Pain - randomised controlled trials and other studies

Double-blind, parallel RCT
Grade 1- High

Ball S, Vickery J, Hobart J, Wright D, Green C, Shearer J, et al. The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Health Technology Assessment 2015; 19: 1-187.

493 adults aged 18-65 with primary or secondary progressive MS at 27 UK sites were randomised in a 2:1 ratio to dronabinol (Marinol, Insys Therapeutics, Arizona) oral capsules with a maximum dose of 28mg/day or placebo over 36 months to establish the safety and efficacy of dronabinol for slowing progression of primary and secondary MS.

Double-blind, parallel RCT
Grade 1- High

Serpell M, Ratcliffe S, Hovorka J, Schofield M, Taylor L, Lauder H, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. European Journal of Pain 2014; 18: 999-1012.

246 adults, mean age 57, with peripheral neuropathic pain at multiple sites in the UK, Belgium, Canada, Czech Republic, and Romania were randomised to nabiximols (Sativex) THC:CBD spray self-titrated up to a maximum dosage of 24 sprays/day or placebo over 15 weeks.

Double-blind, parallel RCT
Grade 1- High
see also [53]

Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, et al. 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 2013; 260: 984-97.

339 patients at 33 sites in the UK, Czech Republic, Canada, Spain and France with a mean age of 49 and central neuropathic pain due to MS were randomised to nabiximols (Sativex) THC:CBD oromuscosal spray (maximum dosage of 12 sprays per day) or placebo over 14 weeks as an add-on treatment in phase 1 of a 3 phase study.

Double-blind, parallel RCT
Grade 1- High

GW Pharmaceuticals Ltd. A study to evaluate the effects of cannabis based medicine in patients with pain of neurological origin (clinical trial record only). US National Library of Medicine 2012a; NCT01606176.

70 adults with MS or other defect of neurological function with a qualifying symptom of chronic refractory pain were randomised to nabiximols (Sativex) or placebo over 4 weeks.

Double-blind, parallel RCT
Grade 1- High
see also [80]

Toth C, Mawani S, Brady S, Chan C, Liu C, Mehina E, et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain 2012; 153: 2073-82.

26 adults with a mean age of 61 with refractory diabetic peripheral neuropathic pain who completed a 4 week flexible-dose single-blind run-in phase were randomised to nabilone (Cesamet) in stable doses of between 1-4mg/day as an adjuvant treatment or placebo over 5 weeks.

Double-blind, parallel RCT
Grade 1- High

Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. Journal of Neurology, Neurosurgery, and Psychiatry 2012; 83: 1125-32.

279 adults with MS aged 32-64 (treatment), 28-64 (placebo) at 22 UK centres were randomised to oral cannabis (THC:CBD) extract of Cannabis sativa standardised to 2.5mg of THC per capsule (Cannador, provided by the Berlin Society for Oncological and Immunologic Research) or placebo.

Double-blind, parallel RCT
Grade 1- High

Wong BS, Camilleri M, Busciglio I, Carlson P, Szarka LA, Burton D, et al. Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology 2011; 141: 1638-47 e1-7.

75 patients aged 18-67 with irritable bowel syndrome recruited by the Mayo Clinic, Rochester, Minnesota were randomised to treatment with a single dose of either 2.5mg dronabinol (Marinol), 5mg dronabinol or placebo.

Double-blind, parallel RCT
Grade 1- High

Collin C, Ehler E, Waberzinek G, Alsindi Z, Davies P, Powell K, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurological Research 2010; 32: 451-9.

337 subjects with a mean age of 48 and spasticity from MS not wholly relieved with current therapy at 15 centres in the UK and 8 centres in Czech Republic were randomised to treatment with nabiximols (Sativex) THC:CBD spray or placebo over 14 weeks.

Double-blind, parallel RCT
Grade 1- High

Hadassah Medical Organization. Efficacy trial of oral tetrahydrocannabinol in patients with fibromyalgia (clinical trial record only). US National Library of Medicine 2010; NCT01149108.

An unreported number of adult patients estimated at 80 with fibromyalgia at the Pain Relief Unit, Hadassah Medical Organization, Jerusalem were randomised to oral THC in olive oil in doses of 5mg/0.2ml, two to four times/day as tolerated, or placebo olive oil.

Double-blind, parallel RCT
Grade 1- High

GW Pharmaceuticals Ltd. A study of Sativex for pain relief due to diabetic neuropathy (clinical trial record only). US National Library of Medicine 2008; NCT00710424.

297 patients with diabetic peripheral neuropathy in the UK, Czech Republic and Romania were randomised to nabiximols (Sativex) THC:CBD spray or placebo for 14 weeks.

Double-blind, parallel RCT
Grade 1- High

Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68: 515-21.

55 adults, mean age 47, with HIV-associated sensory neuropathy who had previously used cannabis and agreed not to use except for controlled administration during the trial period were randomised to treatment with US NIDA-supplied smoked cannabis cigarettes with 3.6% THC or identical placebo cigarettes at the rate of 3/day over 5 days.

Double-blind, parallel RCT
Grade 1- High

Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 2007; 133: 210-20.

125 adults at multiple sites in the UK and Belgium with a mean age of 52 (treatment) and 54 (placebo) with neuropathic pain were randomised to receive nabiximols (Sativex) THC:CBD spray (maximum 48 sprays/day) or placebo over 5 weeks.

Double-blind, parallel RCT
Grade 1- High

Heidelberg University. Supporting effect of dronabinol on behavioral therapy in fibromyalgia and chronic back pain (clinical trial record only). US National Library of Medicine; NCT00176173.

An unreported number of patients estimated at 240 with fibromyalgia or back pain were randomised to behavioural therapy and dronabinol (Marinol), behavioural therapy and placebo, behavioural therapy only, or standard medical therapy.

Double-blind, parallel RCT
Grade 1- High

Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65: 812-9.

66 adults aged 49-71 with MS spasticity and pain at a single centre in the UK were randomised to receive nabiximols (Sativex) THC:CBD spray or placebo over 5 weeks.

Double-blind, parallel RCT
Grade 1- High

Wade DT, Makela P, Robson P, House H, Bateman C. 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 2004; 10: 434-41.

160 outpatients with MS aged 27-74 drawn from 3 sites in the UK with at least one of five target symptoms (spasticity, spasms, bladder problems, tremor or pain) were randomised to treatment with nabiximols (Sativex) THC:CBD spray or placebo over 6 weeks with a maximum of 48 sprays/day.

Single-blind, parallel RCT
Grade 1- High

Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003; 362: 1517-26.

657 adults at 33 sites in the UK with a mean age of 50, stable multiple sclerosis and muscle spasticity were randomised to dronabinol (Marinol), oral cannabis extract containing THC:CBD (Cannador, Berlin), or placebo over 15 weeks, with a maximum of 25mg/day.

Double-blind, crossover RCT
Grade 1- High

Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ Case Reports 2008; 336: 199-201.

96 adults aged 23-84 with chronic neuropathic pain compared adjuvant treatment with nabilone (Cesamet) and dihydrocodeine over 6 weeks with a 2 week washout between treatment periods.

Double-blind, parallel RCT
Grade 2- Moderate

de Vries M, van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, van Goor H, Pain Nociception Neuroscience Research Group. Tetrahydrocannabinol does not reduce pain in patients with chronic abdominal pain in a Phase 2 placebo-controlled study. Clinical Gastroenterology and Hepatology 2017; 15: 1079-86 e4.

