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Pain Associated with Multiple Sclerosis (MS)>

Spasticity (stiffness) is a common symptom of MS and occurs, as the disease evolves, in more than 60% of people with Multiple Sclerosis (MS). Spasticity is usually associated with painful spasms {call-out, text:Involuntary and abnormal muscular contraction}, sleep disturbance and pain, and it contributes to reduced mobility.1Classically recommended medications for generalized spasticity, including baclofen, tizanidine, dantrolene, benzodiazepines, and clonazepam, have shown limited clinical benefit in systematic reviews.2 For MS patients with central pain {call-out, text:Pain caused by damage or malfunction of the central nervous system} or painful spasms, cannabis extracts have shown to be effective for experiencing a reduction of central pain and spasms. Various studies have looked at the effects of different cannabis products administration methods. Research has found that oromucosal nabiximols (Sativex), containing THC+CBD in a 1:1 ratio can be effective for treating MS related pain, spasticity, and related symptoms,1, 3, 4, 5 6, 7, 8 while a study by Corey-Bloom found that smoking flower had an improvement over placebo (inactive treatment) on treatment resistant spasticity.9 On the other hand, Koppel and colleagues concluded that smoked cannabis was of unclear efficacy for reducing pain.10 Researcher Langford and colleagues concluded that more research is needed, as their study had mixed results.11

MS – Oromucosal

Several studies have looked at the effects of Sativex on the symptoms of MS. Patients in these studies were instructed to increase their dose via a step-by-step protocol (so-called up-titration) until the right dose was found (see titration schedule), if the starting dose of 2.7 mg THC + 2.5 mg CBD was not effective.1, 3, 4, 5, 6, 7, 8 When looking at the results from studies by Collin and colleagues,3, 4 it takes about 4-6 weeks to reach a plateau of the cannabis effect, in both the active treatment group and the placebo group. This implies that if you start using the cannabis extract, you can expect that it may take more than a month before you notice any effects, according to these studies. The response rate (% of people getting beneficial effects ofrom oromucosal THC+CBD) after 4 weeks of treatment lies between 47% and 70.5%, meaning that many patients, but not everyone, experience beneficial effects from oromucosal THC+CBD.1, 2, 5 These patients are typically referred to as responders. Markova and colleagues found in their study that evidence is accumulating to suggest that patients receiving THC+CBD spray in daily practice gain sufficient benefit at an average a dosage of about 7 sprays/day, which comes down to 18.9mg THC + 17.5mg CBD (the THC to CBD ratio is almost, but not entirely 1:1) . It is important to note that this is a suggestion of the average among responders, and that an effective dose is different for every individual.5 Moreover, studies by Rog and colleagues followed patients for 2 years and showed that the benefits from the treatment were still present and that the patients did not develop tolerance to the oromucosal THC+CBD medication, even after 2 years of treatment.6, 7

MS – Oral THC and Oral THC+CBD

Studies on oral administrations of cannabis products so far have given conflicting results. There are two studies which looked at the effects of oral THC capsules (2.5mg) or THC+CBD capsules (2.5mg + 1.25mg per capsule respectively, taken from a cannabis extract) compared to placebo. The treatments were titrated {call-out, text:to adjust the dose via a step-by-step protocol} by adding  1 capsule twice a day at a weekly interval until the tolerated dose was reached, with a maximum of 25mg THC per day. Treatments were given for an 8-week term, after which a down-titration followed. Then, patients were offered the opportunity to resume medication at the previously determined dose, for a maximum of 12 months.12, 13 Overall, the shorter treatment period did not produce beneficial effects, whereas the 12-month treatment resulted in small reductions of pain, spasticity and other MS-related symptoms. The beneficial effects were still present after a so-called intention–to-treat analysis, which means that every patient who had started the study , even if they dropped out or did not follow the study protocol entirely, was still included in the results analysis.. While both active treatment groups, THC and THC+CBD, were somewhat beneficial at the end of the 12-month study, the THC group had a slightly greater beneficial effect. The THC group’s spasticity scores on the total Ashworth scale were 1.82 points better at the end of the study compared to 0.10 points in the cannabis extract group, while the placebo group scored -0.23 points.12, 13

Smoking

A study by Corey-Bloom had the objective to determine the short-term effect of smoked cannabis on spasticity. The research found that patients suffering from MS that smoked an average of 4 puffs from an 800mg cannabis cigarette with 4% THC once a day for 3 days had an improvement over placebo on (treatment resistant) spasticity by 2.74 out of 30 points on a physician-scored spasticity scale called the Modified Ashworth Scale.9 The researchers also found a 5.28-point improvement in spasticity on a 100-point patient-reported scale. Observed side-effects included: dizziness, headache, fatigue, nausea and feeling “too high”, and five out of 37 subjects dropped out due to the severity of the side-effects.9

