ASRA Pain Medicine Update

Cite as: Howard R, Varlotta C, Lynn RR. Cannabis in the management of multiple sclerosis-related pain and spasticity. ASRA Pain Medicine News 2024;49. https://doi.org/10.52211/asra110124.012.

Introduction

Multiple sclerosis (MS) is an immune-mediated inflammatory disease affecting 2.3 million people worldwide.¹It is characterized by demyelination lesions in the gray and white matter, reflecting loss of myelin and associated oligodendrocytes. These pathologic changes impair nerve transmission throughout the central nervous system. The degree of deficits is closely related to axonal atrophy and loss compared to the extent of demyelination. Spasticity and pain are common symptoms through the course of MS and affect 60%-84% of patients.^2–4 Patients with MS reported decreased health-related quality of life due to pain.⁵ Pain associated with MS can be continuous or intermittent, neuropathic, musculoskeletal, or related to spasticity. Neuropathic pain in MS is postulated to result from corticospinal disinhibition or chronic activation of nociceptive afferents.⁴

Pathophysiology

Injured neural and nonneural tissues produce endocannabinoids, which are arachidonic acid derivatives involved in the inflammatory cascade. The two predominant cannabinoids in the cannabis plant, delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) act at the CB1 and CB2 receptors. The CB1 receptor is present mainly in the nervous system, including the sensory neurons of the dorsal root and trigeminal ganglion, and in immune system cells, such as macrophages.⁸ CB1 has a role in the modulation of spasticity. It is also responsible for cannabinoid-induced psychoactivity.⁹ CB-2 receptors are located predominantly in the peripheral tissues and are involved with immunomodulation.^10,11 Studies have found dysregulation in the endocannabinoid system in MS, suggesting a therapeutic role for cannabinoids.^12,13

Cannabis represents a potential therapy for the management of pain and spasticity in patients with MS. The mechanistic action of medical cannabis involves the innate endocannabinoid system, but effects on other signaling systems, such as serotonin (5HT) and Transient Receptor Superfamily (TRPV1, TRPM8, TRPA1), may also be implicated.^6,7

Although it is rarely used as the first drug to mitigate pain, pain relief is the most common reason for the medical use of cannabis.⁸ Multiple randomized control trials show cannabis is effective for chronic pain reduction but with an amount needed to treat much higher than other commonly prescribed analgesics, and sample sizes and effect sizes have been small overall.^14,15 Many patients with MS have used cannabis for their chronic pain with one recent study quantifying such usage at 27%.¹⁶

Cannabis Formulations

Medical cannabis can be sourced from plants or manufactured synthetically. There are multiple routes of administration for medicinal cannabis, including oral, mucosal, subcutaneous, and transdermal routes. Formulations can be smoked, inhaled, mixed with food, or made with tea, which allows for patient-specific approaches. For example, a patient with a diet restricted to pureed consistencies would be able to ingest cannabinoids mixed with compatible foods. Pharmaceutical-grade cannabinoids include synthetic THC products, such as dronabinol and nabilone capsules and plant extract-derived products including nabiximols oromucosal spray and cannabidiol oils such as Epidiolex. The FDA-approved formulations in the United States include Epidiolex and three synthetic cannabis-related products: Marinol (dronabinol), Syndros (dronabinol), and Cesamet (nabilone).^17–20 Nabiximols (brand-name Sativex) is a combined THC and CBD extract that was approved for the treatment of MS-related spasticity in the United Kingdom in 2010. It has since been approved in 29 other countries but is not FDA-approved. The nabiximols oromucosal spray has a favorable pharmacokinetic profile that may avoid the psychoactive effects seen with smoked cannabis.²¹This is due to less first-pass metabolism and low plasma concentration. The recommended therapy is a 14-day dose titration with maximum dosing of 12 sprays per day spaced at least 15 minutes apart.²² Studies have demonstrated that the combination of THC with CBD is superior in alleviating cancer pain compared to CBD alone, and another study found this formulation alleviated severe pain in cancer that was not resolved with opioid therapy.^23,24 There may be a synergistic interaction with low doses of THC and CBD in combination, leading to reduced euphoric effects and improved symptomatic relief of spasticity and pain, which may be of benefit in MS.²²

Although it is rarely used as the first drug to mitigate pain, pain relief is the most common reason for the medical use of cannabis.

Trials Studying Cannabis for Multiple Sclerosis

The Multiple Sclerosis Extract of Cannabis trial demonstrated a twofold increased rate of relief from muscle stiffness with oral cannabis extract containing THC after 12 weeks and increased rates of spasticity relief, physical and psychological impact, and walking ability in patient-reported outcomes.²⁵ In contrast, a more recent randomized controlled trial (RCT) investigating the effects of THC, CBD, and a THC/CBD combination compared to placebo on pain and spasticity intensity in patients with MS found no significant differences between the three treatment groups and the placebo group with all groups experiencing a significant reduction in pain and spasticity levels.²⁶ A previous systematic review and meta-analysis found moderate quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity with the aforementioned small effect size.¹⁹ In contrast, Riera et al. performed a systematic review of three studies assessing the effects of cannabis on pain and spasticity in multiple sclerosis and failed to identify significant clinical benefit.²⁷ However, each study included in this review lacked standardized dosing or formulation of cannabis.

