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Exploring the Clinical Implications of Cannabinoid Use in Rheumatoid Arthritis

The potential benefits of cannabinoid substances have long been considered for rheumatoid arthritis (RA), following their successful treatment of other diseases involving chronic pain, such as cancer and multiple sclerosis (MS). Although preliminary evidence has found an association between the cannabinoid system and other rheumatic conditions, the studies have not provided conclusive results that could drive recommendations.1 In particular, evidence from clinical trials has been derived from small samples and has not consistently supported positive results from animal studies.1

These limitations have hampered clinical decision making for rheumatologists who treat RA, leaving them to rely on the efficacy and safety demonstrated in clinical trials in other disease states. According to Allen C. Bowling, MD, PhD, medical director of the MS Program and director of the Complementary and Alternative Medicine Service at the Colorado Neurological Institute, “For MS, we have many well-conducted studies that indicate benefit for pain and subjective spasticity.” In an interview with Rheumatology Advisor, he stated that, “…cannabis may have efficacy for multiple conditions, including RA and other ‘arthritides,’ but robust efficacy data to support use in these conditions [are] lacking.”

 

A 2018 comprehensive review conducted by Katz-Talmor et al1 reported that cannabinoids show potential benefits in the treatment of rheumatic diseases in general, with RA as a specific target for pain reduction. Coauthor Yehuda Shoenfeld, MD, FRCP, MaACR, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, in Tel Hashomer, Israel, told Rheumatology Advisor, “Regrettably, though preclinical trials show great promise, there [are] no clinical data attesting to the ability [of cannabis] to reduce disease severity in RA. At the present time, recommendation for cannabinoid treatment as a disease-modifying agent in RA should not be made.”

Cannabinoid Receptors and Other Mechanisms

One of the most compelling arguments in support of the therapeutic possibilities of cannabinoids to modulate severe pain was the discovery of cannabinoid receptor sites in the human body and the presence of naturally occurring endocannabinoids that bind to them.2 In recent years, the endocannabinoid system (comprised of cannabinoid receptors and their endogenous ligands, as well as the enzymes that regulate the system) has also been linked to inflammatory conditions such as MS, atherosclerosis, inflammatory bowel disease, sepsis, and allergic inflammation, and it is believed to have a modulatory role in the development of RA.2

Two types of cannabinoid receptors appear to play a role in RA when activated: cannabinoid receptor 1 (CB1), which mediates the psychotropic effects of cannabis, and particularly, cannabinoid receptor 2 CB2, which is primarily known for its expression on immune cells.1 Gui et al2 suggested that CB2 receptors may have beneficial effects on RA through multiple mechanisms, including the production of autoantibodies, proinflammatory cytokines, and matrix metalloproteinases. The same study noted other possible benefits of cannabinoids via suppression of bone erosion and immune response mediated by T cells and the proliferation of fibroblastlike synoviocytes, which are known to engage immune responses and actively promote joint destruction.2

Potential Benefits

Although many researchers suspect that cannabinoids may have multiple beneficial effects on disease activity, there is little clinical evidence. Results of a single controlled trial conducted in 2006 by Blake et al3 demonstrated significant reduction of both pain and suppression of RA disease activity with the use of an oromucosal cannabinoid spray, Sativex®, derived from a formulated extract of the cannabis sativa plant containing delta-9-tetrahydrocannibinol (THC) and cannabidiol as the principal cannabinoids.

At the same time, many are convinced of the analgesic benefits. “Contrary to the paucity of evidence regarding cannabis’ ability to modify RA disease progression, evidence supporting cannabis’ therapeutic effect in chronic pain is relatively abundant,” Dr Shoenfeld reported. “Recently, a committee sponsored by the [United States] government concluded that there is substantial evidence supporting cannabis’ ability to reduce chronic pain.”4

An important subset of patients with RA who are likely to benefit from cannabinoids are those already consuming opioids, due to a possible synergistic effect between cannabinoids and opioids that causes augmentation of pain reduction.5,6 Dr Shoenfeld added that, “epidemiological analysis revealed that states [that] implemented medicinal cannabis laws [have] a lower rate of mortality due to opioid overdose.7 Ergo, patients receiving opioids should be targeted for potential cannabis treatment in an effort to reduce their opioid dependency.”

Adverse Effects of Cannabinoids

A review of 4779 adverse events from 31 studies conducted over 40 years reported a wide range of adverse events associated with cannabinoid use, including dizziness, nausea, dry mouth, and tachycardia.8 Serious adverse events were rare and most often involved the respiratory, gastrointestinal, or neurologic systems. Other serious adverse events involved the cardiovascular system or kidney damage.8 The largest number of both serious and nonserious adverse events were neurologic or psychiatric.