65 adults with chronic abdominal pain for 3 months or more after surgery or because of chronic pancreatitis were randomised to oral tablets with purified standardised THC content (Namisol; Echo Pharmaceuticals, Weesp, the Netherlands) or identical matching placebo administered orally for 50-52 days beginning with two step up stages to a stable dose of 8mg 3 times/day for 40 days.

Double-blind, parallel RCT
Grade 2- Moderate
see also [27]

van Amerongen G, Kanhai K, Baakman AC, Heuberger J, Klaassen E, Beumer TL, et al. Effects on spasticity and neuropathic pain of an oral formulation of delta9-tetrahydrocannabinol in patients with progressive multiple sclerosis. Clinical Therapeutics 2017; February 9: 10.1016/j.clinthera.2017.01.016.

24 patients with progressive MS and moderate spasticity who completed a crossover challenge study phase were randomised to receive oral THC in tablet form (ECP002, Echo Pharmaceuticals BV) at a potency of 1.5mg with that of 5mg, and with placebo thrice daily over 4 weeks at dosages determined during the challenge phase.

Double-blind, parallel RCT
Grade 2- Moderate

Riva N, Mora G, Soraru G, Luncetta C, Falzone Y, Marinou K, et al. The CANALS study: a randomized, double-blind, placebo-controlled, multicentre study to assess the safety and efficacy on spasticity symptoms of a Cannabis sativa extract in motor neuron disease patients (abstract only of paper presented at the 27th International Symposium on Amyotrophic Lateral Sclerosis/Motor Neuron Disease). Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2016; 17: 44.

60 consecutive motor neuron disease patients at several treatment sites in Italy were randomised to nabiximols (Sativex) or placebo over 6 weeks.

Double-blind, parallel RCT
Grade 2- Moderate

Turcotte D, Doupe M, Torabi M, Gomori A, Ethans K, Esfahani F, et al. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain Medicine 2015; 16: 149-59.

15 relapsing-remitting adult MS patients aged 18–65 with MS-induced neuropathic pain were randomised to adjunctive treatment with nabilone (Cesamet) or placebo.

Double-blind, parallel RCT
Grade 2- Moderate

GW Pharmaceuticals Ltd. A study of cannabis based medicine extracts and placebo in patients with pain due to spinal cord injury (clinical trial record only). US National Library of Medicine 2012b; NCT01616202.

116 adults with non-acute spinal cord injury related central neuropathic pain not wholly relieved by current therapy were randomised to nabiximols (Sativex) or placebo; each dose delivered 2.5mg THC and 2.5mg CBD. The maximum permitted was 8 doses in any 3 hour period, and 48 in any 24 hour period.

Double-blind, parallel RCT
Grade 2- Moderate

Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, et al. 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 2011; 18: 1122-31.

241 subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy were randomised to nabiximols (Sativex) or placebo over 19 weeks as an adjunctive treatment.

Double-blind, parallel RCT
Grade 2- Moderate

Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care 2010; 33: 128-30.

30 patients with a mean age 58 and diabetic peripheral neuropathy were randomised to adjuvant treatment with nabiximols (Sativex) THC:CBD spray or placebo over 12 weeks.

Double-blind, parallel RCT
Grade 2- Moderate

Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. Journal of Pain 2008; 9: 164-73.

40 adults meeting diagnostic criteria for fibromyalgia were randomly assigned to receive nabilone (Cesamet) or placebo over 4 weeks. Participants had a mean age of 47 (treatment), and 50 (placebo)

Double-blind, parallel RCT
Grade 2- Moderate

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 arthritis. Rheumatology 2006; 45: 50-2.

58 patients with a mean age of 62 and pain caused by rheumatoid arthritis at 8 UK centres were randomised to treatment with nabiximols (Sativex) THC:CBD spray or placebo over 5 weeks.

Double-blind, crossover RCT
Grade 2- Moderate
see also [19]

van Amerongen G, Kanhai K, Baakman AC, Heuberger J, Klaassen E, Beumer TL, et al. Effects on spasticity and neuropathic pain of an oral formulation of delta9-tetrahydrocannabinol in patients with progressive multiple sclerosis. Clinical Therapeutics 2017; February 9: 10.1016/j.clinthera.2017.01.016.

24 patients with progressive MS and moderate spasticity compared oral THC in tablet form (ECP002A, Echo Pharmaceuticals BV) at a potency of 1.5mg with that of 5mg, and with placebo in a dose-finding phase preceding a crossover RCT.

Double-blind, crossover RCT
Grade 2- Moderate

de Vries M, Van Rijckevorsel DC, Vissers KC, Wilder-Smith OH, Van Goor H. Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. British Journal of Clinical Pharmacology 2016; 81: 525-37.

24 patients suffering from abdominal pain as result of chronic pancreatitis compared single daily doses of THC (Namisol) 8mg or active placebo (5mg/10mg diazepam) administered orally in a double dummy design. Each patient subsequently received the alternative after a washout period of at least 14 days.

Double-blind, crossover RCT
Grade 2- Moderate

Wilsey B, Marcotte TD, Deutsch R, Zhao H, Prasad H, Phan A. An exploratory human laboratory experiment evaluating vaporized cannabis in the treatment of neuropathic pain from spinal cord injury and disease. Journal of Pain 2016; 17: 982-1000.

42 patients, mean age 46 with neuropathic pain related to spinal cord injury or disease compared US NIDA-supplied cannabis containing 2.9% THC, with cannabis containing 6.7% THC and with cannabis with 0% (placebo) administered with a vaporiser in 8 hour treatments

Double-blind, crossover RCT
Grade 2- Moderate

Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. Journal of Pain 2015; 16: 616-27.

16 patients with painful diabetic peripheral neuropathy compared US NIDA-supplied cannabis with THC concentrations of 1% with 4%, 7% and 0% (placebo) administered in vaporised form.

Double-blind, crossover RCT
Grade 2- Moderate

Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Journal of Pain and Symptom Management 2014; 47: 166-73.

18 patients, mean age 56, with chemotherapy-induced neuropathic pain and stable concurrent analgesia recruited from the pain management unit, Queen Elizabeth II Health Sciences Center, Nova Scotia compared nabiximols (Sativex) THC:CBD spray with placebo as an adjuvant treatment in two 4 week periods with a 2 week washout.

Double-blind, crossover RCT
Grade 2- Moderate

Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. Journal of Pain 2013; 14: 136-48.

39 adults, mean age 50, with peripheral neuropathic pain who had previously used cannabis, but not in the past 30 days compared vaporised cannabis containing 3.5% THC with 1.3% THC and with 0% (placebo) in six hour treatments with 3-7 days washout.

Double-blind, crossover RCT
Grade 2- Moderate

Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ: Canadian Medical Association Journal 2012; 184: 1143-50.

37 adult patients, mean age 51, with multiple sclerosis and spasticity recruited through regional clinics and by specialist referral compared cannabis containing 4% THC with placebo cigarettes smoked under clinical supervision once daily over two 3 day treatment periods separated by an 11 day washout.

Double-blind, crossover RCT
Grade 2- Moderate

Pini LA, Guerzoni S, Cainazzo MM, Ferrari A, Sarchielli P, Tiraferri I, et al. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. Journal of Headache and Pain 2012; 13: 677-84.

30 adult outpatients in Modena aged 35-65 with medication overuse headache compared nabilone (Cesamet) with ibuprofen over two 8 week treatment periods with a 1 week washout.

