Spasticity associated with MS

Seriousness of medical condition(s)

Epidemiological studies indicate that spasticity is a significant problem for between 60% and 80% of people with MS and is a major contributor to disability in this population. Spasticity can significantly affect motor performance and the activities of daily living among people with MS, such as controlling the body during functional tasks, mobilising, completing personal care tasks, diminished joint mobility, decreased muscle flexibility, and sleep disorders secondary to airway obstruction (Beard et al., 2003; Rizzo et al., 2004). Left untreated, spasticity may lead to deformities, such as kyphoscoliosis and contractures, which can be difficult to correct. There is an association between the degree of spasticity and level of disability. Severe spasticity can lead to contracture. Some people who experience severe spasticity become bedbound. Positioning difficulties and fixed postures can lead to bedsores, which further exacerbate muscle spasms

Who could benefit from this treatment?

MS patients when other treatment and management strategies have not completely resolved symptoms, failed, are contraindicated or caused side effects.

Clinical justification for using Medicinal Cannabis

  1. The medicinal cannabis’s suitability for the intended indication
  2. The medicinal cannabis’s efficacy and expected benefits


In 2017, the US National Academies of Sciences, Engineering, and Medicine have reviewed evidence and provided recommendations on the health effects of cannabis and cannabinoids

There is conclusive or substantial evidence that cannabis or cannabinoids are effective:

  • For the treatment of chronic pain in adults (cannabis)
  • As antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids)
  • For improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids)


The National Academies Review found that oral cannabis extracts, Nabiximols (1:1 THC: CBD oromucosal spray) and oral THC are effective treatments to reduce patient-reported spasticity (National Academies 2017). This conclusion was based on systematic reviews of patients with MS (Whiting et al., 2015; National Academies 2017) and an additional trial of Nabiximols (Leocani et al., 2015). Meta-analysis of 3 RCTs showed that medical cannabinoids (nabiximols) increased the number of patients achieving a 30% improvement in spasticity, with a risk ratio of 1.37 (95% CI 1.07 to 1.76)(Whiting et al., 2015). Eleven other trials of medicinal cannabis for MS showed similar results (for review, see Allan et al., 2018). The European Federation of Neurological Societies task force lists cannabinoids as level A for effectiveness in MS-related central pain and recommends cannabinoids as second- or third-line treatment for refractory cases (Attal et al., 2010).


  1. any unknown or expected adverse effects, risks and safety issues & d. related toxicology:

A systematic review by Whiting et al. (2015) stated in their conclusions that “Cannabinoids were associated with an increased risk of short-term adverse effects”.

According to the Guidance for the Use of Medicinal Cannabis in Australia: Overview, Therapeutics Good Administration (2017):

Cannabis is not appropriate for patients who:

  • Are under the age of 25 (with the exception of intractable epilepsy or severe pain syndrome)
  • Have a personal history or strong family history of psychosis
  • Have a current or past cannabis use disorder, or active substance use disorder
  • Have unstable respiratory or cardiovascular disease (including angina, peripheral vascular disease, cerebrovascular disease, arrhythmias)
  • Are pregnant, planning to become pregnant, or breastfeeding


Cannabis should be authorized with caution in patients who:

  • Smoke tobacco
  • Have risk factors for cardiovascular disease
  • Are heavy users of alcohol
  • Are taking sedating medications or any other medication metabolized by the CYP450 pathway
  • At risk or have liver disease


Drug Interactions – CYP P450 Enzyme System

THC and CBD are metabolized by Cytochrome P450 enzyme system, including CYP1A2, CYP2C9, CYP2D6, CYP2C19 and CYP3A4. Based on in vitro and animal studies with cannabis, there is a potential for interactions with the medications metabolized by the P450 enzymes (2C9, 2C19, 3A4). It’s notable, however, that the inhibitory effects in vitro and in animal models were only seen at exposures significantly higher than the maximum observed in clinical trials. For instance, in clinical trials were Sativex® has been taken concomitantly with other drugs metabolized by the Cytochrome P450 enzyme system, no clinically apparent drug-drug interactions have been seen in these trials at clinical doses. In an in vitro study with 1:1% (v/v) THC botanical drug substance (BDS) and CBD BDS, no relevant induction of the Cytochrome P450 enzymes was seen for human CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in human hepatocytes at doses of up to 1µM (314ng/mL) (Stout and Cimino, 2014).


