Fibromyalgia is a common cause of chronic musculoskeletal pain, with an estimated prevalence of 2 percent to 8 percent in the United States. There is heightened suspicion with the presence of unexplained diffuse pain, fatigue, and sleep disruptions lasting greater than three months. However, diagnosis of fibromyalgia is complicated by variability in accepted diagnostic criteria, symptom overlap with other musculoskeletal pain generators, and the absence of confirmatory tests. Typical treatment regimens include combinations of pharmacological interventions with patient education, cognitive behavioral therapy, and exercise.

Cannabinoids are chemical compounds that act on receptors in the endocannabinoid system. They have emerged as a popular option among the public for pain relief in a variety of musculoskeletal conditions, including fibromyalgia. In a survey of fibromyalgia patients from the United Kingdom, 77 percent reported use of cannabis-based products and 52 percent reported daily medicinal use. Preclinical evidence suggests a role for endocannabinoids in bone mass regulation and mesenchymal stem cell differentiation, and one pathophysiological theory implicates endocannabinoid deficiencies in the fibromyalgia disease process.

Cannabinoids may originate from the body, plants of the Cannabis genus, or a laboratory. The endocannabinoid system regulates metabolic and immune homeostasis in multiple organ systems. Relevant endogenous compounds include anandamide and 2-arachidonoylglycerol, but much attention has been directed at the therapeutic potential of two exogenous cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is a psychoactive compound preferentially binding CB1 receptors, which are concentrated in the central nervous system in areas that regulate appetite, nausea, pain, and memory. CBD has been proposed to have antiepileptic, antiemetic, and anti-inflammatory effects via CB2 receptors found on peripheral immune cells.

Generally, clinical studies on cannabinoids in musculoskeletal conditions have been inconclusive. For clinicians, understanding the clinical evidence for use of these products in fibromyalgia is critical to shared decision-making. The favorable safety profile of Food and Drug Administration (FDA)-approved CBD formulations has contributed to the rise in their use. Clinicians should be aware that products purchased commercially may not contain advertised cannabinoid concentrations and should advise patients on choosing high-quality products. See sidebar for a checklist to guide selection of a commercial CBD product.

Regulatory status

In the United States, regulatory restrictions on cannabinoid products vary by location. In all but three states, CBD and hemp oils containing a THC concentration of less than 0.3 percent are legal for consumers. Although the legal status of recreational or medicinal use of products exceeding 0.3 percent THC varies at the state level, high-THC products remain classified as schedule 1 substances at the federal level. Four cannabinoid drugs have received FDA approval for indications other than musculoskeletal conditions, such as seizures associated with Lennox-Gastaut syndrome and anorexia in AIDS patients.

Clinical studies in fibromyalgia

CBD-based products 

Only one study has evaluated the use of low-THC, high-CBD products in fibromyalgia. The small, single-center, double-blind, randomized, controlled trial (RCT) of 20 fibromyalgia patients found no analgesic benefit with Bedrolite® in the three hours following administration. The three most frequent adverse events (AEs) were coughing, drug high, and bad taste.

THC-based products

There are conflicting results in clinical studies of high-THC products. A 2016 Cochrane review of two RCTs concluded that no high-quality evidence was available for use of nabilone, a synthetic THC analog, in fibromyalgia. More participants dropped out of the trials due to AEs in the nabilone groups relative to the control groups. A subsequent RCT found no statistically significant difference in short-term pain reduction with high-THC, low-CBD or high-THC, high-CBD formulations relative to placebo.

However, there has been evidence of therapeutic benefit in observational studies. Giorgi et al., found that in 102 fibromyalgia patients with persistent symptoms after a standard analgesic regimen, the prescription of Bedrocan (22 percent THC, < 1 percent CBD) and Bediol® (6.3 percent THC, 8 percent CBD) resulted in 33 percent of patients experiencing significant improvement in Fibromyalgia Impact Questionnaire scores at six-month follow-up. In a cross-sectional comparative study of 28 users of high-THC products and 28 nonusers, Fiz et al., reported significant improvements in visual analog scale scores for pain, stiffness, relaxation, somnolence, and well-being two hours after administration. However, at least one AE was recorded in 96 percent of patients. Habib and Artul’s single-center study of 30 Israeli patients with fibromyalgia found significant improvements in Fibromyalgia Impact Questionnaire scores at median three-month follow-up among licensed medical cannabis users.

Conclusion

The popularity of cannabinoid products is growing, but the clinical evidence for use in musculoskeletal conditions is sparse and inconclusive. At this time, cannabinoids should not be considered as first-line treatment for fibromyalgia or any other musculoskeletal pain condition. However, patients may be interested in trying cannabinoid products, especially after failure of established pharmacological modalities. Upon considering local regulatory policies, clinicians open to nonintoxicating CBD products should counsel patients on relevant AEs and selection of reliable manufacturers.

Dominic Carreira, MD, FAAOS, is a hip, foot, and ankle specialist at Peachtree Orthopedics in Atlanta. He is founder and president of the Multicenter Arthroscopic Study of the Hip and the Multicenter Arthroscopic Study of the Ankle and Foot.

Thomas Ueland, BS, is a student and research coordinator at Peachtree Orthopedics in Atlanta.

References 

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8. Food and Drug Administration: FDA Regulation of Cannabis and Cannabis-derived Products, Including Cannabidiol (CBD). Available at: www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. Accessed May 27, 2020.
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10. Food and Drug Administration: FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy. Available at: www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms. Accessed May 27, 2020.
11. Food and Drug Administration: Warning Letters and Test Results for Cannabidiol-related Products. Available at: www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products. Accessed May 27, 2020.
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Checklist for finding a high-quality cannabidiol or hemp oil product

• Does it meet the following quality standards?
  • Current Good Manufacturing Practices certification from the Food and Drug Administration
  • European Union, Australian, or Canadian organic certification
  • National Science Foundation International certification
• Does the company have an independent program for reporting adverse events?
• Is the product certified organic or ecofarmed?
• Has the product been laboratory tested by batch to confirm
  tetrahydrocannabinol level < 0.3 percent and to confirm that it contains no pesticides or heavy metals?

REPRODUCED FROM VANDOLAH HJ, BAUER BA, MAUCK KF: CLINICIANS’ GUIDE TO CANNABIDIOL AND HEMP OILS. MAYO CLIN PROC 2019;94:1840-51, UNDER CREATIVE COMMONS CC-BY-NC-ND LICENSE