Double-blind, crossover RCT
Grade 2- Moderate

Rintala DH, Fiess RN, Tan G, Holmes SA, Bruel BM. Effect of dronabinol on central neuropathic pain after spinal cord injury: a pilot study. American Journal of Physical Medicine and Rehabilitation 2010; 89: 840-8.

7 adult patients with neuropathic pain from spinal cord injury compared dronabinol (Marinol) 5mg/day titrated up to 20mg/day to diphenhydramine.

Double-blind, crossover RCT
Grade 2- Moderate

Ware MA, Fitzcharles MA, Joseph L, Shir Y. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesthesia and Analgesia 2010a; 110: 604-10.

32 adults aged 26-76 with a diagnosis of fibromyalgia and chronic insomnia compared nabilone (Cesamet) with amitriptyline over two 14 day treatment periods separated by a 14 day washout phase.

Double-blind, crossover RCT
Grade 2- Moderate

Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ: Canadian Medical Association Journal 2010b; 182: E694-701.

23 adults aged 25-77 with neuropathic pain from trauma or surgery compared treatment with smoked cannabis containing 2.5% THC with that containing 6% THC, with 9.4% THC and with 0% (placebo) over 5 days of treatment with a 9 day washout.

Double-blind, crossover RCT
Grade 2- Moderate

Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34: 672-80.

34 adults, mean age 49 with HIV related neuropathic treatment-resistant pain compared smoked cannabis with placebo cigarettes supplied by US NIDA as an adjuvant treatment over two 5 day periods of 4 smoking sessions/day with 2 weeks washout. Patients assigned to the active treatment started at 4% THC and individually titrated doses (ranging from 8% to 1%) to balance pain relief with side effects; 28 completed the trial.

Double-blind, crossover RCT
Grade 2- Moderate
see also [54]

Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. Journal of Pain 2008; 9: 254-64.

30 adults aged 21-67 with chronic non-cancer pain recruited at several Harvard Medical School teaching hospital sites compared dronabinol (Marinol) 20mg/day with dronabinol 10mg/day and with placebo as an adjuvant treatment over the course of three 8 hour visits with 72 hour washouts between treatments.

Double-blind, crossover RCT
Grade 2- Moderate

Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. Journal of Pain 2008; 9: 506-21.

38 patients with central and peripheral neuropathic pain compared high-dose (7% THC) with low-dose (3.5% THC) and with placebo smoked cannabis supplied by US NIDA.

Double-blind, crossover RCT
Grade 2- Moderate
see also [57]

Pinsger M, Schimetta W, Volc D, Hiermann E, Riederer F, Polz W. [Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trial]. Wiener klinische Wochenschrift 2006; 118: 327-35 (in German with English abstract).

30 adults in an Austrian treatment centre aged 50-63 with chronic refractory pain of musculoskeletal origin compared nabilone (Cesamet) with placebo in self titrated doses of up to 1mg/day of the active agent as an adjuvant treatment over 14 weeks (two 4 week medication phases plus a 5 week wash-out).

Double-blind, crossover RCT
Grade 2- Moderate

Wissel J, Haydn T, Muller J, Brenneis C, Berger T, Poewe W, et al. Low dose treatment with the synthetic cannabinoid nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. Journal of Neurology 2006; 253: 1337-41.

13 adult patients aged 19-68 with chronic upper motor neuron syndrome suffering from disabling spasticity-related pain refractory to previous pain treatment compared adjuvant treatment with nabilone (Cesamet) to placebo.

Double-blind, crossover RCT
Grade 2- Moderate

Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain 2004; 112: 299-306.

48 adults aged 23-63 with central neuropathic pain from brachial plexus avulsion compared nabiximols (Sativex) THC:CBD spray, maximum 48 sprays per day, with THC oromucosal spray and with placebo for 2 weeks with no washout between treatment periods.

Double-blind, crossover RCT
Grade 2- Moderate

Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, et al. Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology 2004; 63: 1245-50.

19 adults aged 18-75 with a clinical diagnosis of ideopathic Parkinson disease recruited from UK outpatient clinics in Devon and Cornwall compared an oral cannabis (THC:CBD) extract of Cannabis sativa with placebo as an adjuvant treatment. Study medication was standardised to 2.5mg of THC and 1.25mg CBD per capsule (Cannador, Institute for Clinical Research, IKF, Berlin) with a maximum dose of 0.25mg/kg of THC per day, taken twice daily.

Double-blind, crossover RCT
Grade 2- Moderate

Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ Case Reports 2004; 329: 253.

24 patients aged 23-55 with multiple sclerosis and central pain compared dronabinol (Marinol) with placebo over 3 week treatment periods with 3 week washouts.

Double-blind, crossover RCT
Grade 2- Moderate

Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003; 290: 1757-62.

21 adults aged 29-65 with chronic neuropathic pain compared synthetic cannabinoid CT-3 with placebo in 1 week treatment periods with 1 week washouts.

Double-blind, crossover RCT
Grade 2- Moderate
see also [59]

Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehabilitation 2003; 17: 21-9.

20 patients with neuropathic pain from several conditions including MS who completed a 2 week open label phase using known THC:CBD entered an 8 week phase of four 2 week stages comparing THC with CBD, with THC:CBD spray and with placebo in a double-blind crossover study.

Double-blind, crossover RCT
Grade 3- Low
see also [69]

Chung SA, Hossain NK, Blackman AS, Shapiro CM. Can the cannabinoid nabilone help with pain and sleep in fibromyalgia patients? Sleep 2009; 32: A325-A26.

6 female fibromyalgia patients, median age 52, compared nabilone (Cesamet, Valeant Canada Ltd, Montreal) with placebo in 1mg doses in a 4 week crossover pilot.

Parallel RCT
Grade 2- Moderate

Schimrigk, S., Marziniak, M., Neubauer, C., Kugler, E. M., Werner, G., & Abramov-Sommariva, D. (2017). Dronabinol is a safe long-term treatment option for neuropathic pain patients. European Neurology, 78, 320-329.

Treatment of neuropathic pain (NP) symptoms associated with multiple sclerosis (MS) is frequently insufficient. Yet, cannabis is still rarely offered for treatment of pain. This clinical trial aimed at showing the positive benefit-risk ratio of dronabinol. Two hundred forty MS patients with central NP entered a 16-weeks placebo-controlled phase-III study followed by a 32-weeks open-label period. One hundred patients continued therapy for overall up to 119 weeks. Primary endpoint was change of pain intensity on the 11-point Numerical Rating Scale over a 16-weeks treatment period. Safety was assessed on the basis of adverse reactions (ARs), signs of dependency and abuse. Pain intensity during 16-weeks dronabinol and placebo treatment was reduced by 1.92 and 1.81 points without significant difference in between (p = 0.676). Although the proportion of patients with ARs was higher under dronabinol compared to placebo (50.0 vs. 25.9%), it decreased during long-term use of dronabinol (26%). No signs of drug abuse and only one possible case of dependency occurred. The trial results demonstrate that dronabinol is a safe long-term treatment option.