Potential drug interactions

Increasing THC concentration:

Examples of inhibitors:

– Antidepressants (e.g. Fluoxetine, Fluvoxamine)

– Proton Pump Inhibitors (e.g. Omeprazole)

– Cimetidine

– Macrolides (Clarithromycin, Erythromycin)

– Antimycotics (e.g. Itraconazole, Fluconazole, Ketoconazole, Miconazole)

– Calcium Antagonists (e.g. Diltiazem, Verapamil)

– HIV protease inhibitors (e.g. Ritonavir)

– Amiodarone

– Isoniazid

– Grapefruit juice


Increasing CBD concentration:

– Metabolized by CYP 2C19 and CYP 3A4

– Bioavailability could be increased by many of the same substances as for THC


Decreasing THC and CBD concentration:

  • CYP 2C9 and 3A4 Inducers accelerate THC and CBD metabolism
  • Examples of inducers:

– Rifampicin

– Primidone

– Carbamazepine

– Phenobarbital

– Phenytoin

– Rifabutin

– Saint John’s Wort


Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen in the study by Gaston et al (2017) on interactions between cannabidiol (Epidiolex®) and commonly used antiepileptic drugs. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with supraphysiological doses of CBD (e.g. 1000mg/kg).


  • Caution with blood thinners like Warfarin, Heparin, Clopidogrel (Plavix)
  • Additionally, pharmacodynamic interactions should be expected between cannabis and drugs with sympathomimetic activity (tachycardia, hypertension), central nervous system depressants (drowsiness, ataxia), and drugs with anticholinergic effects (tachycardia, drowsiness).


Many of these drug interactions can be mitigated in complex patients with polypharmacy by slowly titrating cannabis.

Approved treatments for this medical condition

Currently available pharmacological treatments include:

  • Baclofen
  • Gabapentin
  • Diazepam
  • Dantrolene
  • Tizanidine

Why is medicinal cannabis appropriate for use?

Medicinal cannabis will only be trialled after an approved therapeutic goods have been trialled and failed due to ineffective response or undesirable effects.


A recent systematic review demonstrated that the efficacy and tolerability of oral anti-spastic drugs is still poorly documented, and no prescribing advice can be recommended (Shakespeare et al., 2001). All anti-spastic medications produce adverse side effects. The most common side effect is muscle weakness, while other effects include drowsiness, dizziness, dry mouth, nausea, increased urinary frequency, light-headedness, and withdrawal effects. Each of these side effects can be troublesome for people with MS who may already be experiencing symptoms of weakness, fatigue and/or incontinence (Chou et al., 2004). It can be difficult to differentiate between weakness caused by disease progression or weakness that is a side effect of an anti-spastic drug. It is not uncommon to see people with MS take these drugs for many years without review. In many cases they may be taking doses that are too low to adequately manage their spasticity, or so high that they cause functional or quality-of-life impairments (Spasticity and Multiple sclerosis, MS Australia).  Baclofen is considered the first-line treatment for spasticity, especially in adult SCIs. Because of potential hepatotoxicity, there is a need to monitor liver function with baclofen use. Oral baclofen is not recommended for elderly patients because of excessive drowsiness. Furthermore, there has been some evidence of deleterious effects on brain plasticity. Withdrawing baclofen treatment has been associated with hyperthermia, seizures, and altered mental status. Side effects of Gabapentin were discussed in the above section. Common side effects of Tizanidine are sedation, hypotension, xerostomia, muscle weakness, and hallucinations. Because of a potential side effect of modestly lowered blood pressure, Tizanidine is contraindicated in patients taking hypertension medication. It also has been known to prolong the QT interval. With the use of Dantrolene, there have been reports of liver failure with the use of the drug. Because Dantrolene does not selectively target specific muscles, it may lead to the adverse effect of general muscle weakness. In some rare cases it has been fatal in high doses and is therefore not considered a first-line drug.


  • Allan GM, Finley CR, Ton J, Perry D, Ramji J, Crawford K, et al. Systematic review of systematic reviews for medical cannabinoids. Pain, nausea and vomiting, spasticity, and harms. Can Fam Physician 2018; 64:e78-94.
  • Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113-e88.
  • Beard S, Hunn A, Wight J. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess 2003; 7: 1–111.
  • Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage 2004; 28: 140–75.
  • Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP; UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Sep;58(9):1586-1592. doi: 10.1111/epi.13852. Epub 2017 Aug 6. PMID: 28782097.
  • Leocani LNuara AHoudayer ESchiavetti IDel Carro UAmadio SStraffi LRossi PMartinelli VVila CSormani MPComi G. Sativex and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis. J Neurol.2015 Nov;262(11):2520-7.
  • Rizzo MA, Hadjimichael OC, Preiningerova J, et al. Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler 2004; 10: 589–95.
  • Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst Rev 2001; 4: CD001332.
  • Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 2015;313(24):2456-73. Errata in: JAMA 2016;315(14):1522, JAMA 2015;314(21):2308, JAMA 2015;314(5):520, JAMA 2015;314(8):837.
  • Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 2015;313(24):2456-73. Errata in: JAMA 2016;315(14):1522, JAMA 2015;314(21):2308, JAMA 2015;314(5):520, JAMA 2015;314(8):837.