Potential for addiction, however small, is a serious concern when prescribing cannabinoid therapy. “Approximately 9% of cannabis consumers will [have] cannabis dependence,”9 Dr Shoenfeld reported, noting that patients considering cannabis treatment should be informed regarding the potential adverse effects. “A devastating adverse effect is the potential triggering of schizophrenia or psychosis,” he said, “thus, physicians must warn patients prior to cannabis treatment.4 Cannabis consumption is also associated with alcohol abuse, [and] patients self-medicating with cannabis might be at risk for ethanol-cannabis interaction.4,10 Simultaneous consumption of cannabis and alcohol can potentially increase THC plasma levels and should be avoided.10 Patients should also be cautioned against driving under the influence of cannabis, since cannabinoids consumption is associated with increased risk for car accidents.”4

Dr Bowling pointed out that drug interactions with cannabinoids remain poorly understood. “Staff at state dispensaries generally lack any significant training, yet make specific recommendations, many of which are not evidence based and some of which are dangerous. Products from state dispensaries may [also] contain contaminants, including pesticides, microbes, mycotoxins, heavy metals, and solvents. In the end, I present the objective information and have patients decide on their own,” he said.

Barriers to Acceptance of Cannabinoid Therapies

Physicians have remained reluctant to use cannabinoids despite evidence of potential benefits in RA, which according to Dr Shoenfeld, can be attributed to 2 key factors: “The main reason in our eyes is the paucity of data, with only 1 clinical trial published thus far.2 Current clinical data simply do not suffice for recommendations to be made regarding cannabinoid treatment in RA.”

An additional challenge is a lack of physician training in the appropriate use of cannabinoids. Dr Shoenfeld pointed to a survey of 258 American residents and fellows in which 89.5% of physicians responded that they lacked confidence in prescribing medical cannabis.11 “Furthermore, 84.9% of participants declared they received no medical education regarding cannabis during medical school nor during their period of residency.8 Similar concerns were voiced in a survey of Canadian rheumatologists, with 70% of physicians stating their lack of confidence regarding their knowledge in cannabinoids.12 Therefore, incorporation of cannabinoids in the medical practice for RA requires not only additional clinical data but also proper medical training and quantification of dosing.”

Dr Shoenfeld noted that, “hesitancy is prudent while recommending cannabis as an analgesic in RA. Currently only 1 clinical trial examined the efficacy of cannabinoids in pain reduction in [patients with RA].”2

 

References

  1. Katz-Talmor D, Katz I, Porat-Katz BS, Shoenfeld Y. Cannabinoids for the treatment of rheumatic diseases – where do we stand?Nat Rev Rheumatol. 2018;14:488-498.
  2. Gui H, Tong Q, Qu W, Mao CM, Dai SM. The endocannabinoid system and its therapeutic implications in rheumatoid arthritisInt Immunopharmacol. 2015;26:86-91.
  3. Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritisRheumatology (Oxford). 2006;45:50-52.
  4. National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.Washington, DC: National Academies Press; 2017.
  5. Fitzcharles MA, McDougall J, Ste-Marie PA, Padjen I. Clinical implications for cannabinoid use in the rheumatic diseases: Potential for help or harm? Arthritis Rheum. 2012;64:2417-2425.
  6. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid–opioid interaction in chronic painClin Pharmacol Ther. 2011;90:844-851.
  7. Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010JAMA Intern Med. 2014;174:1668-1673.
  8. Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ. 2008;178:1669-1678.
  9. Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol. 1994;2:244-268.
  10. Hartman RL, Brown TL, Milavetz Get al. Controlled cannabis vaporizer administration: blood and plasma cannabinoids with and without alcoholClin Chem. 2015;61(6):850-869.
  11. Evanoff AB, Quan T, Dufault C, Awad M, Bierut, LJ. Physicians-in-training are not prepared to prescribe medical marijuana. Drug Alcohol Depend. 2017;180,:151-155.
  12. Fitzcharles MA, Ste-Marie PA, Clauw, DJ, et al. Rheumatologists lack confidence in their knowledge of cannabinoids pertaining to the management of rheumatic complaints. BMC Musculoskelet Disord. 2014;15:258.
  13. _________________________________________________________________

Medical Cannabis Shows Promise in Treating Symptoms of Multiple Sclerosis

Medical cannabis has led to patient-reported improvements in several symptoms of multiple sclerosis (MS), according to research presented at the 32nd Annual Meeting of the Consortium of Multiple Sclerosis Centers, held May 30-June 2, 2018, in Nashville, Tennessee.

This ongoing, retrospective chart review includes approximately 160 subjects with MS who are using medical cannabis to manage their symptoms. The researchers are studying outcomes using subject-reported metrics such as Becks Depression, Zung Self-Rating Anxiety, MOCA, and medical pain.

The researchers will continuously evaluate data using statistical analysis in order to improve percentiles on outcomes in the study. The e outcomes reported by subjects are analyzed in comparison with baseline. Differing formulations and ratios of the subjects’ medical cannabis regimens have also been accounted for, though further information about ratios of CBD and TCH are subject to change due to continued ongoing research. The review researchers are looking specifically at responses concerning muscle spasms, difficulty sleeping, restless legs, headache, cognition, appetite, depression, anxiety, fatigue, and pain.