Placebo Effects

A large effect in the study group receiving placebo (inactive treatment) can occur, causing the difference between the active treatment and placebo groups to be small.3, 4 For example, in one study,3 the group receiving oromucosal THC+CBD had a 40% reduction in spasticity, whereas the placebo group experienced a 21.9% reduction. This large placebo effect was also seen in studies with oral THC+CBD and THC products,12, 13 where a 60% improvement in spasticity was seen in the active groups, versus a 40% improvement for placebo. The large placebo effects can make it difficult for a study to show a (statistical) significant difference between a placebo and the active treatment. For example, a researcher sees the 60% improvement after treatment ‘only’ as an absolute 20% when one subtracts the 40% from placebo effect. References:
  1. Novotna, A.; Mares, J.; Ratcliffe, S.; Novakova, I.; Vachova, M.; Zapletalova, O.; Gasperini, C.; Pozzilli, C.; Cefaro, L.; Comi, G. (2011). A randomized, double‐blind, placebo‐controlled, parallel‐group, enriched‐design study of nabiximols (Sativex®), as add‐on therapy, in subjects with refractory spasticity caused by multiple sclerosis. European Journal of Neurology, 18(9), 1122--1131.
  2. Patti, F.; Messina, S.; Solaro, C.; Amato, M. P.; Bergamaschi, R.; Bonavita, S.; Bruno Bossio, R.; Brescia Morra, V.; Costantino, G. F.; Cavalla, P.; Centonze, D.; Comi, G.; Cottone, S.; Danni, M.; Francia, A.; Gajofatto, A.; Gasperini, C.; Ghezzi, A.; Iudice, A.; Lus, G.; Maniscalco, G. T.; Marrosu, M. G.; Matta, M.; Mirabella, M.; Montanari, E.; Pozzilli, C.; Rovaris, M.; Sessa, E.; Spitaleri, D.; Trojano, M.; Valentino, P.; Zappia, M. (2016). Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. Journal of Neurology, Neurosurgery & Psychiatry, 87(9), 944 LP -- 951.
  3. Collin, C.; Davies, P.; Mutiboko, I. K.; Ratcliffe, S. (2007). Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. European Journal of Neurology, 14(3), 290--296.
  4. Collin, C.; Ehler, E.; Waberzinek, G.; Alsindi, Z.; Davies, P.; Powell, K.; Notcutt, W.; O'leary, C.; Ratcliffe, S.; Nováková, I. (2010). A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurological research, 32(5), 451--459.
  5. Markovà, Jolana; Essner, Ute; Akmaz, Bülent; Marinelli, Marcella; Trompke, Christiane; Lentschat, Arnd; Vila, Carlos (2018). Sativex®as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial. International Journal of Neuroscience, 1--10.
  6. Rog, David J.; Nurmikko, Turo J.; Friede, Tim; Young, Carolyn A. (2005). Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology, 65(6), 812--819.
  7. Rog, David J.; Nurmikko, Turo J.; Young, Carolyn A. (2007). Oromucosal D9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: An uncontrolled, open-label, 2-year extension trial. Clinical Therapeutics, 29(9), 2068--2079.
  8. Wade, Derick T.; Makela, Petra; Robson, Philip; House, Heather; Bateman, Cynthia (2004). Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Multiple Sclerosis Journal, 10(4), 434--441.
  9. Corey-Bloom, Jody; Wolfson, Tanya; Gamst, Anthony; Jin, Shelia; Marcotte, Thomas D.; Bentley, Heather; Gouaux, Ben (2012). Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Canadian Medical Association Journal
  10. Koppel, B. S.; Brust, J. C. M.; Fife, T.; Bronstein, J.; Youssof, S.; Gronseth, G.; Gloss, D. (2014). Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, 82(17), 1556--1563.
  11. Langford, R. M.; Mares, J.; Novotna, A.; Vachova, M.; Novakova, I.; Notcutt, W.; Ratcliffe, S. (2013). A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. Journal of Neurology, 260(4), 984--997.
  12. Zajicek, John; Fox, Patrick; Sanders, Hilary; Wright, David; Vickery, Jane; Nunn, Andrew; Thompson, Alan (2003). Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. The lancet, 362(9395), 1517--1526.
  13. Zajicek, J. P.; Sanders, H. P.; Wright, D. E.; Vickery, P. J.; Ingram, W. M.; Reilly, S. M.; Nunn, A. J.; Teare, L. J.; Fox, P. J.; Thompson, A. J. (2005). Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. Journal of Neurology, Neurosurgery & Psychiatry, 76(12), 1664--1669.