Efficacy of cannabis-based medications compared to placebo for the treatment of chronic neuropathic pain: a systematic review with meta-analysis

1. Cannabis interventions

Existing evidence suggests that the Cannabis plant has been used by humans for hundreds of years for various purposes, including its therapeutic properties, such as pain relief; appetite stimulation; alleviation of fatigue, anger, and fear; and the treatment of epilepsy [7,8]. In 1970, the Controlled Substances Act made it unlawful to grow and sell hemp and marijuana in the United States (USA), thereby limiting the possibility to explore its properties. Progressive social and political changes in the USA and other countries and the passing of the 2014 Agricultural Act, which differentiated hemp and marijuana’s legality, has allowed researchers to investigate the benefits of cannabis and its potential therapeutic use for the management of several medical conditions, including chronic NP [9].

Cannabis is a genus of plants in the Cannabaceae family [10]. Two recognizable species within the cannabis genus are Cannabis sativa and Cannabis indica, and are known as marijuana [11]. Marijuana and hemp are two strains of C. sativa; marijuana is cultivated mainly for its delta 9-tetrahydrocannabinol (delta 9-THC) content, and hemp for its usefulness in the production of industrial products such as clothing, paper, oil, and food [12]. The scientific investigation of C. sativa has made significant progress in the past 35 years, as the numerous active ingredients of C. sativa strains have been identified, and major breakthroughs have been made concerning the human body’s endogenous cannabinoids (CBs) and the endocannabinoid system (ECS) with its regulatory functions in health and disease [13].

The ECS is the pathway by which tetrahydrocannabinol (THC) and other CBs interact in an animal’s body. Prior research has shown that CB receptors and ligands are present in the bone, immune system, peripheral nervous system, and CNS [14]. Studies have shown that the ECS has three functions in mammals [15]. The first function affects stress recovery in animals, acting in a feedback loop where endocannabinoid signaling is activated by stress and acts to return nervous, behavioral, and endocrine systems to a homeostatic balance [16]. The second role is thought to regulate the body’s energy balance through regulation of food intake, utilization, and storage [17]. The third function involves immune system tasks, whereby endocannabinoid signaling is activated by tissue injury [18] and modulates immune and inflammatory responses [19]. Thus, the ECS is involved in multiple homeostatic and physiological functions, such as antinociception, inflammation, cognition and memory, nausea and vomiting, endocrine function, and immune system recognition [20].

Cannabis reportedly contains over 450 compounds, with 70 classified as phytocannabinoids. Delta 9-THC is the main active component, with psychoactive (e.g., reduction of anxiety and stress) and pain-relieving properties. Cannabidiol (CBD) is another component of interest. Studies have shown that CBD has a lower affinity for CB receptors and may counteract the undesirable effects of THC on memory, cognition, and mood, but may also have an effect on pain modulation by anti-inflammatory properties [21]. The specific functions of the identified cannabinoids that act as ligands at CB receptors within the nervous system have only been partially elucidated [14]. However, according to data from prior pharmacological studies and research using CB receptor knock-out mice, the mechanisms involved in the analgesic effects of CBs are thought be based on the activation of CB1 and/or CB2 receptors, causing a decrease in pain signal transmission and/or anti-inflammatory effects [22,23,24]. Two major endocannabinoids described so far, 2-arachidonylglycerol and anandamide, have been shown to influence the transmission of pain signals by acting on CB1 and CB2 receptors [22]. Additionally, these endogenous receptors in humans may play a role in reducing changes in cognitive and autonomic processing in chronic pain states [25].

Preclinical data demonstrate that the CB1 receptor is expressed in regions of the CNS, such as the dorsal root ganglia [26], periaqueductal gray area and nucleus raphe [27,28], dorsal horn of the spinal cord [29], and forebrain [30]. Additionally, evidence from several animal models demonstrates an upregulation of CB receptors in the CNS following nerve injury, suggesting a role of cannabinoids in the possible treatment of NP conditions [31,32,33]. Studies examining plant-based and synthetic cannabis-based interventions have provided data suggesting the use of cannabis-based medications as a possible approach for the management of chronic NP of different origins [34].