The researchers concluded that “[the] use of [medical cannabis] for symptom management for patients diagnosed with MS is becoming more widely accepted. This study, although subjective, demonstrates patient-reported benefits in all of the above-measured metrics. Additional studies can help confirm these results.”

 

McCormack KE, Mazhari AC. Multiple sclerosis and use of medical cannabis: a retrospective review evaluating symptom outcomes. Presented at: 2018 CMSC Annual Meeting. May 30-June 2, 2018; Nashville, TN. Abstract SX06.

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Cannabis Use High in Migraine

A high percentage of cannabis users take the drug — particularly strains with high concentrations of Δ9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid and low cannabidiol (CBD)/cannabidiolic acid content — to treat headache and probable migraine, according to a study published in The Journal of Headache and Pain.

Patients taking medicinal cannabis were asked to fill out an electronic survey regarding their cannabis use (n=2032). The survey sought to determine the study participants’ primary illness, reasons for taking cannabis, frequency and quantity of use, preferred types and strains (eg, hybrid, Indica, Sativa), methods of use, and prescription medications that were substituted with cannabis. The ID Migraine™ questionnaire was incorporated into the survey to determine migraine prevalence.

 

Nearly half of the cohort reported pain syndromes as the primary reason for cannabis use (42.4%; n=861), with chronic pain (29.4%; n=598), arthritis (9.3%; n=188), and headache (3.7%, n = 75) being the most frequently reported conditions. Cannabis was used to treat headache in 24.9% (n=505) of patients. According to the ID Migraine™ questionnaire, 68% (n=343) and 20% (n=102) of patients with headache gave 3 and 2 “yes” answers, respectively, corresponding to a 97% and 93% probability of having migraine, respectively. This finding translated to cannabis being used in the treatment of probable migraine in 88% (n=445) of patients with headache.

Patients with headache as the primary illness were more likely to prefer Sativa over strains with equal proportions of CBD and THC compared with patients with chronic pain and arthritis (chronic pain: odds ratio, 2.66; 95% CI, 1.52-4.66; <.001; arthritis: odds ratio, 3.35; 95% CI, 1.57-7.12; P=.001).

Approximately half of the cohort (41.2%-59.5%) used cannabis as a substitute for prescription medications, with 40.5% to 72.8% of patients substituting cannabis for opioid medications. In patients with headache, substituted prescription medications were opioids (43.4%), antidepressant/antianxiety medications (39%), nonsteroidal anti-inflammatory drugs (21%), triptans (8.1%), anticonvulsants (7.7%), muscle relaxers (7%), and ergots (0.4%).

Considering many patients with headache in this study had comorbidities, the findings from the survey may not be specific to headache or migraine. In addition, the use of a survey for data collection represents a potential limitation of the analysis.

“Identifying differences in use patterns between migraine, headache, arthritis, and chronic pain syndromes may be helpful in optimizing crossbred cannabis strains, synergistic biochemical profiles, or dosing differences between these pain subsets,” concluded the study authors.

 

Reference

Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohortJ Headache Pain. 2018;19:37.

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Cannabis May Be Effective for Migraine Treatment

Cannabis may be an effective treatment for headache management, according to a study to be presented at the 2018 World Congress on Pain, held September 12-16 in Boston, Massachusetts.

The trial included 3500 patients in a university-based tertiary headache clinic, 310 of whom were self-identified as marijuana users. Researchers evaluated the perceived effectiveness and concomitant effects of marijuana for headache management using a detailed patient intake questionnaire. New patients who self-identified as marijuana users were asked to complete a supplemental institutional review board (IRB)-approved study questionnaire.

 

The results revealed that 90.3% of marijuana users found it helpful for managing headache pain, with only 7.7% of patients experiencing any adverse events. Furthermore, 54% of patients reported trying marijuana for daily headache prevention, and of these 47.7% were currently using marijuana for headache prevention.

Of the participants who were sent the IRB-approved questionnaire, 94 responded; 91.9% (n=82) used marijuana in the previous year and 97.8% (n=72) used marijuana in the previous month.

Marijuana was used for headache-related pain management in 88.9% of patients, and 61.1% used it to manage other pain. Of the patients who used marijuana for headache management, 8 reported a complete resolution of headache and 44 reported some relief of headache-related pain but not complete resolution.

Researchers added, “To address the concern for substance use disorder and whether cannabis may function as a ‘gateway drug,’ our review shows a low incidence of comorbid substance use disorder in this group. The rate of educational attainment and employment were also assessed. [The] majority of patients in the study have anxiety unrelated to marijuana use, perceive marijuana as safe, and are not concerned about using marijuana.”

While case reports and retrospective reviews are suggestive of marijuana’s beneficial use for the treatment of migraines, randomized clinical trials on its effects ultimately represent a lacuna in marijuana medical research.

 

Reference

Krashin D, Murinova N, Mannava A, Schorn N, Murin M. Marijuana use in headache.
Presented at the World Congress on Pain 2018; September 12-16, 2018; Boston, MA. Poster 65961.

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