Double blind, randomised placebo-controlled trial
Grade 1- High

Hunter, D. Oldfield, G. Tich, N. Messenheimer, J. Synthetic transdermal cannabidiol for the treatment of knee pain due to osteoarthritis. Osteoarthritis and Cartilage 2018; 26 (Supplement 1)

Purpose: Cannabidiol (CBD) has shown promise in reducing pain and inflammation in pre-clinical models of arthritis. However, there have been no well controlled studies evaluating CBD for osteoarthritis (OA) in humans. This study evaluated safety and efficacy of ZYN002 (transdermal synthetic CBD gel) for the treatment of knee pain due to OA in adults. Method(s): A Phase 2A, randomized, double-blind, placebo-controlled, multiple-dose study assessed ZYN002 administered twice daily for 12 weeks to adults with knee pain due to OA. Patients met ACR criteria for OA of the knee and underwent a 1-week washout to stop current anti-inflammatory agents/ other analgesics (except paracetamol) followed by a 7 to 10-day baseline period capturing daily worst pain ratings using a 0 to 10 numeric rating scale. Eligible patients were randomized 1:1:1 to ZYN002 250 mg daily in 2 divided doses, ZYN002 500 mg daily in 2 divided doses, or placebo. The primary efficacy endpoint was change from baseline in the weekly mean of the 24-hour average worst pain score at Week 12. A key secondary endpoint was a responder analysis, defined as average weekly improvement in worst pain score of > 30% and decrease in WOMAC physical function sub scale of at least 20% at last observation. Result(s): Three hundred and twenty patients were randomized. Mean age was 62 (41-78) years, baseline mean worst knee pain score was 6.9. ZYN002 was not statistically different from placebo on the primary endpoint; week 12 mean reduction from baseline in average worst knee pain was -2.64 for ZYN002 250 mg/day (n = 106), -2.83 for ZYN002 500 mg/day (n = 105) and -2.37 for placebo (n = 103). However, patients using ZYN002 250 mg/day (n = 93) significantly outperformed placebo (n = 88) for the responder analysis (52.7% vs 34.1%, p = 0.016). Post-hoc analyses revealed that men treated with ZYN002 250mg/day (n = 43) had significantly greater reductions from baseline in average worst knee pain scores than placebo-treated men (n = 31; 2.68 vs 1.70, p = 0.049) and greater performance in the responder analysis (n = 45; 60% vs 26.7%, p = 0.003), as compared to men who received placebo (n = 45). Indeed, women on ZYN002 did not differ from placebo in changes in average worst knee pain scores or responder analysis. Patients with the least amount of variability in baseline pain scores had greater performance in the responder analysis in both the 250 mg/day (n = 34; p = 0.055) and 500 mg/day (n = 29; p = 0.046) compared to placebo (n = 37). There were 2 treatment emergent adverse events that exceeded 3% of patients on ZYN002 and were greater than placebo: application site dryness (3.8% vs 0.9%) and headache (3.3% vs 1.9%). Conclusion(s): After 12 weeks of blinded treatment, while ZYN002 250 mg/day produced numerically better mean reductions from baseline in average worst knee pain scores, it was not statistically different than placebo. In contrast, the responder endpoint showed statistically significant differences between 250 mg/day and placebo. Significant gender differences were noted with the responder analysis and pain scores. Both doses of ZYN002 were well tolerated.

Double blind, randomised placebo-controlled trial
Grade 1- High

Malik, Z. Bayman, L. Valestin, J. Rizvi-Toner, A. Hashmi, S. Schey, R. Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial. Diseases of the Esophagus 2017; 30: https://dx.doi.org/10.1111/dote.12455 - external site

Noncardiac chest pain is associated with poor quality of life and high care expenditure. The majority of noncardiac chest pain is either gastresophageal reflux disease related or due to esophageal motility disorders, and the rest are considered functional chest pain (FCP) due to central and peripheral hypersensitivity. Current treatment of FCP improves 40-50% of patients. Cannabinoid receptors 1 (CB1) and 2 (CB2) modulate release of neurotransmitters; CB1 is located in the esophageal epithelium and reduces excitatory enteric transmission and potentially could reduce esophageal hypersensitivity. We performed a prospective study to evaluate its effects on pain threshold, frequency, and intensity in FCP. Subjects with FCP received dronabinol (5 mg, twice daily; n = 7; average age, 44 years; mean body mass index, 26.7) or placebo (n = 6; average age, 42 years; mean body mass index, 25.9) for 28 days (4 weeks). Chest pain, general health, and anxiety/depression questionnaires were assessed at baseline and at 4 weeks. Subjects underwent an esophageal balloon distention test prior to treatment and on last day of the study. Dronabinol increased pain thresholds significantly (3.0 vs. 1.0; P = 0.03) and reduced pain intensity and odynophagia compared to placebo (0.18 vs. 0.01 and 0.12 vs. 0.01, respectively, P = 0.04). Depression and anxiety scores did not differ between the groups at baseline or after treatment. No significant adverse effects were observed. In this novel study, dronabinol increased pain threshold and reduced frequency and intensity of pain in FCP. Further, large scale studies are needed to substantiate these findings.

Double blind, randomised placebo-controlled trial
Grade 1- High

Markovà , J. Essner, U. Akmaz, B. Marinelli, M. Trompke, C. Lentschat, A. Vila, C. 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 2019; 129: 10.1080/00207454.2018.1481066

Purpose/aim: To evaluate the efficacy of tetrahydrocannabinol (THC): cannabidiol (CBD) oromucosal spray (Sativex®) as add-on therapy to optimised standard antispasticity treatment in patients with moderate to severe multiple sclerosis (MS) spasticity. Methods: Sativex® as add-on therapy vs. further optimised first-line ANTispastics (SAVANT) was a two-phase trial. In Phase A, eligible patients received add-on THC: CBD spray for 4 weeks to identify initial responders [≥20% improvement from baseline in spasticity 0–10 numerical rating scale (NRS) score]. Following washout, eligible initial responders were randomised to receive THC: CBD spray or placebo for 12 weeks (double-blinded, Phase B). Optimisation of underlying antispasticity medications was permitted in both groups across all study periods. Results: Of 191 patients who entered Phase A, 106 were randomised in Phase B to receive add-on THC:CBD spray (n = 53) or placebo (n = 53). The proportion of clinically relevant responders after 12 weeks (≥30% NRS improvement; primary efficacy endpoint) was significantly greater with THC:CBD spray than placebo (77.4 vs. 32.1%; p < 0.0001). Compared with placebo, THC:CBD spray also significantly improved key secondary endpoints: changes in mean spasticity NRS (p  < 0.0001), mean pain NRS (p = 0.0013), and mean modified Ashworth’s scale (p = 0.0007) scores from Phase B baseline to week 12. Adverse events, when present, were mild/moderate and without new safety concerns. Conclusions: Add-on THC:CBD oromucosal spray provided better and clinically relevant improvement of resistant MS spasticity compared with adjusting first-line antispasticity medication alone.