Given the current challenges in the treatment of chronic NP in combination with the ongoing fear of the long-term effects of the opioid epidemic, chronic pain management physicians as well as orofacial pain specialists need more innovative, effective, and safer options to alleviate NP [35]. Although opiates and non-steroidal anti-inflammatory medications are the primary pharmacological treatments for nociceptive pain, these medications have a modest effect and only in a minority of patients with NP due to the inability to precisely target the underlying mechanisms [36]. High-potency opioids have a number needed to treat one patient to experience a reduction of pain by at least 50% (NNTB) of 4.3 NP (NNTB 3.4-5.8) [37]. Current pharmacological treatments for chronic NP have largely been limited to tricyclic antidepressants (TCAs) and neuromodulators (i.e., sodium channel blockers and anticonvulsants), but these have also only shown partial efficacy in most patients [38], with a NNTB for these first-line drugs falling in the range of 3.5 to 7.7 for one patient to achieve at least a 50% reduction in pain [37]. Individuals with chronic NP conditions struggle to find effective treatment options and often undergo multiple trials with commonly used medications in search for an effective treatment and relief. The financial, social, psychological, and physical toll that poorly treated chronic NP can contribute significantly. Individuals with painful neuropathic disorders show a three-fold increase in healthcare costs compared to the matched control groups [39]. The prevalence of NP in the general population has been reported to be between 7% and 10% in some countries [2,40].

There is a need to explore additional treatment options for NP; with the increasing awareness and use of cannabinoids for medical purposes, a systematic review with meta-analysis is needed to summarize its effectiveness and safety as a therapeutic option for the treatment of chronic NP.

2. Inclusion and exclusion criteria

The studies included in this systematic review were limited to publications in English of randomized placebo-controlled trials. Studies identified with no placebo control, abstract only, not in English, with conditions other than NP, where cannabinoid medications were adjuvant only, and duplicate studies were excluded from this review.

3. Search methods for identification of studies

Four electronic databases (EMBASE, MEDLINE through PubMed, Web of Science, and Cochrane) were searched up to 2/1/2021 using the strategies described in Table 1.

4. Data collection and analysis

After removing duplicates, the references were screened by three authors (J.B., B.S., M.P.). The titles and abstracts of all records were analyzed using the inclusion and exclusion criteria. If there was no agreement among the reviewers, the full PDF was retrieved and analyzed. The reference sections of all literature reviews, systematic reviews, meta-analyses, and clinical guidelines in addition to all eligible RCTs were then scanned by three authors (J.B., B.S., M.P.) for any further applicable references. Any new relevant study was screened using the same inclusion and exclusion criteria and subsequently reviewed by the same three authors. If a consensus was not reached by the authors, the full article was reviewed, and a fourth author (R.E.) was involved if there was no consensus.

5. Data Extraction and Management

Three authors (J.B., B.S., M.P.) independently extracted the data obtained from the identified RCTs. Data included participants’ demographics, control groups, intervention groups, funding, and outcomes. Any disagreement among the three authors (J.B., B.S., M.P.) was reviewed and resolved by consensus with a fourth author (R.E.).

6. Assessment of risk of bias in included studies

The risk of bias for each eligible trial was independently identified by three reviewers (J.B., B.S., M.P.) and reviewed by a senior author (R.E.), following the recommended guidelines in the Cochrane Handbook [42].

7. Statistical analyses

RCTs on cannabis-based medications compared to placebo groups for NP were included. Means and standard deviations (SD) were calculated based on reported medians (m) and interquartile range (IQR) = (q1, q3), with q1 = 25% quartile, and q3 = 75% quartile, as: mean = (q1 + m + q3)/3; SD = (q3 – q1)/1.35. SD was calculated based on the reported standard error of the mean (SEM) as follows: SD = SEM × sqrt (N), where N is the total sample size in the intervention group. For pain intensity, outcomes reported on a 0–10 scale were converted to a 0-100 scale by multiplying by 10.

Treatment effects for pain intensity reported on a 0–100 Visual Analog scale (VAS) or a 0-100 Numerical Rating scale (NRS) were expressed as the difference in means (DM) of the change in outcomes from baseline with 95% confidence intervals (CI). Treatment effects for percent reduction in NP intensity from baseline as well as post-treatment pain disability scores, McGill pain questionnaires, and SF-36 were reported as DM of post-treatment outcomes with 95% CI. For the number of patients with 30% (or 50%) reduction in pain intensity, treatment effects were expressed as risk ratios (RR) with 95% CI.

