Fibromyalgia is serious chronic pain condition which is often accompanied by sleep disturbances, fatigue and disability and reduced quality of life. There is no cure and treatments are based on reliving symptoms and maintaining function. The currently available medical treatments are not helping many patients, and many get side-effects. Medical cannabis is sought after among patients and many use this medication un-licenced, although it is not properly documented if it works or is safe. Therefore, it is necessary to investigate the effects and safety of medical cannabis in a properly designed randomized trial. The aim of the study is to investigate if cannabidiol (CBD) can improve pain, sleep, function and quality of life in patients with fibromyalgia. The study will include 200 patients, who will receive either cannabidiol or placebo over a period of 24 weeks. Participants will be closely looked after for improvements in their condition and for potential side-effects to ensure safety.

BACKGROUND: Fibromyalgia is a serious chronic pain condition affecting 2-5 % of the background population. The disease burden in most affected individuals is substantial; with widespread musculoskeletal pain, high pain intensity, often accompanied by sleep disturbances, fatigue, cognitive dysfunction, and emotional distress. Fibromyalgia is associated with disability and muscle fatigue, affecting daily life activities, leading to poor social participation and incapacity for normal employment. Studies have shown that many patients, are not satisfied with the treatments offered, and rate their health and quality of life after treatment as poor.

There is currently is no cure for fibromyalgia, and management aiming at symptom reduction and maintenance of optimal functioning is recommended by clinical guidelines, including both non-pharmacological and pharmacological treatment strategies. Recommendations for the pharmacological treatment of fibromyalgia propose antidepressants and anticonvulsants, which target central pain processing mechanisms. These treatments have been tested in controlled trials for their efficacy in patients with fibromyalgia, and meta-analyses on these interventions have revealed that overall effect sizes are modest, as only a minority of patients have substantial benefit (patient reported pain relief of 50% or greater), while more have moderate benefit (patient reported pain relief of 30% or greater). Many patients have no or minimal benefit or will discontinue the treatment due to side effects. However, it appears that even moderate reductions in pain may lead to considerable increase in self-reported quality of life and other outcome domains in this specific patient population.

Medical cannabis is popularly advocated for different health conditions including chronic pain, both among politicians and in the general population in Denmark, although evidence is sparse efficacy and on what types of medical cannabis to use and what dosages to prescribe for the different conditions. In addition, safety issues such as adverse events and serious adverse events is not properly assesed. Physicians are reluctant to prescribe medical cannabis to their patients, and many patients living with chronic pain are known to self-administer unlicensed medical cannabis. The extent of actual cannabis use is unknown, although, one study has documented that 13% of patients with fibromyalgia use cannabis regularly with a more extensive use among male patients compared to females. Numbers from a Danish context show that only 17 out of 286 (6%), patients with fibromyalgia participating in a multidisciplinary rehabilitation program in Bispebjerg and Frederiksberg hospital during 2018, stated that they were using self-administrated cannabis on a regular basis (unpublished data). As self-administrated off-label use of cannabis is illegal in Denmark, this number may well be underreported. Still, individuals diagnosed with fibromyalgia who do admit to cannabis use, are sharing stories with health professionals about how unlicensed cannabis has improved their coping with everyday life, functional ability, pain, sleep, fatigue, mood and overall health related quality of life. Such compelling stories cannot be ignored and underline the necessity of exploring the efficacy of medical cannabis in a proper research design (i.e. with good internal validity).

The use of the cannabis plant for medical purposes is limited in Europe and the European addiction societies stresses the need for further studies on the efficacy and possible dangers regarding medical cannabis intake. Regulations are lacking on registration and medical indications, and the development of uniform compounds regarding strength and types of products and rules concerning sales and marketing.

In Denmark, production and distribution of medical cannabis is illegal. However, starting from January 1st, 2018, a four-year pilot scheme has been legalized and approved by the Danish Medicines Agency, allowing for medical cannabis in the treatment of conditions such as multiple sclerosis, spinal injuries and nausea after chemotherapy and neuropathic pain. Although patients suffering from fibromyalgia have few treatment options for management of their disabling condition, this group is not included in the pilot scheme. However, it is legal for physicians to prescribe cannabis for this and other patient groups.

