This study is an uncontrolled case series of patients enrolled in the clinic registry. The clinic registry, set up in July 2020 and still ongoing, captures longitudinal data of consenting adult patients who are prescribed CBM at the clinic.

All participants voluntarily and formally consented to the registry. Participants did not receive any compensation and enrollment in the study did not affect their clinical care.

Inclusion criteria for the registry are being over 18 years old, receiving CBMs, and being able to complete questionnaires in either French or English. Exclusion criteria include current pregnancy or lactation, and current psychotic disorder. Due to the coronavirus disease 2019 (COVID-19) pandemic, all visits were conducted by telemedicine. Eligibility for CBMs and the corresponding treatment plan is determined at the discretion of the clinic physicians based on individualized clinic assessment [31]. Patients coming to the clinic are predominantly referred by their family physician or specialist after not responding to conventional pain management. CBMs are added to the patient’s current regime of prescription medications as a complementary treatment.

Demographics, complete medical history (primary diagnosis according to the International Classification of Diseases-Tenth Revision), primary symptoms, secondary symptoms, concomitant medications, and previous cannabis use (regularly is defined as every day; occasionally as several times during a month) are collected at baseline. All recorded outcomes and adverse drug reactions (ADRs) questionnaires are patient-reported and are administered during routine clinical care visits at baseline, 3 months, 6 months, and 12 months.

For this analysis, registry data collected from July 14th, 2020 to July 17th, 2021 for patients with a primary symptom of CNCP, who were authorized to receive CBMs, and had complete recorded questionnaires at both baseline and follow-up 3 months (FUP3M) were extracted from electronic medical records (EMR). Pain mechanism was clinically assessed (e.g., pain description and characteristics, perceptual qualities of pain, sensory intensity, temporal features, findings in physical exam that includes location and bodily distribution of pain, relationship with the primary diagnosis, etc.) during the initial visit by the clinic physicians and verified during the database review by a pain specialist.

Questionnaires included the Edmonton Symptom Assessment System-Revised (ESAS-r), the Brief Pain Inventory-Short Form (BPI-SF), and the 36-Item Short Form Health Survey (SF-36). The ESAS-r is a self-administered scale, which rates the severity of physical (pain, tiredness, nausea, drowsiness, lack of appetite, and shortness of breath), emotional (depression, anxiety) symptoms and overall well-being from 0 (absence of symptom) to 10 (worst possible severity) at the time of assessment [32]. The BPI-SF is a self-administered scale, rating different aspects of pain severity from 0 (no pain) to 10 (pain as bad as you can imagine), as well as how pain interferes with seven different activities (0 = no interference, 10 = completely interferes) [33]. The SF-36 is a 36-item survey assessing physical and mental HRQoL (0 = very poor, 100 = excellent) [34].

ADRs were either self-reported or reported during routine clinic visits and included information on ADR terms, severity, causality, outcome, and seriousness.

CBM information included type of CBM (medical cannabis and/or pharmaceutical cannabinoids), method of administration (oral extracts vs. inhaled dried flower vs. other such as topical and edibles), and cannabinoid profiles (CBD-dominant, THC-dominant or THC:CBD balanced).

The product selection based on the cannabinoid profile and the methods of administration is displayed in Figure 1.

Pharmaceutical cannabinoids are approved medications containing synthetic or plant-derived cannabinoids; in Canada, nabilone and nabiximols are available. Medical cannabis products are plant-derived cannabinoids that have been legalized and regulated for medical use but are yet considered unapproved treatments [29]. Medical cannabis products include dried flowers and concentrates for inhalation, oral formats such as oils, sprays, and edibles as well as topical and suppository products. Multiple formulations of each product format are available in Canada, with distinct concentrations of THC and CBD. Products may also contain very limited concentrations of other cannabinoids, terpenes, and flavonoids.

