Systematic Review and Meta-analysis Seem to Indicate that Cannabinoids for Chronic Primary Pain Treatment Have Limited Benefit

Search Results and Study Characteristics

We identified 3007 records (1242 from PubMed, 1765 from EMBASE, and 0 from Cochrane Library) from the initial search strategy. After the removal of duplicates, 2518 records were screened and 2452 of these were excluded by title and abstract. Sixty-six potentially eligible studies were read in full text and 58 were excluded for various reasons. Eight studies were included in the qualitative synthesis and in the meta-analysis [25,26,27,28,29,30,31,32] (Fig. 1). The percentage of agreement was 99.8% and the Cohen’s kappa was 0.73, implying substantial agreement. All included studies were RCTs, published between 2008 and 2021, four with a parallel design and four with a crossover design. Among them, two crossover studies evaluated cannabinoids as single-dose administrations of different compounds on different days (single doses studies), while the remaining six RCTs administered the same compounds daily for a determined period (longitudinal daily-dose studies) (Table 1). The overall population consisted of 240 patients across eight studies. A total of 115 patients had fibromyalgia [25, 27, 28, 31], 19 had chronic primary chest pain [26], and 68 had IBS [29, 30]. One study enrolled 22 patients with CRPS type I (57.9%) among a total population of 38 subjects, with the remaining having various chronic secondary pain conditions (Table 1) [32]. For this reason, we performed a sensitivity analysis excluding this study.

Fig. 1figure 1Table 1 Characteristics of included studies

Among included RCTs, seven studies administered different cannabinoid compounds and preparations, including sublingual cannabis THC-rich oil [25], dronabinol oral capsules [26, 29], oral nabilone [27], CBD gums [30], inhaled vaporized pharmaceutical-grade medicinal cannabis (Bedrocan, Bediol, Bedrobinol) [31], different doses of delta-9-THC pharmaceutical-grade medicinal cannabis smoked cigarettes [32], all compared to matching placebo. One RCT compared nabilone to amitriptyline oral capsules [28].

Outcomes extracted and included in our meta-analysis are outlined in Table 1.

Risk of Bias

Overall, we considered one study at low risk of bias; five studies had some concerns regarding risk of bias, and two studies were at high risk of bias (Fig. 2). We considered all studies at low risk of bias for the randomization process. We considered two studies to have some concerns [25, 30] and two others to be at high risk of bias [26, 27] because of deviations from intended interventions, mainly due to the exclusion of patients from the analyses or a large dropout from the study, without accounting for the missingness of the patients and performing the analysis itself in a per-protocol fashion. For the missing outcome data domain, we considered three studies to have some concerns [26, 30, 31] and one was at high risk of bias [27]. We considered all studies at low risk of bias for measurement of the outcome. One study was considered at low risk of bias [28] in the selection of the reported result while we considered the others to have some concerns of risk of bias [25,26,27, 29,30,31,32] for this domain since we did not find information on whether the analyses were performed according to a prespecified plan.

Fig. 2figure 2

Risk of bias of included studies a for individual studies and b across risk of bias domains

Pain Reduction

Overall, we were able to extract data on pain reduction from seven studies, six evaluated cannabinoids efficacy against placebo and one against amitriptyline, with a total population of 182 patients included in the analyses. Among these patients, 46 were from the crossover RCT comparing nabilone to amitriptyline in fibromyalgia. Pain was re-expressed in VAS units. In a primary analysis, we assessed cannabinoids efficacy against placebo or any active comparator. When comparing cannabinoids to placebo the difference was non-significant (MD = − 0.64 95% CI − 1.30 to 0.02) (Fig. S1A, Table 2). Nabilone and amitriptyline were not significantly different in pain reduction (MD = – 0.19; 95% CI − 0.58 to 0.19) (Fig. S1B). When grouping included studies by study design (parallel or crossover) and by treatment duration (at least 4 weeks or less than 4 weeks), we observed a significant reduction of pain in parallel studies with more than 4 weeks of cannabinoid treatment compared to placebo (MD = – 1.28; 95% CI − 2.33 to − 0.22). This difference was not significant for crossover studies with a treatment duration less than 4 weeks compared to placebo (MD = – 0.34; 95% CI − 1.1 to 0.42) (Fig. S2A, Table 2). These results were confirmed after a sensitivity analysis excluding the study that also enrolled chronic secondary pain patients (Fig. S3).