Medical cannabis Medical cannabis is the term for medications derived from dried cannabis plants in the form of capsules, pills or extracts/oils. The top shoot of the plant contains 100 cannabinoids that are divided into two subgroups; Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), affecting the cannabinoid type 1 receptors located in the central nervous system, and the cannabinoid type 2 receptors located outside of the central nervous system. While the THC cannabinoids have psychoactive, appetite stimulating and nausea reducing effects, cannabidiol has anti-inflammatory, anti-convulsive and immune modulating effects. Studies are inconclusive regarding the effect of cannabidiol on appetite and food intake. Cannabinoids are known to be highly lipophilic and to accumulate in fatty tissue, and may influence the metabolism, fat distribution and accumulation in users. It has been implicated that both TCH and CBD have pain reducing effects. CBD is confirmed to have a favorable safety profile compared to THC.

The US Food and Drug Administration (FDA), has approved Epydiolex® as the first prescription cannabis drug derived from the cannabis plant, for treating rare and severe forms of epilepsy. Synthetically manufactured cannabis such as dronabinol (USA) and nabilone (USA and UK), have been approved earlier in the treatment of nausea after chemotherapy. The only synthetic cannabis based approved drug in Denmark is Sativex® for the treatment of multiple sclerosis. However, none of the cannabis drugs are currently approved for the treatment of chronic pain conditions.

Evidence is sparse on medical cannabis in the treatment of fibromyalgia. In a Cochrane review on herbal cannabis (hashish, marihuana), plant-based and synthetic cannabinoids for fibromyalgia, only two out of four identified studies on the topic were included, due to small sample sizes, short-term duration and poor reporting of the other studies. The two studies were both on synthetic cannabinoid (nabilone). No high-quality studies on plant-based cannabis could be identified. Evidence for efficacy was inconsistent as one study favored nabilone on pain and quality of life, compared to placebo, and the other study favored nabilone on sleep compared to Amitriptyline (anti-depressant). However, the quality of the studies was low, and tolerability was low due to side effects.

Recent systematic reviews, have investigated the existing evidence on the effectiveness of cannabinoids for chronic non-cancer pain, including fibromyalgia. No impact on physical and emotional functioning has been found, and only low-quality evidence found improved sleep and patient global impression of change. Thus, it was concluded to be unlikely that cannabinoids are effective in the treatment of non-cancer pain, as findings were inconsistent. Survey studies, however, have showed favorable effect on fibromyalgia symptoms and health-related quality of life, and improved pain management and sleep, among users of unlicensed cannabis compared to non-users, although no information on type and dosages of cannabis was given in the surveys. Negative patients' perspectives themes such as the high cost, the negative effects of cannabis and the "views of others", including their health care professionals, were also identified. A recent retrospective study showed significantly favorable outcomes on fibromyalgia symptoms among medical cannabis users, and only mild adverse events. However, the retrospective design, the relatively small sample size and short duration reduced the quality of the study.

Based on the high demand and an increasing popularity of medical cannabis - which is currently used unlicensed among many patients with fibromyalgia, despite the lack of high-quality evidence on efficacy and safety, a well-designed randomized trial with a large sample size and clinically relevant duration is warranted.

OBJECTIVES: The aim of this trial is to assess the efficacy and safety of cannabidiol use compared to placebo, and to evaluate the safety and tolerability of cannabidiol compared to placebo in patients with fibromyalgia over 24 weeks.

HYPOTHESES: The primary hypothesis of the study is that pain intensity will be significantly reduced in participants receiving cannabidiol compared to those receiving identically appearing placebo after 24 weeks.