Multiple trials have been conducted evaluating nabiximols in the treatment of MS pain and spasticity. One RCT comparing placebo with THC/CBD spray (nabiximols) on pain reduction found conflicting results within the two phases of the study.²⁸ The study’s first phase involved a double-blind, 14-week period in which patients were randomized to receive either nabiximols or placebo as an add-on to existing treatment regimens. No significant difference was observed between the spray and placebo at the end of the 14 weeks. However, in week 10, they found a significantly greater proportion of patients who achieved >30% pain relief from baseline than those who achieved placebo. It is worth noting that the placebo group was self-administering more doses than the treatment group by the end of the study, which could have augmented the placebo effect.

The second phase consisted of 12 weeks of treatment with nabiximols followed by a double-blind, randomized 4-week withdrawal phase where participants either received nabiximols or placebo, investigating time to treatment failure. This phase showed that participants who continued using nabiximols maintained or further improved their pain reduction compared to those who switched from nabiximols to placebo. Most systematic reviews have focused on spasticity instead of pain given the available research, with recently published systematic reviews finding that nabiximols can be effective as an adjunctive treatment option for spasticity in MS patients, who are not achieving optimal relief with first-line antispastic medications.²⁹ Kleiner et al included seven high-quality RCTs that showed nabiximols to significantly affect spasticity reduction when compared with placebo with longer-term interventions having a greater effect.³⁰

In summarizing current data of cannabinoids vs placebo for MS, a Cochrane review concluded that nabiximols have moderate certainty evidence for spasticity improvement with most effectiveness seen for patients with moderate to severe spasticity that has not responded well to other treatments.³¹ The conclusion for chronic neuropathic pain was less robust with low certainty evidence given the reporting variation and low sample sizes, making it difficult to generalize results to a larger clinical population. Given the variability between study dosing, duration, and outcomes, among other features, more evidence is necessary to discern optimal patient characteristics, dosing, and duration of treatment with nabiximols for multiple sclerosis, particularly as it relates to chronic neuropathic pain.

Adverse Effects of Cannabis in Multiple Sclerosis

Although typically well tolerated, adverse effects of cannabis may occur at low doses regardless of the route of administration. Gustavsen et al recommended initial treatment with low doses of oral cannabis, such as 1.25 mg of THC. If tolerated, the dose can be increased in increments of 1.25 mg every 3 days until the desired effect is achieved with a maximum daily dose of 20-25 mg THC with up to 7.5 mg per administration.³² Providers should be aware sublingual administration of cannabis oils may have a faster onset of action (typically within 15-45 minutes) compared to the enteral route.^32,33 Published side effects of cannabis include somnolence, nausea, dizziness, dry mouth, disorientation, euphoria, anxiety, hallucinations, memory and cognitive issues, addiction, and provocation of pre-existing psychiatric disorders or heart disease.³⁴ The prevalence and intensity of side effects vary and are dose and frequency-dependent. ³⁴

Patients should be advised on various components within specific cannabis formulations. For example, the oromucosal spray includes alcohol and peppermint. Therefore, patients using the spray should inspect their oral cavity regularly as adverse effects in a small observational study included stinging from chemical irritation.³⁵ Patients who inhale cannabis products should be counseled on increased risk of respiratory illness, sputum production, and airway obstruction.³⁵ Tolerance to cannabis needs further studying, but one study did note stable efficacy without increased dosage over time.³⁶ 

When orally ingested, THC and CBD are metabolized by the CYP450 hepatic enzyme system, involving 3A4 and 2C9, and CYP2C19 also metabolizes CBD. In trials of Epidiolex for pediatric seizure prevention as well as one study of CBD to treat Parkinson’s disease, in which higher doses of CBD were administered than in any of the studies described above, significant transaminase elevations were noted that resolved with cessation of the medication.^37–39 Both THC and CBD levels may be reduced with concomitant administration of CYP3A4 inducers and increased with CYP3A4 and CYP2C9 inhibitors.^40,41 Additionally, THC induces CYP1A2 while CBD inhibits CYP3A4 and CYP2D6, leading to a variety of drug-drug interactions.⁴² When prescribing oral formulations of THC and CBD for MS, providers should be cautious of increasing serum concentrations of antidepressants, opioids, benzodiazepines, and corticosteroids. THC and CBD have also been found to increase warfarin levels. ⁴³ Risk of sedation increases in patients prescribed other sedating agents, antihistamines, or concurrent alcohol use. Tricyclic antidepressants and stimulants used with cannabis may produce tachycardia. Smoking cannabis can lead to increased theophylline metabolism.¹⁷

Conclusion

Although cannabis is a potential alternative treatment for pain and spasticity in multiple sclerosis, further research is needed to guide prescription practices of products containing THC and/or CBD. However, patients may benefit from a trial of cannabis for pain and spasticity related to multiple sclerosis, especially if other therapies and medications have failed.

References

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