Randomised controlled trial
Grade 1- High

Nicolodi, M. Sandoval, V. Torrini, A. Therapeutic use of cannabinoids-dose finding, effects and pilot data of effects in chronic migraine and cluster headache. European Journal of Neurology 2017; 24 (Supplement 1): http://dx.doi.org/10.1111/ene.13367 - external site

Background and aims: Aim was to verify therapeutic effect of 19% THC (bedrocan) + <0.4% THC, 9% CBD (bedrolite) in both prophylaxis and acute treatment of chronic cluster headache (CH) and migraine (M). Method(s): Step 1-we performed a dose finding observations in 48 chronic M volunteers, during 4 test-retest of THC+CBD. Starting dose was 10mg/orally. Step 2-M (n=370) and CH sufferers (n=190) volunteered the prospective observation. Entry criteria were: normal examines, normal elctrocardiogram. After a 10-days washout period, M sufferers were randomly assigned to a 3 months-treatment with 25mg/day amitriptyline or THC+CBD 200 mg/day in 200 ml 50% fat emulsion. CH received THC+CBD or 480mg/day verapamil. One-month follow-up was provided. Two hundred mg THC+CBD were also administered as acute treatment. Rescue treatment was 6 mg/s.c. sumatriptan. Result(s): Therapeutic dose was 200mg THC+CBD inducing 55% pain decrease. Doses lower than 100mg induced 0% relief. Pilot data refer to 79 M and 48 CH. In M THC+CBD prophylaxis induced 40.4% benefit versus 40.1% amitriptyline-evoked pain relief. In CH, THC+CBD prophylaxis induced scant decrease of severity and number of attacks. Acute THC+CBD decreased attack pain-43.5% in both M and CH who had an history of M when children. Relief was 0% in CH without M history. Adverse effects were drowsiness and inattention. These effects and decrease (range-70%-100%) of stomach ache, colitis and musculoskeletal pain strictly related to female sex, p>0.0001. Conclusion(s): Discussion Cannabinoids may be a prophylaxis for M and an acute treatment for CH in case M occurred during childhood.

Double blind, randomised placebo-controlled trial
Grade 1- High

Riva, N. Mora, G. Soraru, G. Lunetta, C. Ferraro, O. E. Falzone, Y. Leocani, L. Fazio, R. Comola, M. Comi, G. Formaglio, F. Rossi, P. Clerici, M. Falzone, Y. M. Pozzi, L. Martinelli, D. Cerri, F. Lopez, I. D. Martinelli-Boneschi, F. Quattrini, A. Pieri, E. Marinou, K. Querin, G. Sansone, V. Maestri, E. Calvo, A. Chio, A. Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet Neurology 2019; 18: http://dx.doi.org/10.1016/S1474-4422%2818%2930406-X - external site

Background: Spasticity is a major determinant of disability and decline in quality of life in patients with motor neuron disease. Cannabinoids have been approved for symptomatic treatment of spasticity in multiple sclerosis. We investigated whether cannabinoids might also reduce spasticity in patients with motor neuron disease. Method(s): We did an investigator-initiated, randomised, double-blind, placebo-controlled, phase 2 clinical trial at four tertiary motor neuron disease centres in Italy. Eligible patients were aged 18-80 years; had possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis as defined by revised El Escorial criteria, or primary lateral sclerosis according to Pringle's criteria; had spasticity symptoms due to motor neuron disease for at least 3 months; had spasticity scores of 1 or greater in at least two muscle groups on the Modified Ashworth Scale; and were taking an antispasticity regimen that was maintained at a stable dose for 30 days before enrolment. Participants were assigned (1:1) by an independent statistician via a computer-generated randomisation sequence to a standardised oromucosal spray (nabiximols) containing a defined combination of delta-9-tetrahydrocannabinol and cannabidiol (each 100 muL actuation contained 2.7 mg delta-9-tetrahydrocannabinol and 2.5 mg cannabidiol) or to placebo for 6 weeks. Participants self-titrated during the first 14 treatment days according to a predefined escalation scheme (maximum 12 actuations per 24 h), then maintained that dose for 4 weeks. The primary endpoint was the change in the score on the Modified Ashworth Scale, which was assessed at baseline and after 6 weeks. Safety and tolerability were also monitored. Participants, investigators, site personnel, and the study statistician were masked to treatment allocation. All randomised participants who received at least one dose of study drug were included in the analysis. This trial is registered with ClinicalTrials.gov, number NCT01776970. The trial is closed to new participants with follow-up completed. Finding(s): Between Jan 19, 2013, and Dec 15, 2014, 60 participants were randomly assigned, and 59 participants were included in the final analysis (29 in the nabiximols group and 30 in the placebo group). Modified Ashworth Scale scores improved by a mean of 0.11 (SD 0.48) in the nabiximols group and deteriorated by a mean of 0.16 (0.47) in the placebo group (adjusted effect estimate -0.32 [95% CI -0.57 to -0.069]; p=0.013). Nabiximols was well tolerated, and no participants withdrew from the double-blind phase of the study. No serious adverse effects occurred. Interpretation(s): In this proof-of-concept trial, nabiximols had a positive effect on spasticity symptoms in patients with motor neuron disease and had an acceptable safety and tolerability profile. These findings should be investigated further in larger clinical trials.
Funding(s): Italian Research Foundation for Amyotrophic Lateral Sclerosis. Copyright © 2019 Elsevier Ltd

Double blind, randomised placebo-controlled trial
Grade 1- High

Turner, S. Kumar, R. Fairhurst, C. Safety, efficacy and tolerability of oro-mucosal tetrahydrocannabinol/cannabidiol therapy to reduce spasticity in children and adolescents. results of a multicentre, double blind placebo-controlled trial. Developmental Medicine and Child Neurology 2017; 59 (Supplement 4): http://dx.doi.org/10.1111/dmcn.13622 - external site

Objective: To assess the safety, tolerance and efficacy of oro-mucosal tetrahydrocannabinol/cannabidiol (THC/CBD, Sati-vex, GW pharma,) as an adjunct therapy for children and adolescents aged 8-18 with spasticity due to cerebral palsy, or traumatic CNS injury and inadequate response to existing treatment Method: 72 children and adolescents, were randomised to receive THC/CBD or placebo (2:1 ratio) for a period of 12 weeks. Titration occurred up to a maximum of 12 sprays/per day, dependent on outcome and tolerance. The primary outcome was a change from baseline in a spasticity numerical rating scale (NRS 0-10) at 12 weeks (7 day mean values). Secondary outcomes included additional ratings for spasticity, Sleep, Pain, health related quality of life of patient and carer Comfort, Depression, adverse events and clinical laboratory tests. Result(s): Efficacy-There was no significant difference in spasticity (NRS) between THC/CBD and placebo groups at study end (primary endpoint, p=0.73). Improvements in secondary outcome measures, though not to statistical significance, were observed, in the areas of pain (pain 1-p 0.079; pain 2 a p 0.021), sleep (p 0.36) and MTS (p 0.43). However, post-hoc covariate analysis in the adolescent population, age 12-17 (n=37), showed a mean treatment difference between groups of-1.96 (p 0.0135). Safety and tolerability-2 patients withdrew from THC/CBD group (4.3%) and 1 from placebo group (4.0%) due to adverse events. Adverse events were predominantly mild to moderate. Dose tolerance between the treatment arms was similar (Mean 9.6: 10.2 puffs/day). Conclusion(s): Tetrahydrocannabinol/cannabidiol therapy was generally well tolerated in this study. However, treatment with tetrahydrocannabinol/cannabidiol did not demonstrate a significant reduction in spasticity compared to placebo in this population. Further research based upon subgroup analyses is indicated.

Randomised placebo-controlled cross-over trial
Grade 2 - Moderate

van de Donk, T. Niesters, M. Kowal, M. A. Olofsen, E. Dahan, A. van Velzen, M. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain 2019; 160: https://dx.doi.org/10.1097/j.pain.0000000000001464 - external site

In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in 20 chronic pain patients with fibromyalgia. We tested 4 different cannabis varieties with exact knowledge on their [INCREMENT]-tetrahydrocannabinol (THC) and cannabidiol (CBD) content: Bedrocan (22.4-mg THC, <1-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bediol (13.4-mg THC, 17.8-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bedrolite (18.4-mg CBD, <1-mg THC; Bedrocan International BV, Veendam, the Netherlands), and a placebo variety without any THC or CBD. After a single vapor inhalation, THC and CBD plasma concentrations, pressure and electrical pain thresholds, spontaneous pain scores, and drug high were measured for 3 hours. None of the treatments had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol displayed a 30% decrease in pain scores compared to placebo (90% vs 55% of patients, P = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (rho = -0.5, P < 0.001). Cannabis varieties containing THC caused a significant increase in pressure pain threshold relative to placebo (P < 0.01). Cannabidiol inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, indicative of synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores, THC-CBD interactions, and the role of psychotropic symptoms on pain relief.

