Is a Low Dosage of Medical Cannabis Effective for Treating Pain Related to Fibromyalgia? A Pilot Study and Systematic Review

1. Introduction

Fibromyalgia (FM) is a term introduced in the early 1970s denoting a multifaceted and challenging clinical condition that transcends conventional medical classifications. FM definition has been revised significantly over the years, reflecting the evolving understanding of the condition. Initially considered mainly as a rheumatic disorder, it is now acknowledged as a pain processing disorder and sensitization of the central nervous system [1]. FM is, indeed, one of the most common causes of persistent chronic widespread pain (CWP). However, although pain is its main feature, it is represented by a complex polysymptomatology comprising fatigue, sleep disturbances, generalized hyperalgesia, stiffness, palpation-specific tender points, and cognitive and somatic dysfunction [2]. Pain might be initially generalized or localized in a specific body region, such as the neck or lower back. Fatigue is chronic in FM patients and is frequently referred to as moderate to severe, while cognitive problems are informally reported as part of the “fibro fog” and consist of compromised memory, attention, and concentration [3]. Due to FM’s multifaceted and complex nature, it poses a significant diagnostic challenge for doctors. For this reason, an FM diagnosis takes about two years, and patients usually have to see several medical specialists during this time [4]. Failure to diagnose FM in the past was exacerbated by the medical community’s skepticism, considering it as a psychosomatic disorder. This skepticism has hindered the recognition and understanding of FM due to the lack of objective diagnostic criteria and markers. However, as studies progressed, an expanding body of evidence illuminated the intricate interplay of psychological, biological, and social factors influencing the syndrome outbreak [1]. Nowadays, several diagnostic criteria have been developed, but those approved by the American College of Rheumatology (ACR) and first introduced in 1990 are normally used. Following the ACR, for the FM diagnosis, pain must be triggered by exerting pressure (tender points) up to 4 kg/cm² in at least 11 of the 18 specified body points, and patients must have a multisite or widespread pain lasting more than 3 months [4]. In this context, widespread pain was labeled as right- and left-side pain, axial pain, and lower- and upper-segment pain [5]. However, the ACR classification criteria did not consider symptoms recently related to FM, such as cognitive problems and somatic symptoms. For this reason, in 2010, two variables best defined FM and its symptom aspect were identified: the widespread pain index (WPI) and the symptom severity (SS) scale. The WPI is strongly related to nineteen tender points (Figure 1), while the SS scale evaluates fatigue grade, unrefreshed sleep, and physician-rated cognitive symptoms (Table 1).

These two criteria were combined to define a new FM case definition: WPI ≥ 7 and SS ≥ 7 or WPI 3–6 and SS ≥ 9 [5].

For FM, a multidisciplinary intervention is advocated since pharmacological treatments are generally combined with approaches involving psychotherapy, patient education, physiotherapy, and pharmacological treatments [2,6]. The commonly prescribed drugs are antidepressants, anticonvulsants, muscle relaxants, analgesics, hypnotics, and antipsychotics [6,7]. Table 2 lists the main drugs used to treat FM [8,9].