Cochran’s Q test [43] and the I2 statistic [44] were used to test for heterogeneity. A random-effects model was employed when there was heterogeneity (Q-test P<.10); otherwise, a fixed-effect model was used. All statistical analyses were performed using the Comprehensive Meta-Analysis v3 software. (Biostat, Englewood, NJ, USA). Statistical significance was defined as P ≤ .05.

8. Subgroup and sensitivity analyses

Sensitivity analyses for low risk of bias versus unclear/high risk of bias due to the small number of studies could not be conducted, nor a funnel plot to assess for publication bias. Subgroup analyses were conducted for THC/CBD, THC, CBD, cannabidivarin (CBDV), and synthetic cannabis therapies (dronabinol, CT-3).

2. Included studies

Seventeen references were included in the qualitative analysis [47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63], as shown in Table 2. Four studies followed an RCT parallel design [50,58,61,63], and 13 studies followed a crossover design [47,48,59,60,62,49,51,52,53,54,55,56,57].

3. Risk of bias in included studies

The trials included in this review were analyzed for the presence of risk of bias, including but not limited to allocation concealment, random sequence generation, blinding of investigators and participants, selective reporting, incomplete outcome data, and other potential sources of bias. Overall, the risk of bias was unclear in nine of the 17 RCTs (52.9%) [48,50,51,52,53,54,55,62,63], and a high risk of bias was found in eight of the 17 RCTs (47.1%) [47,49,56,57,58,59,60,61] (Tables 4 and ​and5;5; Fig. 2).

4. Adverse events

Adverse events (AEs) and side effects for the RCTs [47,49,62,63,51,52,53,54,56,58,60,61] included but were not limited to anxiety, sedation, dizziness, nausea, and fatigue. Two publications [55,59] reported that there were no serious side effects related to the study. One study [48] reported that thirty-one patients, (91.2%) had at least one study related AE, stating that diarrhea and dry mouth of mild severity were the most common AEs, and one patient withdrew due to an AE (cough) during CBDV treatment. Another RCT [57] reported side effects of the trial in a subsequent paper [46]. One study [50] did not list the adverse events but stated that, of the 30 patients randomized, six withdrew because of adverse events.

5. Meta-analyses

2. Agreements and disagreements with other studies or reviews

Several reviews [89,90,91] share optimistic conclusions that the use of cannabis-based medications is moderately effective, tolerable, and safe in the treatment of patients with NP. In a qualitative systematic review of cannabis-based medications for non-cancer pain [89], which included 11 RCTs on chronic NP, the authors reported that cannabis-based medications were “modestly” effective in the treatment of NP, and that it was “reasonable to consider cannabinoids as a treatment option in the management of chronic neuropathic pain.” Several of the included trials also demonstrated a significant improvement in sleep without serious adverse events, which were generally described as well tolerated, short lived, or mild-to-moderate [89].

In a review of the effectiveness of cannabinoids in the management of chronic nonmalignant NP [90], the authors concluded that cannabinoids provided significant pain reduction in both the short and long term, and that cannabinoids should be considered as an effective add-on, if not an alternative therapy, for the treatment of chronic NP. Their review also suggested that cannabis-based therapies may provide effective analgesia in chronic NP conditions that are refractory to other interventions, and that cannabinoids also improve nausea, sleep quality, anxiety, and appetite. Adverse events were described as minor in nature [90].

In an individual patient data meta-analysis of inhaled cannabis for the treatment of chronic NP [91], data from 178 participants in five RCTs provided evidence that inhaled cannabis resulted in short-term reductions in chronic NP for every five to six patients treated (NNTB = 5.6, CI = 3.4 to 14) for a more than 30% reduction in pain scores compared to placebo. From their data, they inferred that this effect applies to chronic painful neuropathies of different etiologies. They also reported that withdrawals due to adverse events were rare. Other clinical guidelines and systematic reviews consider cannabis-based medications as third-or fourth-line therapy for chronic NP if the already accepted therapies (tricyclic antidepressants (TCAs), anticonvulsants) have failed to achieve effective results [92,93].