Randomised, double-blinded, placebo-controlled crossover study
Grade 2 - Moderate

Wallace, M. Correlation of tetrahydrocannabinol plasma levels with pain reduction in diabetic peripheral neuropathy. Pain Medicine (United States) 2017; 18 (3): http://dx.doi.org/10.1093/pm/pnx033 - external site

There is emerging evidence that inhaled cannabis is effective in the treatment of neuropathic pain. However, few studies have looked at the correlation between THC plasma concentration and pain relief. A randomized, double-blinded, placebo-controlled crossover study was conducted in sixteen patients with painful diabetic peripheral neuropathy. Subjects participated in four sessions where they were exposed to placebo, low (1% tetrahydrocannabinol, THC), medium (4% THC), or high (7% THC) dose of cannabis. Subjects were administered aerosolized cannabis or placebo and the spontaneous and evoked (von frey and stroking) pain intensity was measured and a blood sample for plasma THC levels were taken at 5, 15, 30, 45, 60minutes and then every 30 minutes for an additional 3 hours. Analysis was done for both the administered dose and peak plasma concentrations. Within each dose level, subjects were divided into those with peak plasma concentration < 15 ng/ml or>15 ng/ml. There was a significant dose dependent reduction in both spontaneous and evoked pain with the highest dose being most effective. Evoked pain showed the tightest correlation and was used to analyze THC concentration and pain reduction. There was a significant correlation between pain reduction between 5- 15 ng/ml (p=0.0319) which was lost at>15 ng/ml THC (p=0.9111). There appears to be a therapeutic window for the analgesic effects of THC and patients should be counseled that more is not better.

Randomised, double-blinded, placebo-controlled trial
Grade 2 - Moderate

Weizman, L. Dayan, L. Brill, S. Nahman-Averbuch, H. Hendler, T. Jacob, G. Sharon, H. Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity. Neurology 2018; 91: https://dx.doi.org/10.1212/WNL.0000000000006293 - external site

OBJECTIVE: To characterize the functional brain changes involved in delta-9-tetrahydrocannabinol (THC) modulation of chronic neuropathic pain.
METHODS: Fifteen patients with chronic radicular neuropathic pain participated in a randomized, double-blind, placebo-controlled trial employing a counterbalanced, within-subjects design. Pain assessments and functional resting state brain scans were performed at baseline and after sublingual THC administration. We examined functional connectivity of the anterior cingulate cortex (ACC) and pain-related network dynamics using graph theory measures.
RESULTS: THC significantly reduced patients' pain compared to placebo. THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex. Moreover, the degree of reduction was predictive of the response to THC. Graph theory analyses of local measures demonstrated reduction in network connectivity in areas involved in pain processing, and specifically in the dorsolateral prefrontal cortex (DLPFC), which were correlated with individual pain reduction.
CONCLUSION: These results suggest that the ACC and DLPFC, 2 major cognitive-emotional modulation areas, and their connections to somatosensory areas, are functionally involved in the analgesic effect of THC in chronic pain. This effect may therefore be mediated through induction of functional disconnection between regulatory high-order affective regions and the sensorimotor cortex. Moreover, baseline functional connectivity between these brain areas may serve as a predictor for the extent of pain relief induced by THC.

Double-blind, placebo-controlled crossover trial [PROTOCOL]
Grade: N/A

NCT02892591 2019. Cannabis versus oxycodone for pain relief: A Double-Blind, Placebo-Controlled Crossover Study Comparing the Analgesic Efficacy of Cannabis Versus Oxycodone. Clinicaltrials.gov: NCT NCT02892591, https://clinicaltrials.gov/ct2/show/NCT02892591?te... - external site.

Overview: This study investigates the ability of cannabis to reduce chronic back and neck pain and to reduce sensitivity to an acute painful stimulus. Cannabis will be compared to both oxycodone and a placebo. 100 participants will be randomised to receive medium dose THC, 5-10mg oxycodone hydrochloride or placebo in a double-blind, placebo-controlled crossover design. Primary outcome measures include pain intensity (numerical rating scale) and pain threshold. Secondary outcome measures include patient global impression of change score. Recruitment is ongoing with an estimated study completion date of December 2020.

Double blind, randomised placebo-controlled trial [PROTOCOL]
Grade: N/A

Euctr, D. K. Can-Art Effect and safety of using Canabis derivatives for the treatment of pain in patients with inflammatory Arthritis, such as reumatoid arthritis and ankylosing spondylitis, the latter being a type of arthritis that causes a long-term inflammation of the joints of the spine. A randomized, double blinded, placebo-controlled trial, i.e. in this drug trial, a control group is given a placebo while another group is given the Cannabis derivative being studied. http://www.who.int/trialsearch/Trial2.aspx?TrialID... - external site 2018