However, many of these drugs offer few benefits and are frequently associated with side effects that may reduce patient compliance [10]. In the last year, particular attention was paid to the use of natural products in clinical practice [11,12,13]; specifically, cannabinoid-containing products were investigated in clinical settings due to their anti-inflammatory and immunomodulatory activity, making them useful for managing pain-associated symptoms [14]. The current literature has indeed demonstrated that medicinal cannabis (Cannabis sativa L.) can be associated with an improved quality of life for patients suffering from chronic pain [15]. Two different types of cannabinoid-containing products exist on the market: isolated compounds [delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)] and plant-based (cannabis) products. In the present 6-month pilot study, the effect of a plant-based formulation (cannabis: Bedrocan^®, 22% THC, <1% CBD) has been studied on a sample of 30 adult patients with FM resistant to opioid therapy. The choice of testing a plant-based formulation, and not an isolated compound, was made considering that cannabis, besides THC and CBD, contains other cannabinoid and non-cannabinoid molecules like terpenes that can synergically contribute to reducing pain [16,17]. In fact, for the so-called “entourage effect”, terpenes interact with cannabinoids, improving their pharmacodynamic effects by increasing cannabinoids’ charge binding to their receptors and pulmonary uptake [18]. Further, terpenes have their own effects, like analgesic, anti-inflammatory, and antidepressant effects [19]. Therefore, this study aims to evaluate the effectiveness of cannabis (Bedrocan^®) therapy in fibromyalgia patients by analyzing their quality of life, as measured by the SF-12 short-form health questionnaire and by measuring pain intensity with the Numerical Pain Rating Scale (NRS). In addition, to place this study in the context of the existing evidence base, a systematic review of all clinical studies investigating the use of cannabis to reduce FM was also undertaken.

2. Materials and Methods

3. Results

4. Discussion

In this study, the efficacy of MC in FM patients was evaluated, obtaining results that suggest a possible implication of MC as an alternative treatment for patients with FM not responsive to conventional pharmacological therapy. As in other studies [29,30,31,32,36], in the current pilot study, most of the patients were women since they represent 89.3% of the patients. Considering that, as previously stated, the male-to-female ratio with FM syndrome is 1:3 [39], the current investigation confirmed that FM patients with clinical pain are women. Noteworthy is the NRS at baseline since patients with a pain score comprised between 8 and 10, representing the maximum level of pain, were 24 (80% of subjects). This basal pain score is higher than that registered in other clinical trials investigating the effect of a synthetic derivative of Δ-9-THC, nabilone [40,41], while it is in line with that registered by Mazza et al. and Sagy et al. [32,36]. As in the last clinical study [32], the current one revealed a significant reduction in NRS from a median of 8 (95% CI 7.66–8.54) at a baseline to a median of 4 (95% CI 3.28–4.79) after 6 months (p-value < 0.001; t-test). Hence, there was a reduction in pain score in the 6th-month follow-up of 4 points, comparable to the pain decrease that was assessed by Mazza et al. in the 12th month (4.3 points) [36]. An improvement in pain symptoms was also assessed in two observational studies [30,34] and two randomized, double-blind, placebo-controlled clinical trials [33,35]. Even if the data obtained in these investigations are not comparable with those of the current one since another evaluation parameter was used, the Fibromyalgia Impact Questionnaire (FIQ) and the pressure pain test. Finally, a reduction in pain evaluated with the VAS score was detected in an observational cross-sectional survey investigating the short-term effect of cannabis inhalation, while only a low analgesic effect was detected [29]. In the complex, these results may indicate a potential application of cannabis in reducing pain. In the current pilot study, the improvement of pain symptoms was corroborated by the data from the SF-12 consisting of 12 items (taken from the 36 items of the original SF-36 questionnaire) that produce two measures relating to two different aspects of health: physical health (PCS-12) and mental health (MCS-12). In the current trial, the PCS-12 was significantly improved from the baseline to the 6th month for 96.67% of FM subjects [mean (M) = 28.21 ± 8.72 to 47.62 ± 9.81 for baseline and 6th-month evaluation, respectively, p-value < 0.001; t-test]. In the same way, the MCS-12 increase significantly for 83.33% of FM patients (M = 38.56 ± 12.41 to 56.09 ± 7.28 for baseline and 6th-month evaluation, respectively, p-value < 0.001; t-test). These results are indicative of an improvement in the quality of life and are in line with those of previous clinical trials since an increase in mental score was also seen when it was evaluated with the SF-36 [29]. SF-36 is the SF-12 extended version and has been demonstrated to be complementary to the SF-12, confirming the comparable nature of results obtained from the SF-36 and SF-12 questionnaire [42]. Enhanced mental health was further evidenced in another survey, where 85% and 62% of FM patients ameliorated depressive and anxious states after cannabis assumption [31]. Contrarily, no differences in mental mood were observed when two synthetic Δ-9-THC derivatives, nabilone and amitriptyline, were administered [43]. Improved quality of life was also seen in two more observational studies when it was evaluated with the Likert scale regarding appetite, sleep quality, and sexual activity [15,32]. Thus, based on these results, it is possible to assert the potential therapeutic effect of cannabis for the treatment of FM. This assumption was further supported by the demonstrated safety of MC taken as decoction since only 6.25% of subject reported psychomotor agitation, while no other side effects were reported.