CBD-dominant products contain a high concentration of CBD and are limited in THC concentration. In the Canadian medical cannabis program, CBD-dominant ingested cannabis oils contain approximately 0.5–1 mg/mL of THC and 20–25 mg/mL of CBD. CBD may be extracted from both hemp plants and other varieties of cannabis plants and products must be manufactured in accordance with the Cannabis Act [29]. THC-dominant products contain a high concentration of THC and limited CBD. THC-dominant oral cannabis oils generally contain 20–25 mg/mL of THC and 0.5–1 mg/mL of CBD. The category THC:CBD balanced indicates that the treatment plan includes both THC and CBD in significant concentration, which may be a product with a similar concentration of each cannabinoid (for example 10 mg/mL of THC and 10 mg/mL of CBD) or a personalized combination of CBD-dominant, THC-dominant, and THC:CBD products. For participants taking multiple cannabis products, the cannabinoid profile was determined by the overall THC:CBD concentration of all products. The delineation of the composition of each product and dosing schedule requires more investigation, which is beyond the focus of this study.

Quantitative data was summarized using mean and range, and qualitative data using frequency and proportion. Separate linear mixed effect models were used to assess the clinical impact of CBMs between baseline and 3 months on core outcomes (scores of each symptom for ESAS-r, pain severity and pain-related interference respective scores for the BPI-SF and physical health and mental health respective scores on the SF-36). For each model (total = 14), the participant was a random intercept and time, pain mechanism (nociceptive, neuropathic, mixed, undefined), and initial treatment cannabinoid profile (CBD-dominant, THC-dominant, THC:CBD balanced) were modeled as fixed factors. Questionnaires completed at the 3-month visit assess the self-reported effectiveness of initial visit treatment recommendations. Based on these responses, treatment adjustments or additional recommendations were proposed during the 3-month visit. Therefore, the initial treatment cannabinoid profile was assessed in the analyses. Statistical significance was set at P = 0.01 to account for potential type-I errors associated with testing multiple models and interactions terms were dropped if non-significant. The association between the presence of ADRs and socio-demographic variables was assessed with Chi-squares tests (χ²). All statistical analyses were performed using IBM Statistical Package for Social Sciences (SPSS) software [35].

The frequency of the type of CBMs, the cannabinoid profile and the formulation characteristics per visit are displayed in Table 2. At baseline, a large majority (73.9%) of patients were authorized exclusively medical cannabis products. Overall, oral oil extracts were the preferred formulation (81.6%) followed by a combination of oral oil extracts and dried flower (14.5%).

The proportion of each cannabinoid profile differed according to the visit [χ²(3) = 39.10, P < 0.001], CBD-dominant products proportion decreased at the FUP3M whereas THC:CBD and THC-dominant proportion products increased. There is no association between pain mechanism and baseline treatment recommendations [χ²(6) = 1.32, P < 0.97] which indicates that pain mechanism is not a primary consideration in treatment recommendations relative to other factors, such as pain severity and previous cannabis use.

Mean differences and 95% confidence interval (CI) Bonferroni-adjusted for multiple post hoc pairwise comparisons for all outcomes measures (total = 14) are reported in Table 3.

During the study period, 158 (31.9%) patients reported a total of 262 AEs which were assessed to have some level of relationship to CBMs and therefore were classified as ADRs. Over half (54%) of ADRs were reported about a month after treatment initiation, 3% within the first 2 weeks after baseline, and 43% at FUP3M. The ADRs severity, causality, outcome, and action taken according to the initial cannabinoid profile are reported in Table 4. Over three-quarters (77.5%) of ADRs were recovered or recovering and 14.9% were not recovered at the time of data extraction.

Overall, dizziness and giddiness, headache, and somnolence were the most reported ADRs (13.4%, 12.2%, and 11.1% respectively). Fatigue accounted for 7.6% and buzz sensation for 6.1%. Dyspepsia and nausea accounted for 5.7% each of total ADRs, diarrhea for 4.2%, and dry mouth for 3.4%. Other ADRs (for a total of 30.6%) accounted for less than 3% of total ADRs reported and included constipation, palpitations, polyphagia, and shortness of breath among others.