On the other hand, there are also reviews [21,94,95] that do not support cannabis-based medications for the treatment of NP. The Neuropathic Pain Special Interest Group (NeuPSIG) conducted a systematic review of randomized double-blind studies of oral and topical pharmacotherapy for NP [94]. The authors identified nine trials of Sativex (an oromucosally applied spray containing 27 mg/ml of THC and 25 mg/ml of cannabidiol) in NP. Only two of these studies were found to be favorable, leading to a weak recommendation against their use in NP. Abuse, negative results, diversion, potential misuse, and long-term mental health risks in susceptible individuals were all reasons for their recommendation against the use of Sativex in NP.

In a systematic review of cannabis-based medications for chronic NP in adults [21], the authors analyzed eight studies with 1,001 participants. A total of 20.9% of participants in the cannabis-based medications and 17.3% in the placebo group reported pain relief of 50% or greater (NNTB = 20). According to their predefined categories, there were no clinically relevant benefits of cannabis-based medications. Cannabis-based medications were superior to placebo in the reduction of mean pain intensity (P =.008). According to Cohen’s categories, there was a small effect size, indicating minimal clinically important improvement. Finally, 39.4% of participants in the cannabis-based medications and 32.7% of participants in the placebo group reported pain relief of 30% or greater (NNTB = 11). The quality of evidence was determined to be moderate to low due to indirectness, imprecision, and inconsistency. They concluded that there is “no high-quality evidence for the efficacy of any cannabis-based medicine (herbal cannabis, plant-derived THC (dronabinol), synthetic THC (nabilone), and plant-derived THC/CBD combinations) in any condition with chronic NP”. Mücke et al. [21] stated that they performed a quantitative analysis, which included unpublished studies with negative results, while the authors of the studies with more favorable outcomes did not include the data of studies that are only available in databases; they also excluded studies with a very short duration. In addition, the same authors found that using cannabis-based medications for chronic NP showed moderate-quality evidence that more participants dropped out due to AEs with cannabis-based medications compared to placebo, and low-quality evidence that more participants reported any AEs and AEs of the central nervous system and psychiatric disorders with all cannabis-based medications pooled together than with placebo. This was also in accordance with another systematic review [96] that analyzed eight trials of cannabis-based medicine in chronic NP.

Another systematic review and meta-analysis that examined cannabis treatment for chronic pain [95] concluded that the current evidence might suggest that treatment of chronic pain with cannabinoid compounds may pose a greater risk than benefit to the patient because of the possible appearance of the pain as a secondary problem in the subject.

3. Overall completeness and applicability of evidence

Parallel RCTs or crossover placebo-controlled studies were identified from electronic databases including MEDLINE, Web of Science, EMBASE, and the Cochrane library limited to English language up to 2/1/2021. Cannabis-based medications included THC, THC/CBD, CBD, CBDV, CT-3, and dronabinol. The results of this systematic review apply to patients with chronic NP between ages 18–77. The trials were conducted in the USA, UK, Europe, and Israel, and may not reflect or apply to other countries.

These results are applicable to NP conditions including central NP (MS, brachial plexus avulsion), complex regional pain syndrome (CRPS) type II, HIV-related neuropathy, painful diabetic neuropathy, peripheral polyneuropathies of other etiologies, phantom limb pain, postherpetic neuralgia, postoperative or traumatic peripheral nerve lesions, spinal cord injuries, nerve plexus injuries, and trigeminal neuralgia (TN).

The applicability of the evidence to routine care is limited because some of the included studies excluded individuals with current or past alcohol and/or substance abuse, significant medical issues (cardiovascular disease, poorly controlled hypertension, active epilepsy), significant psychiatric illnesses, and those naïve to cannabis-derived products.

The reliability of the combined results is limited because of the small sample size, short duration, different types of interventions, routes of administration, doses and dose schedules, and the different types of NPs.

