluated using the MR-Egger intercept value. The P-value of the pleiotropy test was then used to analyze the existence of pleiotropy. Where P > 0.05, the possibility of pleiotropy in the causal analysis was considered to be less or non-existent. Leave-one-out analysis was used to tested the consistency of results. RESULTS: 171 single nucleotide polymorphisms were extracted for MR analysis where breast cancer was the exposure and periodontitis the outcome. The total sample size of periodontitis was 198,441, and 139,274 for breast cancer. Overall results showed breast cancer had no effect on periodontitis (IVW P = 0.1408, MR-egger P = 0.1785, weighted median P = 0.1885), with Cochran's Q analysis showing no heterogenicity amongst these instrumental variables (P > 0.05). 7 single nucleotide polymorphisms were extracted for MR analysis where periodontitis was the exposure and breast cancer the outcome. No significant correlation was found between periodontitis and breast cancer (IVW P = 0.8251, MR-egger P = 0.6072, weighted median P = 0.6848). CONCLUSIONS: Based on the use of different MR analysis methods, there is no evidence to support a causal relationship between periodontitis and breast cancer.

Does the use of cooled saline irrigation during third molar surgery affect post-operative morbidity?

Design This study is a double-blind, single-centre, split-mouth, prospective randomised control trial. In total, 48 patients had bilateral third molars removed during two separate operations at least 21 days apart by the same maxillofacial surgeon. During the control operation, the tooth was irrigated with saline at 25°C. During the test operation, patients were randomised to tooth irrigation with saline at either 10°C (n = 24) or 4°C (n = 24). Local anaesthetic, flap design, burr design and sutures remained consistent throughout. Patients were prescribed amoxicillin, chlorhexidine and were advised to take paracetamol as needed. The patients remained blinded to which test group they were randomised to and to the order of the control or test operations performed. Participants self-recorded analgesia use and post-operative pain daily for seven days using a visual analogue scale (VAS). A second maxillofacial surgeon examined patients on days one, three and seven. Facial swelling was assessed by measuring the distance between various soft tissue points compared to pre-operative levels. Trismus was determined by measuring maximum inter-incisal opening compared to pre-operative levels.Case selection In total, 28 female and 20 male medically fit adult patients with a mean age of 24.6 ± 3.8 with bilateral mandibular asymptomatic third molar teeth were selected. Second molars with periodontal probing depths >4 mm or impacted third molars associated with cysts or tumours were excluded. Patients had no antibiotic prescription in the preceding month nor analgesic consumption in the 12 hours before surgery.Data analysis The Shapiro-Wilk test was used to evaluate if the sample fit a normal distribution. Relationships between the categorical variables of the groups was tested using chi-square statistics. Data comparisons were examined with the Duncan, Kriskal-Wallis, Dunn and Friedman test (p <0.05).Results The median duration of the control and test group operations were similar (p = 0.051). Test group patients reported lower pain VAS values and consumed less analgesics compared to the control groups (p = 0.001), with the lowest values seen in the 4°C group (p <0.001). A greater decrease in trismus levels was also seen on day three and seven in the test groups (p <0.001) compared to the control group (p = 0.07). Swelling was greatest in the control group (p <0.001) and reduced on day seven (p <0.001) in all groups. While trismus and swelling values were lower in the 10°C test group compared to the control (p <0.001), the lowest values of these parameters at all time points was in the 4°C group (p <0.001).Conclusions Early complications following third molar removal include facial swelling, trismus and pain. In this study, intraoperative cooled saline irrigation to 4°C and 10°C was more effective than saline irrigation at 25°C in reducing the intensity of these conditions.

Surveying the Cost-Effectiveness of the 20 Procedures with the Largest Public Health Services Waiting Lists in Ireland: Implications for Ireland's Cost-Effectiveness Threshold.

OBJECTIVES: To survey the cost effectiveness of procedures with the largest waiting lists in the Irish public health system to inform a reconsideration of Ireland's current cost-effectiveness threshold of €45,000/quality-adjusted life-year (QALY). METHODS: Waiting list data for inpatient and day case procedures in the Irish public health system were obtained from the National Treatment Purchase Fund. The 20 interventions with the largest number of individuals waiting for inpatient and day case care were identified. The academic literature was searched to obtain cost-effectiveness estimates from Ireland and other high-income countries. Cost-effectiveness estimates from foreign studies were adjusted for differences in currency, purchasing power parity, and inflation. RESULTS: Of the top 20 waiting list procedures, 17 had incremental cost-effectiveness ratios (ICERs) lower than €45,000/QALY, 14 fell below €20,000/QALY, and 10 fell below €10,000/QALY. Only one procedure had an ICER higher than the current threshold. Two procedures had ICERs reported for different patient and indication groups that lay on either side of the threshold. CONCLUSIONS: Some cost-effective interventions that have large waiting lists may indicate resource misallocation and the threshold may be too high. An evidence-informed revision of the threshold may require a reduction to ensure it is consistent with its theoretical basis in the opportunity cost of other interventions foregone. A limitation of this study was the difficulty in matching specific procedures from waiting lists with ICER estimates from the literature. Nevertheless, our study represents a useful demonstration of a novel concept of using waiting list data to inform cost-effectiveness thresholds.