Alan Fayaz’s research while affiliated with University College London Hospitals NHS Foundation Trust and other places

BACKGROUND: There is substantial theoretical, anecdotal, and preclinical evidence to support the potential efficacy of cannabinoids for the treatment of pain. However, randomized controlled trials (RCT) have yielded conflicting evidence regarding cannabis-based products for medicinal use (CBPMs) in chronic pain. To some extent, these trials have been hampered by heterogeneity in treatments and participants, in common with much of pain research. There are also the pragmatic challenges of maintaining consistency when investigating a complex, organic product. For these reasons there have been calls to consider real-world data (RWD) in the belief that it may offer some insights into the role of CBPMs in pain management that are lost within the constraints of an RCT. AIMS: To investigate real-world outcomes of individuals using CBPMs for chronic pain in the United Kingdom, including assessing for differences in response rates between pain phenotypes. METHODS: Project Twenty21 is a UK initiative collecting RWD, incentivising participation via discounted access to certain CBPMs. We present 18-month outcomes from the 1993 individuals with chronic pain, enrolled in the registry as of November 2023. We grouped individuals by pain phenotype and categorized CBPMs according to substrate and by Δ9-tetrahydrocannabinol (THC) content. Comparing baseline with follow-up, we investigated changes in brief pain inventory severity (BPI-S), interference (BPI-I), quality of life (EQ5D index), sleep score, and opioid use. We investigated between-phenotype variability in treatment response (>30% improvement in either BPI-S or BPI-I scores). We then built logistic regression models to identify participant and CBPM factors that were predictive of treatment response at 3-months. Individual 18-month longitudinal trajectories were plotted at 3-monthly intervals. All analyses were performed in R version 4.2.3. RESULTS: The median age was 43, and 59% were male. 58% reported already using cannabis to manage their condition prior to enrolment, 25% had prior experience with cannabis but no current use, and 16% were cannabis-naïve. THC-dominant flower was the most prescribed treatment, followed by balanced oils. 1385 participants had at least one follow-up. Average BPI-S, BPI-I, sleep score, and quality of life were improved at all time-points vs baseline (p<0.05), with scores plateauing after 6-months. 43% participants with 3-month data were responders. Optimised logistic regression models suggested participants with fibromyalgia had a lower likelihood of response versus undifferentiated chronic pain (odds ratio 0.38, 95% confidence interval 0.23-0.63, p=0.0002). Among responders, improvements in average pain scores were sustained at 18-months. Prescription opioid use, but not paracetamol use, was less prevalent during follow-up versus baseline, amounting to a 13.1% relative (6.9% absolute) reduction at 18-months (p=0.007). Drop-out was similar between those who were using opioids at baseline versus those who were not (log-rank p-value >0.05). At odds with the wider cohort, 67% of cannabis-naïve participants were female. Among this group, balanced oils were the most commonly prescribed, and 38% responded at 3-months. CONCLUSIONS: We performed the largest ever UK-based observational study of CBPM use for chronic pain. Our data corroborates that, for a subset of chronic pain patients, access to medicinal cannabis is accompanied by meaningful and sustained reductions in pain intensity. We found some indications that 6-months may be the optimal trial duration to assess response to CBPMs. Another important finding was that while over 20% of participants with fibromyalgia met criteria for treatment response, they were less likely to achieve response than those with other causes of pain. Our findings are limited in their generalizability due to bias from participant self-selection, and open-label study design. Nonetheless, our data complement those from RCTs, shedding further light on inter-individual variability in treatment response and the potential opioid-sparing effects of CBPMs.