One strength of the current Pilot Study was the evaluation of the cannabis effect in a controlled hospital setting by using only a type of administration mood and not a combination of administration mood (e.g., decoction and oil or smoke) to reduce the risk of bias. Furthermore, it was demonstrated that decoction is patients’ preferred cannabis mode of assumption since it is easy to prepare and has a good safety profile, thus avoiding accidental overdoses of THC and the consequent psychotropic effect [44]. Another strength was the low dosage of 100 mg (1 sachet) per day, which was increased to 200 mg (2 sachets) per day for only two patients (7.14%) who were not responsive to the low dosage. This administered cannabis amount, corresponding approximately to 3.0 g per month, was definitively lower than that used in other investigations (about 31.4 ± 16.3 g per month) [30,31,32,36]. Finally, in the present clinical study, before starting MC therapy, all patients stopped the assumption of conventional drugs, while in all other studies, the pharmacological therapy was continued during the evaluation of MC efficacy [30,32,34,35]. This may suggest that MC can represent a suitable and efficacious alternative to conventional drugs. However, due to the small number of FM patients investigated, the risk of bias is high, and the results obtained should be interpreted carefully. It is also important to take into consideration the limitations of this study since the use of self-administered questionnaires may represent a source of bias. Furthermore, the absence of a control group in the present investigation can represent an additional limitation. Hence, further randomized placebo control clinical trials with a higher number of participants should be needed to better assess the role of MC, administered as a decoction, in FM symptom reduction.

5. Conclusions

FM is one of the most common causes of persistent chronic and widespread pain. However, although pain is its main feature, it is represented by a complex polysymptomatology comprising fatigue, sleep disturbances, generalized hyperalgesia, stiffness, palpation-specific tender points, and cognitive and somatic dysfunction. The current pilot study evidenced a positive effect of a low dosage of MC (Bedrocan^®; 100 mg/day) in treating FM symptomatology. Likewise, data from the literature demonstrated that cannabis administration could be associated with an improved quality of life for patients suffering from chronic pain. Hence, it is possible to conclude that cannabinoids may represent an effective alternative to conventional pharmacological therapy for reducing pain and mind disorders in FM subjects. Further investigations like randomized, placebo-controlled clinical trials are needed to corroborate these findings.

Author Contributions

Conceptualization, methodology, software, validation, formal analysis, investigation, data curation, A.G., R.P., C.A., M.C., A.D.F., L.M. and M.P.; visualization, supervision, writing—original draft preparation, L.M. and M.P.; writing—review and editing, M.P., V.C. and N.B.; project administration, A.G. and L.M.; funding acquisition, L.M. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional After the San Carlo Hospital ethics committee’s (n. of CEUR general register 37/2023, n. protocol of the Potenza’s AOR San Carlo referring to application for approval 20230021536, protocol date 11 May 2023).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This research was partly funded by the project “VALBIOECONOMIA: valorizzazione di biomasse vegetali per un’economia circolare a scarto zero” PO FESR 2014–2020—Azione 1B.1.2.2 prov. 15/2019/0214 CUP: G49J19001420004. Project “SPIA—Valorization of by-products from the agro-food chain” CUP: G49J19001350004; and DGR n. 527/2019 “PO FESR BASILICATA 2014–2020—Axis I—Research, Innovation Action and Technological Development—Action 1B.1.2.1”.