4. Heterogeneity of the review

This systematic review included only RCTs comparing cannabis-based medications with a placebo. There was heterogeneity in terms of the intervention (THC/CBD, CBD, CBDV, synthetic cannabis), for which the review authors conducted subgroup analyses. Review authors conducted subgroup analyses with similarly reported outcomes. Different types of cannabis were utilized in the included studies, with varied mechanisms of action, routes of administration, dosages, and schedule. The route of administration of cannabis varied from smoked, inhaled, vaping, spray, and oil. The minimum and maximum doses of THC were 1% and 9.4%, respectively. NP types varied from HIV distal sensory predominant polyneuropathy, CRPS II, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, focal nerve lesion, radiculopathy, multiple sclerosis, injury and disease of the spinal cord, nerve plexus injury, and postoperative or traumatic peripheral nerve lesions due to trauma. The diagnosis of NP was based on clinical symptoms and various tools depending on the diagnosis (see Results section).

5. Implications for research

This systematic review and meta-analyses demonstrated low to moderate quality of evidence due to high or unclear risk of bias, small number of studies, and limited duration. The quality of the evidence was low to moderate because of the unclear blinding of samples. Some studies received funding from drug companies, while others had co-interventions. However, a few studies have not completely reported the outcome data. In conclusion, a high overall risk of bias was assigned to six studies, and an unclear overall risk of bias was assigned to eight studies. The meta-analyses highlight the need for future high-quality double-blinded randomized, placebo-controlled studies receiving cannabis-based medications with intent-to-treat analyses and full reporting of outcome data as stated in published protocols without biases.

The present systematic review has several limitations that will be valuable for future studies. These limitations included the variability in the length of the studies evaluated, the short trial durations, small sample sizes, variability of route of administration, multiple doses, concomitant therapies, and lack of knowledge of possible drug-drug interactions or long-term effects.

The Committee for Medicinal Products for Human Use (CHMP) published guidelines on clinical medicinal products intended for the treatment of neuropathic pain [97]. These guidelines require that the study duration for chronic NP trials be at least 12 weeks after a stable dose is achieved to exclude a transient effect. Due to the increasing number of drugs approved for NP, they also recommend that a three-arm study (study drug – comparator–placebo) should be undertaken to assess the comparative efficacy and safety of a new product. Long-term clinical trials may also help to determine whether the effect of cannabis on chronic NP is sustainable.

The optimal dose and ratio of THC/CBD need to be determined for different types of NPs. Determining the optimal dose, treatment duration, and individual titrations would allow for a better balance between beneficial and adverse effects, especially in older vulnerable and young populations [98,99].

Medicinal cannabis is controversial and remains illegal and is unavailable in many states in the United States. There may also be a long-lasting stigma associated with smoking cannabis [100]. Some individuals may prefer not to take cannabis-based medications if the route of administration is inhaled due to social stigmas or if long-term adverse effects of smoked cannabis outweigh the benefits [99,101,102,103,104]. Determining the most beneficial route of administration and type of cannabinoid with these factors in mind would allow individuals with an interest in medicinal cannabis to select or decline this treatment option, especially if the reduction in pain intensity is modest. There may also be differences in efficacy, adverse effects, or abuse potential among the different types of cannabinoids and routes of administration.

The use of cannabis for other medical conditions should also be investigated in high-quality randomized placebo-controlled clinical trials. Clinical evidence will help with appropriate prescribing, prevent misuse and harm, and possibly reduce the use of opioids and their associated risks [105,106].

One study [63] in this review required that participants have experience using cannabis-containing products, while another excluded patients with prior experience [54]. Future studies should include individuals who have not used cannabis-based medications and those that used them to study the efficacy, safety, and tolerability of all types of patients. Future studies should also explore other cannabis-based agents that may be useful in reducing pain, such as CT-3.

The types of NP varied greatly in this systematic review with meta-analysis due to a lack of RCTs on cannabis-based medications in the treatment of any specific type of NP. Future research on the efficacy of cannabis-based medications should focus on the specific causes of NP because the mechanisms are different.

The protocol of this systematic review was registered with PROSPERO #CRD42021234766. Drs. Sainsbury, Bloxham, Pour, Padilla, and Enciso contributed to the conceptualization and methodology. Drs. Sainsbury, Bloxham, and Pour conducted data extraction with Dr. Enciso for validation. Dr. Enciso conducted an electronic search and formal analysis. Drs. Sainsbury, Bloxham, Pour, Padilla, and Enciso wrote the original draft and participated in the writing (review and editing) of the final manuscript.