Cannabidiol for Fibromyalgia (The CANNFIB Trial) (CANNFIB)
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.
What Every Person With Arthritis Needs to Know About Cannabis
“I actually don't remember what it was like not to be in pain,” says Bridget Seritt, who has dealt with chronic illness since she was a small girl. “I have both types of arthritis—rheumatoid and osteoarthritis. I have Sjogren's syndrome. I have lupus, and I have Ehlers-Danlos syndrome, which is a genetic collagen disorder that affects all of my joints, ligaments, and tendons.”
When she lived in Georgia, her treatment centered on methotrexate, a drug used to slow down the progression of rheumatoid arthritis.
Unfortunately, Seritt experienced all three of the drug’s most common side effects—nausea, stomach upset, and fatigue—and, for a time, she used black-market cannabis to alleviate those symptoms. (Georgia didn’t have a medical-marijuana program at the time.) Seritt moved to Colorado in 2013, still taking “a handful of opiates and a whole bunch of prescription medications,” and quickly realized that, as a chronic-pain patient requiring high doses, the growing war on opioids might affect her options for relief sooner rather than later.
It didn’t take long: Her new pharmacy wasn’t always able to fill her full oxymorphone prescription on time. “I was consistently running out,” she says, which led to muscle spasms. Since cannabis was legal in Colorado, “I decided to see if it would help with pain and withdrawal. I smoked a couple of joints, but it didn’t do anything except help my insomnia.” That was good enough, and eventually she replaced smoking pot with making her own cannabis butter and topicals.
It wasn’t until about three months later that Seritt noticed another change: “I could walk better. I could be active for longer periods of time, and I didn't need as long to recover.” Between 2014 and 2015, she went from being able to walk just 200 feet to hiking several miles. She credits medical cannabis.
Which States Allow Medical Marijuana for Arthritis?
If Seritt still lived in Georgia, she wouldn’t have achieved this level of relief without breaking the law. Currently, the state allows only cannabis oil with less than 5% THC—the chemical that causes most of pot’s psychoactive effects. In Colorado, however, some form of medical marijuana has been legal since 2000, and patients aren’t limited to low-THC oils. Instead, patients like Seritt have access to a seemingly endless variety of cannabis products with a wide range of potency, along with professional staff equipped to answer medical questions. Colorado also allows home cultivation of up to six plants per patient, so they can grow the specific strains they need to get results.
Though medical marijuana programs exist in 33 states and Washington, D.C., cannabis is still illegal in the eyes of the federal government. As a Schedule I drug according to the Controlled Substances Act (CSA), it’s considered a dangerous substance with "no currently accepted medical use." That means that doctors and patients complying with state laws still operate as federal outlaws, risking fines, arrest, even prison time.
Several bills in congress aim to erase cannabis from the CSA. Among them, Oregon Sen. Ron Wyden’s cleverly-titled S.420 Marijuana Revenue and Regulation Act; Hawaii Rep. Tulsi Gabbard’s March reintroduction of the Ending Federal Marijuana Prohibition Act; New Jersey Sen. Cory Booker’s Marijuana Justice Act; and New York Sen. Charles Schumer’s Marijuana Freedom and Opportunity Act. Passing any of these bills would allow millions of Americans with arthritis to legally benefit from the plant’s therapeutic properties.
How Does Medical Marijuana Relieve Arthritis Pain?
Traditional arthritis treatments are rife with potentially dangerous side effects. Cases in point: Tylenol and non-steroidal anti-inflammatory drugs, or NSAIDs, can exacerbate liver and bleeding issues. Excessive doses of Tylenol can cause liver toxicity and high dose anti-inflammatory drugs, such as NSAIDs, can cause gastrointestinal bleeding and kidney problems. Disease-modifying anti-rheumatic drugs (DMARDs) and biologics can interfere with the immune system's ability to fight infection. And, if those categories don’t work, patients are left with opioids, which can become habit-forming.
“If you put the opioids head-to-head with cannabis for mild to moderate pain, what we find is that they're about equal,” says Jordan Tishler, M.D., a Boston cannabis physician at Inhale MD, Harvard instructor of medicine, and president of the Association of Cannabis Specialists. “In that situation, cannabis may be equally effective, but it's a lot safer.”
Scientific evidence confirming Dr. Tishler’s experience continues to grow, showing cannabis to be “remarkably helpful as a pain medication, interacting with receptors in multiple locations throughout the body,” he says. It also impacts pain processing in the spinal cord and brain. Preclinical data suggest that cannabinoids have particular therapeutic potential for rheumatic diseases like rheumatoid arthritis and osteoarthritis (plus systemic sclerosis and fibromyalgia, too).