INTERVENTION: Product Name: Cannabidiol tablet 10 mg Pharmaceutical Form: Tablet CAS Number: 13956-29-1Other descriptive name: CANNABIDIOL Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Product Name: Dronabinol capsule 2.5. mg Pharmaceutical Form: Capsule INN or Proposed INN: CAS Number: 1972-08-3CONDITION: Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS) ; MedDRA version: 20.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395- Musculoskeletal and connective tissue disorders ; MedDRA version: 20.0 Level: PT Classification code 10002556 Term: Ankylosing spondylitis System Organ Class: 10028395-Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C]-Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: RA and AS are systemic autoimmune diseases characterized by chronic, systemic inflammatory conditions, primarily of the musculoskeletal system. Pain and fatigue are typical symptoms and their treatment is a clinical challenge. The present study aims to clarify the potential of medical cannabis as a complement to the existing treatment in RA and AS.; ; More precisely, the study aims to clarify in RA and AS patients, whether the add-on treatment with CBD (placebo controlled) or the combination of CBD and THC (open label) results in a significantly improved pain situation as assessed by the number of patients achieving an improvement of pain visual analogue scores (VAS) with a reduction of ? VAS > 20. Primary end point(s): The study investigates the effect of CBD, more specific whether the add-on treatment with CBD results in a significantly improved pain situation as assessed by the number of patients achieving an improvement of pain-VAS with a reduction of ? VAS> 20. Assessment takes place after 12 and 24 weeks of active treatment with CBD. ; ; B. If the patient does not experience an acceptable effect of the CBD treatment in the assessment after 12 weeks (as defined by study protocol, i.e. pain VAS reduction > 20), the randomization is terminated and the treatment proceeds by a combination of CBD and THC. ; THC 2.5 mg daily in week 13 and 14, increasing to 5 mg (2.5 mg x 2 daily) in the following two weeks. If no effect has occurred after week 16, the dose increases in the beginning of the 17th week to the maximum of 7.5 mg THC (2.5 mg x 3 daily) in the 3rd week; ; ; 2. Thus, the study investigates the effect of the combination of CBD and THC, more specific whether the add on treatment with CBD for 12 weeks followed by the combined treatment of CBD and THC for another 12 weeks results in a significantly improved pain situation as assessed by the number of patients achieving an improvement of pain-VAS with a reduction of ? VAS> 20. Assessment takes place after 12 and 24 weeks of active treatment with CBD and after 12 weeks of active treatment with CBD followed by another 12 weeks combined treatment with CBD and THC. ; Secondary Objective: A significantly improved pain situation as assessed by the number of AS patients that achieve a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) < 40 and / or improvement in BASDAI with ? > 20 after 12 and/ or 24 weeks of treatment with CBD or 12 weeks of treatment with CBD followed 12 weeks of treatment with the combination of CBD and THC in an open follow-up.; ; A significantly improved life situation as assessed by the number of patients that achieve a Global VAS < 50 and / or an improvement in Global-VAS with ? VAS> 20 after 12 and/ or 24 weeks of treatment with CBD or 12 weeks of treatment with CBD followed by 12 weeks of treatment with a combination of CBD and THC in an open follow-up study.; ; The effect of the intervention on the patients attention and concentration is investigated using cognitive tests (Trail Making Test (TMT) and Digit Symbol Substitution Test (DSST)). Additionally, sleep quality is evaluated with the Pitssburgh Sleep Quality Index. Timepoint(s) of evaluation of this end point: During this study period, the participants are invited to four visits at one of the participating centers. At baseline and after 12 and 24 weeks(7 days) respectively, the key data i.e. the pain VAS scores are determined and registered in the Danish nationwide quality registry DANBIO.; ; Briefly the data are obtained at consultation visit 1 (baseline), a consultation visit at week 12 ± 7 days, another consultation visit at week 24 ± 7 days.; Furthermore a follow up consultation visit will take place at week 36 ± 7 days and define this endpoint 12 weeks after the active treatment is terminated.
SECONDARY OUTCOME: Secondary end point(s): Secondary outcomes; 1) Outcomes: Clinical measurements, i.e. in RA the Disease Activity Score 28-joints (DAS28-CRP), Health Assessment Questionnaire (HAQ) and in the case of AS the Ankylosing spondylitis disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis (BAS)-scores for disease activity (BASDAI), function (BASFI) and measures (BASMI) are registered. Patient Reported Outcome Measures (PROMs) more specific, visual analogue scales (VAS) for fatigue, patient's global; the Quality of Life (QoL)-and pain-scores SF-36 and PainDETECT are obtained. ; Furthermore, the effect of intervention on attention and concentration is investigated using the following cognitive test: Trail Making Test (TMT) and Digit Symbol Substitution Test (DSST). Additionally, sleep quality is evaluated with the Pitssburgh Sleep Quality Index and the expected effect for treatment is measured with Credibility/expectancy Questionnare Devilly and semi-structured course interviews.; ; Thus, the study investigates the effect of CBD, more specific whether the add-on treatment with CBD results in a significantly improved fatigue situation and as well more holistic quality of life situation as assessed by the number of patients achieving an improvement of fatigue-VAS with a reduction of ? VAS> 20 and an improvement of global-VAS with a reduction of ? VAS> 20. ; Assessment takes place after 12 and 24 weeks of active treatment with CBD. ; ; Furthermore, the study investigates the effect of the combination of CBD and THC, more specific whether the add-on treatment with CBD for 12 weeks followed by the combined treatment of CBD and THC for another 12 weeks results in a significantly improved fatigue situation and as well more holistic quality of life situation as assessed by the number of patients achieving an improvement of fatigue-VAS with a reduction of ? VAS> 20 and an improvement of global-VAS with a reduction of ? VAS> 20. ; ; 2) Exposures, i.e. current treatments with DMARDs and/or analgesics including dosing schedule and treatment onset.; 3) Patient demographics, e.g. diagnosis, age and gender, height, weight and Body Mass index (BMI); 4) Comorbidities, e.g. cardiovascular disease, diabetes and hypertension; 5) Life-style (blood pressure, exercise habits and smoking status); Timepoint(s) of evaluation of this end point: At baseline and after 12 and 24 weeks(± 7 days) respectively, the data are registered.; Furthermore, the effect of intervention on attention and concentration is investigated using the following cognitive test: Trail Making Test (TMT) and Digit Symbol Substitution Test (DSST). Additionally, sleep quality is evaluated with the Pitssburgh Sleep Quality Index and the expected effect for treatment is measured with Credibility/expectancy Questionnare Devilly and semi structured course interviews take place at timepoints baseline and after 12 and 24 weeks.; ; INCLUSION CRITERIA: Participants are patients diagnosed with seropositive RA, more specifically inflammatory well-treated patients, characterized by absence of arthritis at 40 counts and normal C-reactive protein (CRP) or with diagnosis AS in accordance with the modified New York criteria, i.e. based on physiotherapy and / or non-steroidal anti-inflammatory drugs (NSAIDs) and / or bDMARD inflammatory well-treated patients, characterized by absence of axial and peripheral arthritis as well as clinically detectable entesitis, as assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS < 2.1) and where normally CRP is documented. Participant with the above-mentioned diagnoses and relevant clinical status quo, followed regularly at one of the four departments are invited to participate in the study. Furthermore: a. Receiving treatment on an outpatient basis b. Diagnosed for at least 2 years c. seropositive (anti CCP and/ or IgM RF) RA, radiology (MRI an

Double blind, randomised placebo-controlled trial [PROTOCOL]
Grade: N/A

Euctr, D. K. Medical cannabis for the treatment of pain in patients with hand osteoarthritis and psoriatic arthritis. http://www.who.int/trialsearch/Trial2.aspx?TrialID... - external site 2018

INTERVENTION: Product Name: Cannabidiol Product Code: CBD Pharmaceutical Form: Tablet INN or Proposed INN: CBD CAS Number: 13956-29-1 Other descriptive name: CANNABIDIOL Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10-Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Psoriatic Arthritis Hand Osteoarthritis ; MedDRA version: 20.0 Level: LLT Classification code 10037160 Term: Psoriatic arthritis System Organ Class: 100000004859 ; MedDRA version: 20.0 Level: LLT Classification code 10019115 Term: Hand osteoarthritis System Organ Class: 100000004859 Therapeutic area: Diseases [C]- Musculoskeletal Diseases [C05]
PRIMARY OUTCOME: Main Objective: To assess the effect of cannabidiol (CBD) on pain in patients with nodal non-erosive hand osteoarthritis (Hand-OA) and psoriatic arthritis (PsA) after 12 weeks Primary end point(s): Changes in VAS pain during the last 24 hours from baseline to 12 weeks Secondary Objective: o Changes is VAS pain during the last 24 hours from baseline to 24 weeks.; o Changes in VAS global from baseline to 12 weeks and 24 weeks.; o Changes in function scores from baseline to 12 weeks.; o Changes in central pain mechanisms measured with quantitative sensory testing from baseline to 12 weeks and 24 weeks.; o Changes in grip and pinch strength from baseline to 12 weeks* and 24 weeks (Hand-OA only).; o Inflammatory and joint degenerative biomarkers will be measured and comparison between baseline and 12 weeks.; Timepoint(s) of evaluation of this end point: 12 weeks SECONDARY OUTCOME: Secondary end point(s): o Changes is VAS pain during the last 24 hours from baseline to 24 weeks.; o Changes in VAS global from baseline to 12 weeks and 24 weeks.; o Changes in function scores from baseline to 12 and 24 weeks.; o Changes in central pain mechanisms measured with quantitative sensory testing from baseline to 12 weeks and 24 weeks.; o Changes in grip and pinch strength from baseline to 12 weeks* and 24 weeks*.; o Inflammatory and joint degenerative biomarkers will be measured and comparison between baseline and 12 weeks and 24 weeks will be made.; Timepoint(s) of evaluation of this end point: 12-24weeks INCLUSION CRITERIA: Hand-OA: Patients (18 years or older) with Hand-OA according to the American college of rheumatology (ACR) criteria (1990) Hand-OA of the phenotype: Nodal, Non-erosive. Ability and willingness to give written informed consent and to meet the requirements of the study protocol. 100mm VAS pain during the last 24 hours over or equal to 30mm PsA: Patients (18 years or older) with PsA according to the classification criteria for psoriatic arthritis CASPAR criteria (2006) Ability and willingness to give written informed consent and to meet the requirements of the study protocol. 100mm VAS pain during the last 24 hours over or equal to 30mm Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 120 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40