Table 2 Summary of findings for cannabinoids compared to placebo

In a subgroup analysis, we evaluated the efficacy of cannabinoids against placebo by different CPP conditions. No significant differences were observed in patients with fibromyalgia (MD = – 0.70; 95% CI – 1.54 to 0.12), chronic primary chest pain (MD = 0.00; 95% CI − 2.19 to 2.19), and IBS (MD = 0.34; 95% CI − 1.06 to 1.73), while we observed a significant reduction in patients with CRPS type I (MD = – 1.62; 95% CI − 3.01 to − 0.26) (Fig. S4, Table 2). However, a sensitivity analysis including studies on fibromyalgia showed that cannabinoids significantly reduced pain compared to placebo in parallel RCTs with more than 4 weeks of follow-up (MD = – 0.82; 95% CI − 1.41 to − 0.24) while it was non-significant in crossover RCTs with less than 4 weeks of follow-up (MD = – 0.01; 95% CI − 0.52 to 0.50) (Fig. S2B, Table 2).

Quality of Life

We extracted QoL outcomes from three studies enrolling patients with fibromyalgia, two evaluating cannabinoids against placebo, and one against amitriptyline, with a total population of 79 patients included in the analyses. To evaluate the quality of life, the FIQ was used in all the three studies. We found statistically non-significant differences when comparing cannabinoids against placebo (MD = – 21.69; 95% CI − 46.20 to 2.82) or amitriptyline (MD = – 0.70; 95% CI − 7.30 to 5.90). Another crossover study comparing CBD to placebo reported QoL data from 30 patients with IBS who completed the IBS-36 questionnaire. No significant differences were observed between CBD and placebo (MD = – 1.0; 95% CI − 6.8 to 4.9) (Fig. S5, Table 2).

Anxiety and Depression

Data on anxiety were available from three studies with a total sample of 63 patients, while two studies reported data on depression with a total sample of 30 patients. Anxiety and depression were re-expressed in BAI and BDI units, respectively, and all studies compared cannabinoids to placebo. A non-significant difference was observed for anxiety (MD = – 2.32; 95% CI − 7.99 to 3.08) and depression (MD = 2.32; 95% CI − 1.71 to 6.35) (Fig. S6A, B, Table 2).

Sleep and Appetite

Other study outcomes were sleep and appetite. We did not extract and analyze data on sleep since they were reported with different and incomparable outcome measures by two studies evaluating cannabinoids against two different comparators; thus, we provide only a description of reported results. One study, comparing cannabis oil to placebo in patients with fibromyalgia, did not find significant differences in the FIQ subscale for morning tiredness [25]. The other, comparing nabilone to amitriptyline, showed that nabilone was superior to amitriptyline in improving the Insomnia Severity Index (MD = – 3.25; 95% CI − 5.26 to − 1.24). Also, nabilone marginally improved restfulness assessed with the Leeds Sleep Evaluation Questionnaire, while other subscales showed no marked differences [28].

Appetite was not evaluated in included studies.

Safety

We managed to extract data on SAE from five studies, with a total population of 152 patients, of whom 95 were from three parallel RCTs and 57 from two crossover RCTs. One crossover RCT compared cannabinoids to amitriptyline, while the remaining four studies used placebo as a comparator. No SAEs were reported.

All eight studies reported data on discontinuation due to AEs. However, two crossover studies did not separate the events by the treatment patients were receiving at the moment of the discontinuation: in one RCT, comparing nabilone to amitriptyline, one patient discontinued the trial after the first dose because of the onset of arm and leg edema, decreased concentration, dizziness, nausea, hyper-alert state, and insomnia; in the other study, which evaluated CBD gums compared to placebo gums, two patients discontinued the treatment because of unpleasant air ingestion. The remaining six studies were included in the meta-analysis. A non-significant difference was found between cannabinoids and placebo in discontinuation due to AEs (OR = 2.15; 95% CI 0.44 to 10.65) (Fig. S6C).

Summary of findings and Publication bias

We produced a summary of findings for cannabinoids compared to placebo (Table 2). We did not observe signs of possible publication bias. The funnel plot evaluating publication bias for studies reporting the primary outcome is presented in Fig. S7.

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