Application for ESRA Abstract Prizes I apply as an Anesthesiologist (Aged 35 years old or less) Background and Aims Background Patients with pre-existing chronic pain or those on high-dose opioid medications while presenting for surgery may be at increased risk of severe post-surgical pain and associated complications. However, findings from existing scientific literature that explore the role of adjunctive therapies to minimise postoperative pain or perioperative opioid use have been discordant. This review aimed to identify and evaluate the effectiveness of opioid-sparing interventions on post-surgical pain in patients with pre-existing chronic pain or high-dose opioid use. Methods The databases PubMed, EMBASE, CINAHL Plus, Web of Science Core Collection and PsychINFO were searched for contemporary studies meeting pre- specified inclusion criteria. Methodological rigour was assessed, and data was extracted using bespoke forms. The last search was conducted on January 29, 2023. Results Sixteen studies were eligible for inclusion. Eight studies were suitable for meta-analysis to explore perioperative ketamine administration. We identified a tendency towards improvement in early postoperative pain scores (-0.27 [-0.79, 0.26]) and opioid use (-0.27 [-0.55, 0.00] SMD); however, this did not achieve statistical significance. Celecoxib improved pain scores in THA and TKA patients p=0.024 and pregabalin reduced opioid consumption by 64.78% p<0.001; however, periarticular liposomal bupivacaine did not show benefit. Conclusions We identified some improvement in postoperative pain scores and reduction in analgesic requirements with the use of ketamine, pregabalin and celecoxib individually as anaesthetic adjuncts in targeted surgical populations. The heterogeneity of study endpoints and the risk of bias limit the ability to make definitive conclusions. More research, in potentially higher risk-of-pain populations, using internationally agreed definitions, would be helpful.

Acute postoperative pain is common, distressing and associated with increased morbidity. Targeted interventions can prevent its development. We aimed to develop and internally validate a predictive tool to pre-emptively identify patients at risk of severe pain following major surgery. We analysed data from the UK Peri-operative Quality Improvement Programme to develop and validate a logistic regression model to predict severe pain on the first postoperative day using pre-operative variables. Secondary analyses included the use of peri-operative variables. Data from 17,079 patients undergoing major surgery were included. Severe pain was reported by 3140 (18.4%) patients; this was more prevalent in females, patients with cancer or insulin-dependent diabetes, current smokers and in those taking baseline opioids. Our final model included 25 pre-operative predictors with an optimism-corrected c-statistic of 0.66 and good calibration (mean absolute error 0.005, p = 0.35). Decision-curve analysis suggested an optimal cut-off value of 20-30% predicted risk to identify high-risk individuals. Potentially modifiable risk factors included smoking status and patient-reported measures of psychological well-being. Non-modifiable factors included demographic and surgical factors. Discrimination was improved by the addition of intra-operative variables (likelihood ratio χ2 496.5, p < 0.001) but not by the addition of baseline opioid data. On internal validation, our pre-operative prediction model was well calibrated but discrimination was moderate. Performance was improved with the inclusion of peri-operative covariates suggesting pre-operative variables alone are not sufficient to adequately predict postoperative pain.

Background Prescribed cannabinoids are now legal in the UK and increasingly being used for a variety of conditions, with one of the most frequent conditions being chronic pain. This paper describes the characteristics of individuals seeking prescribed cannabinoids for the treatment of chronic pain in Project Twenty 21, a UK based real world data registry of prescribed cannabis patients.Method By 1st November 2021 data were available for 1,782 people who had sought treatment with medical cannabis as part of Project Twenty 21. The most common diagnosis among this cohort was chronic pain with 949 (53.5%) of the cohort reporting a primary condition related to chronic pain. Medical and self-report data on the characteristics of these patients, their health status and type/s of cannabinoid/s prescribed are summarized in this report.ResultsOf the 949 people reporting chronic pain as a primary condition 54.7% were male and their average age was 42.0 years (range = 18–84). Patients reported a low quality of life and high levels of comorbidity: people reported an average of 4.6 comorbid conditions with the most common comorbid conditions including anxiety, depression, insomnia and stress. A range of cannabinoid products were prescribed with the most common products being classified as high THC flower (48.5%). The majority of patients also reported using at least one other prescribed medication (68.7%).Conclusions Consistent with findings in other national and international databases, chronic pain was the most common primary condition in this real world study of prescribed cannabinoids. There was considerable variation in the types of chronic pain, comorbid pathology and in the characteristics of products being prescribed to treat these conditions. Together, this evidence supports the utility of real world evidence, as opposed to clinical trial approaches to studying the potential benefits of prescribed cannabinoids in treating chronic pain.