The majority of ADRs (71.4%) were evaluated as mild, 26% as moderate, and 2.7% as severe (Table 4). Three serious ADRs were reported to health regulations as they led to hospitalization, one was due to pulmonary embolism (assessed as unlikely related to the CBD-dominant ingested oil treatment), one due to tachycardia (possibly related to the THC-dominant ingested oil and CBD-dominant ingested oil treatment) and one due to vomiting (probably related to CBD-dominant ingested oil and THC:CBD balanced inhaled dried flower). Treatment was interrupted temporarily for the pulmonary embolism, ceased completely for the tachycardia, and ceased during the day for the vomiting ADR.

The patients who reported at least one ADR did not differ from those who did not in terms of age, sex, and CBM cannabinoid profile category. However, over half of the patients who reported at least one ADR had neuropathic pain. Previous cannabis use was also associated with the presence of ADRs [χ²(3) = 8.57, P < 0.036]; patients who had never tried cannabis accounted for 31% of patients who reported at least one ADR. Among patients who had previously tried both dried flower and/or ingested cannabis oil extracts, there was a higher proportion of no ADRs (75%) vs. at least one ADR (25%) reported.

Standard limitations of registry studies apply to this study, such as population heterogeneity and lack of placebo-control. The registry takes place at a network of clinics in a specific province within the Canadian public healthcare system. The current context of medical cannabis access, including social stigma, high out-of-pocket cost, and limited insurance coverage can increase the patient selection bias. Patients who continue CBM treatment despite these barriers are likely to be those who find CBM helpful. The high cost as well as the privileged environment with supported, efficient access to supportive healthcare professionals may also increase the placebo effect of CBM. The use of complete case analysis, in which only data from patients with both complete baseline and FUP3M questionnaires were extracted, may reduce potential bias and adjust for attrition, however, it further limited the sample size. The small sample size of the THC-dominant product category limits the ability to model it as a separate group, however, the exclusion of this group did not change the results of the analysis, therefore, the three-category model was presented as it is more representative of clinical practice. Furthermore, the pain mechanism groups of both mixed and undefined pain are smaller relative to the other respective categories, which contributes to a somewhat unequal weighting of the statistical models.

Treatment discontinuation is a recurring issue in clinical practice [14, 47, 48]. Patient discontinuation is influenced by various factors, including social and financial challenges, lack of effectiveness, and AEs. The COVID-19 pandemic has increased stress, financial and technological repercussions for many patients and may also have an impact on our population during the study period.

The categorization of initial treatments by the overall THC:CBD ratio instead of by estimated exposure to each cannabinoid limits the generalizability of the results. However, this categorization represents common clinical practices and the tendency to maintain simple initiation regimens during a patient’s first 3 months of medical cannabis treatment.

The cannabis plant has a complex composition of more than 100 unique cannabinoids including CBD, THC, and others such as cannabinol (CBN), cannabichromene (CBC), and cannabigerol (CBG) [49]. Future research is needed to better understand their mechanisms of action and unique effects which will support clinicians as these components become more predominant in medical cannabis products.

This analysis investigated the use of CBM treatment during the initial three-month period according to the mechanism of pain and the initial CBM treatment. It serves as an example of the use of real-world evidence to bridge gaps of limited RCTs and provides a preliminary indication of the effectiveness of specific CBM treatments for nociceptive and mixed pain as well as neuropathic pain. Future research on the role of medical cannabis in pain management must detail the product characteristics and must consider the pain mechanism. Study results indicate that countries where regulatory frameworks limit medical cannabis products to CBD or otherwise continue the prohibition of THC likely fall short of the needs of patients and healthcare professionals in today’s social and cultural climate and escalating rates of CNCP. While CBM treatments are generally considered safe; this study shows that a significant number of ADRs, including some serious ADRs, can occur even within a controlled, conservative supervision of treatment initiation and titration. This emphasizes that CBMs require medical supervision by trained healthcare professionals to support patient safety and ensure appropriate follow-up.