Here’s how it works: Cannabis contains dozens of cannabinoids, chemicals that interact with our body’s own endocannabinoid system, which regulates inflammation and pain. THC is the most well-known (it’s what gets you high) and CBD is another. “The THC in cannabis is the primary pain reliever, so what I do as a doctor is find the smallest dose of the THC or cannabis that will do the job with the minimum side effects,” Dr. Tishler says. The most common side effect, unsurprisingly, is getting stoned. “All pain medications have side effects and cannabis is no different,” he says.
Like any other clinician, Dr. Tishler helps arthritis patients manage side effects through dosing, timing, and route of delivery. For example, for chronic pain, he might recommend an edible with 5 mg THC twice a day for long-lasting coverage, and a vaporizer for acute relief on an as-needed basis.
“One cannabinoid called THC-A—which is different from THC—is a better anti-inflammatory than THC or CBD,” he says. “When I treat somebody with an autoimmune disease like rheumatoid arthritis, I often try to add THC-A to the THC so that we're covering the underlying inflammation as well as deriving pain control.” Dr. Tishler supplements THC-A through an extract; Seritt gets her dose of THC-A and THC from a paste made from fresh plants that she grows herself.
Watch Our Interview with Dr. Tishler.
Why Do Medical Marijuana Programs Matter?
When it comes to CBD for arthritis, Dr. Tishler is unconvinced that the extract is particularly useful for pain at the available doses. (The most compelling research so far has been in rodents, not humans.)
“There's also the issue of how harmful hemp-derived CBD oils may be. Not because of the CBD, but because of whatever else might be in that bottle,” says Dr. Tishler, who cites traces of everything from pesticides and heavy metals to fentanyl, an anesthetic pharmaceutical.
The 2018 Farm Bill loosened regulations on hemp-derived CBD by removing hemp products from the list of Schedule 1 drugs. There’s only one CBD drug that’s been approved by the U.S. Food and Drug Administration (FDA) — Epidiolex for severe epilepsy — and the FDA doesn’t regulate supplements, so scams are rampant. Recent research from Penn Medicine revealed that 70% of CBD products available online mislabeled their CBD content. These are precisely the types of shenanigans medical marijuana laws are meant to prevent, and why medical programs are important, even for states with legal recreational cannabis.
“Medical patients are not the same as recreational cannabis users,” says Dr. Tishler. An arthritis patient wants medicine that’s easy to take, precisely dosed, and provides reliable results with the least intoxication. (Not exactly a recreational user’s idea of a party.)
Having a medical system in place allows physicians to follow up on what patients are purchasing through the registry system. Medical dispensaries and dual-licensed shops are best equipped to answer patient questions about how to dose cannabis or what contraindications there might be.
“It’s completely inappropriate to have this type of advice coming out of the mouth of a budtender,” says Dr. Tishler.
There are other advantages to medical-marijuana programs. In states like Colorado, patients pay standard sales tax on cannabis, but not high excise taxes or additional state taxes applied to recreational cannabis sales. Minors with qualifying conditions can also register as medical marijuana patients, which isn’t addressed by the recreational model.
Advocating for Access
There are many reasons to keep an eye on upcoming cannabis bills, both federal and in your specific state. Even putting the overarching problem of federal prohibition aside, the state laws are a messy patchwork of contradicting rules. For example, cannabis is straight-up illegal—for any reason—in Idaho, Kansas, Nebraska, and South Dakota. There are 33 states offering medical marijuana, but only seven list arthritis as a qualifying condition (Arkansas, California, Connecticut, Hawaii, Illinois, New Mexico, and New York).
Some states allow physicians more leeway by letting them determine “other medical conditions” at their discretion. In some states, even CBD oil is a no-go. In Kentucky, only people participating in a clinical trial or an expanded access program are legally allowed to possess it; in Mississippi, only people with a debilitating epileptic-seizure disorder qualify.
The laws are constantly evolving. If access is important to you, contact your state legislators and congress members and let them know. There are dozens of pending marijuana bills and resolutions on the state and federal level right now. (Check out this list from NORML to see which ones affect you and the arthritis patients in your life. Then refresh your browser and do it again, as cannabis laws can rapidly change.)
Having a medical-marijuana program in place doesn’t necessarily guarantee unfettered access. Seritt, who makes her own cannabis medicine from homegrown plants, laments the passing of House Bill 1220, which lowered the number of plants one residence could grow from 99 to a dozen, max. Her belief? “If your state program doesn’t allow access to fresh plants or cultivation, you don’t have real medical access.”