Secondary hypotheses are that sleep quality and duration, activities of daily living and quality of life, will be improved in participants receiving cannabidiol compared to those receiving placebo after 24 weeks. It is also hypothesized that participants receiving cannabidiol will improve on several supportive exploratory secondary outcomes (see outcome measures section), and that a higher proportion of those receiving cannabidiol will have a substantial benefit (50 % pain reduction) and a moderate benefit (30 % pain reduction).

STUDY DESIGN: The trial is designed as a single-center, randomized, placebo-controlled, double blind and parallel-group trial.; the trial contains three periods: A pre-randomization screening period (week -8 to 0), a main trial period (week 0 to 24), and a post interventional observation period (week 24 to 36). The trial is designed to determine the efficacy and safety of cannabidiol use for patients with fibromyalgia.

The trial is scheduled to start inclusion of first patient first visit, February 2021 or as soon as possible thereafter, and the study period will go on for two year and end with the last patient last visit in December 2022.

Eligible participants, who are included at screening, will be randomized in a 1:1 manner to receive either cannabidiol 50 mg or placebo. Allocation will also be stratified based on sex (male vs. female), age and pain intensity (over vs. under 7 on the Fibromyalgia Impact Questionnaire Revised version (FIQ-R) pain numeric rating scale, to ensure that the groups are equal. A computer-generated randomization sequence will create subject identification numbers and allocate the subjects to treatment arms. The randomization sequence will be created by an independent biostatistician using a random number generator (SAS Proc Plan), and subsequently entered in the electronic Case Report Form (e-CRF), that will be developed specifically for the study, by an independent data manager. If unblinding of a participant is required due to an adverse event, the primary investigator can request to break the randomization code for the individual patient, via the independent data manager. The unblinding will always be performed at patient level and unblinding can take place any time during the day (24/7). Randomization and concealed allocation are done electronically in the e-CRF at the randomization visit (week 0).

The study will be conducted at the Parker Institute, Bispebjerg and Frederiksberg Hospital, University of Copenhagen. The Parker Institute is a well-established research institute and clinical department with secretariat, data managers and Good Clinical Practice (GCP) trained health care professionals including physicians and study nurses. Monitoring will be conducted from the initiation and throughout the trial by the GCP-unit at Bispebjerg and Frederiksberg hospital, in accordance with the GCP rules and regulations.

The trial will end when the last patient has completed the last visit as well as the 12-week post interventional observation period, or prematurely discontinued the intervention or withdrawn from the trial, which comes last.

Inclusion Criteria:

• Informed consent obtained
• Clinical diagnosis of fibromyalgia according to the American College of Rheumatology (ACR) 1990 criteria
• Average pain intensity ≥ 4 on a Numeric Rating Scale
• No use of medical cannabis (THC/CBD) within the last six months
• Proficiency in spoken Danish language and able to read and write in Danish

Exclusion Criteria:

• On-going participation in other medical trials for pain management of fibromyalgia
• Diagnosis of Rheumatoid Arthritis or other inflammatory diseases
• Diagnosis of other serious chronic diseases
• Impaired liver and kidney function
• Pregnancy or insufficient anti-conception therapy for fertile female participants
• Planning pregnancy or insufficient anti-conception use in fertile female partners of male participants
• Breast feeding
• Surgery scheduled for the trial period or within 3 months prior to enrollment
• History of or current diagnosis of cancer
• History of or current epilepsy and seizures
• History of or major depressive disorder
• History of a suicide attempt or any suicidal behavior
• A mental state that may impede compliance with the program
• History of severe psychiatric disorders
• History of or current cannabis abuse
• History of or current drug abuse
• History of or current alcohol abuse
• Severe personality disorder
• Current use of opioids, opioid antagonists (LDN) or similar strong analgesics
• Allergic reactions to the active ingredients in cannabidiol

The project medication is manufactured specifically for research purposes, and the cannabidiol and cannabidiol placebo pills are identical in appearance, taste, and smell. The cannabidiol and placebo tablet packages are labelled with a unique Dispensing Unit Number (DUN). It is concealed to all involved parties (the participant, care provider, investigator qand outcomes assessor), but the database manager, wether the DUN can be identified as cannabidiol package or a placebo package.