Chronic pain conditions are prevalent and cause a significant burden of disease. Intravenous lidocaine infusions have been reported to have an analgesic effect in patients with chronic neuropathic pain, but there is limited data supporting the efficacy of lidocaine across other chronic pain phenotypes. Our study aimed to evaluate the efficacy of a single infusion of intravenous lidocaine for pain relief and the impact on quality of life. We evaluated data from 74 patients with chronic pain who were treated with intravenous lidocaine at a specialist pain centre. Participants completed a questionnaire consisting of the Brief Pain Inventory (BPI) Short Form and additional EQ-5D quality of life metrics, before treatment and at follow-up. Data comparing pain severity did not demonstrate a statistically significant change after treatment when averaged across the entire patient cohort (6.15–5.88, p = .106), irrespective of gender or pain phenotype. Scores for pain interference showed statistically significant reductions following treatment (7.05–6.41, p = .023), which may have been driven through improvements in sleep (7.41–6.35, p = .001); however, these reductions are not clinically significant. The patient cohort was stratified into responders and non-responders based on >30% improvement in response to an overall impression of pain reduction question following treatment. In the ‘responder’ cohort, pain intensity scores showed a statistically significant reduction post-infusion (6.18–5.49, p = .0135), but no change was apparent for non-responders (6.07–6.09, p = .920). There were no differences between responders and non-responders for pain sub-types in our study. This study found no difference in pain outcomes in a cohort of patients with chronic pain, a mean of 63 days following a single lidocaine infusion. However, a specific subgroup of responders may show slight improvements in some pain outcomes that may warrant further exploration.

Background Irritable bowel syndrome (IBS) is a highly prevalent and economically burdensome condition; and pain is often the most unpleasant, disruptive, and difficult‐to‐treat symptom. Visceral hypersensitivity is a common feature driving pain in IBS, suggesting that neuropathic mechanisms may be implicated. We conducted a systematic review of available evidence to examine the role of anti‐neuropathic medicines in the management of pain in IBS. Methods We systematically searched scientific repositories for trials investigating conventional oral, and/or parenteral, pharmaceutical antineuropathic treatments in patients with IBS. We summarized key participant characteristics, outcomes related to pain (primary outcome), and selected secondary outcomes. Key results We included 13 studies (n = 629 participants): six investigated amitriptyline, three duloxetine, three pregabalin, and one gabapentin. There was considerable methodological and statistical heterogeneity, so we performed a narrative synthesis and limited meta‐analysis. Amitriptyline was most extensively studied, though only in diarrhea‐predominant patients. In individual trials, amitriptyline, pregabalin and gabapentin generally appeared beneficial for pain outcomes. While duloxetine studies tended to report improvements in pain, all were un‐controlled trials with high risk of bias. Meta‐analysis of three studies (n = 278) yielded a pooled relative‐risk of 0.50 (95%CI 0.38–0.66) for not improving with anti‐neuropathic agent vs control. We did not identify any eligible studies investigating the role of parenteral anti‐neuropathics. Conclusions and inferences Anti‐neuropathic analgesics may improve pain in IBS, and deserve further, high‐quality investigation, potentially considering parenteral administration and agents with minimal gastrointestinal motility effects. Investigation of amitriptyline’s efficacy in non‐diarrhea‐predominant subtypes is currently lacking, and we recommend particular caution for its use in IBS‐C.

Background Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit–safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit–safety balances remain better than those of the noncannabinoid drugs. Interpretation The benefit–safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.