Double blind, randomised placebo-controlled trial [PROTOCOL]
Grade:N/A

Euctr, D. K. The effect of cannabis products on nerve pain and muscle stiffness in patients with multiple sclerosis and in patients with spinal cord injury. http://www.who.int/trialsearch/Trial2.aspx?TrialID... - external site 2018

INTERVENTION: Product Name: Cannabidiol capsule 5 mg Product Code: N/A Pharmaceutical Form: Capsule INN or Proposed INN: Cannabidiol CAS Number: 13956-29-1 Other descriptive name: CBD Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5-Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Dronabinol capsule 2,5 mg Product Code: N/A Pharmaceutical Form: Capsule INN or Proposed INN: DRONABINOL CAS Number: 1972-08-3 Other descriptive name: THC Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5- Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Cannabidiol / Dronabinol capsule 5 mg+2,5 mg Product Code: N/A Pharmaceutical Form: Capsule INN or Proposed INN: DRONABINOL CAS Number: 1972-08-3 Other descriptive name: THC Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2.5-INN or Proposed INN: Cannabidiol CAS Number: 13956-29-1 Other descriptive name: CBD Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5- Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Central neuropathic pain and spasticity ; MedDRA version: 20.0 Level: PT Classification code 10028335 Term: Muscle spasticity System Organ Class: 10029205 - Nervous system disorders ; MedDRA version: 20.0 Level: LLT Classification code 10077975 Term: Central neuropathic pain System Organ Class: 10029205 - Nervous system disorders Therapeutic area: Diseases [C] - Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To evaluate the efficacy of the cannabinoids THC, CBD and a combination of CBD/THC on central neuropathic pain and spasticity in patients with multiple sclerosis and in patients with spinal cord injury Primary end point(s): 1) Mean pain intensity during the last week of active treatment compared with baseline (Diary, Numeric Rating Scale (NRS)).; 2) Mean severity of spasticity during the last week of active treatment compared with baseline (Diary, NRS 0†10).; ; Secondary Objective: To evaluate the efficacy of the cannabinoids THC, CBD and a combination of CBD/THC on the quality of life, cognition, stress, sleep, ataxia, and to explore the side effects. ; We also want to study the Pharmacodynamic and pharmacokinetic of the study medications.; Timepoint(s) of evaluation of this end point: Mean pain intensity and mean spasticity score are evaluated during the last week of treatment (week 6) (from the patient diary).; ; SECONDARY OUTCOME: Secondary end point(s): 1) Patient Global Impression of Change (PGIC); 2) Quality of life (EQ-5D) ; 3) Farmakodynamic /kinetic: Cmax, Cmin, Cave, AUC0-24, Tmax, Tmin; Timepoint(s) of evaluation of this end point: PGIC and EQ-5D: At last visit (visit 4) in the last week in stable treatment (week 6); ; Farmacodynamic/kinetic are evaluated in 24 hours in the stable period of treatment (week 3-6) INCLUSION CRITERIA: 1) Probable or definite neuropathic pain in more than three months with a mean baseline pain intensity NRS >3 and < 9 and/or spasticity severity NRS > 3. 2) Stable disease (MS and SCI) 3) Age = 18 years 4) Written Informed consent 5) Reliable contraception for fertile women Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 448 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range

Double blind, randomised placebo-controlled trial [PROTOCOL]
Grade: N/A

Hendricks, O. Andersen, T. E. Christiansen, A. A. Primdahl, J. Hauge, E. M. Ellingsen, T. Horsted, T. I. Bachmann, A. G. Loft, A. G. Bojesen, A. B. Ostergaard, M. Lund Hetland, M. Krogh, N. S. Roessler, K. K. Petersen, K. Ho Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: Protocol for a multicentre, randomised, placebo-controlled study. BMJ Open 2019; 9 (6) (no pagination): http://dx.doi.org/10.1136/bmjopen-2018-028197 - external site

Introduction Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic, systemic, inflammatory diseases, primarily in the musculoskeletal system. Pain and fatigue are key symptoms of RA and AS. Treatment presents a clinical challenge for several reasons, including the progressive nature of the diseases and the involvement of multiple pain mechanisms. Moreover, side effects of pain treatment pose an implicit risk. Currently, no well-controlled studies have investigated how medical cannabis affects pain and cognitive functions in RA and AS. The present study aims to evaluate the efficacy and safety of medical cannabis in the treatment of persistent pain in patients with RA and AS with low disease activity. Methods and analysis A double-blinded, randomised, placebo-controlled study of cannabidiol (CBD), followed by an open label add-on of tetrahydrocannabinol (THC) with collection of clinical data and biological materials in RA and AS patients treated in routine care. The oral treatment with CBD in the experimental group is compared with placebo in a control group for 12 weeks, followed by an observational 12-week period with an open label add-on of THC in the primary CBD non-responders. Disease characteristics, psychological parameters, demographics, comorbidities, lifestyle factors, blood samples and serious adverse events are collected at baseline, after 12 and 24 weeks of treatment, and at a follow-up visit at 36 weeks. Data will be analysed in accordance with a predefined statistical analysis plan. Ethics and dissemination The Danish Ethics Committee (S-20170217), the Danish Medicines Agency (S-2018010018) and the Danish Data Protection Agency approved the protocol. The project is registered in the European Clinical Trials Database (EudraCT 2017-004226-15). All participants will give written informed consent to participate prior to any study-related procedures. The results will be presented at international conferences and published in peer-reviewed journals. Copyright © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Double blind, randomised placebo-controlled trial [PROTOCOL]
Grade: N/A

NCT, A Study of Tolerability and Efficacy of Cannabidiol on Motor Symptoms in Parkinson's Disease. https://clinicaltrials.gov/show/NCT03582137 - external site 2018

Persons with PD have progressive disabling tremor, slowness, stiffness, balance impairment, cognitive deficits, psychiatric symptoms, autonomic dysfunction, fatigue and insomnia. Tremor may interfere with necessary daily and work functions. The disorder affects approximately seven million people globally. The total economic cost in the US is around 23 billion dollars. In addition to economic costs, PD reduces quality of life of those affected and their caregivers. Cognitive impairment is a common feature and ranges from delayed recall in early stages to global dementia in up to 80% at end stage. PD with dementia has been associated with reduced quality of life, shortened survival, and increased caregiver distress. Community-based studies have estimated the point prevalence for dementia in PD to be 28% and 44%. Depression, anxiety and psychosis are also common and are particularly disabling in PD, even at the earliest stages. These symptoms have important consequences for quality of life and daily functioning, are associated with increased carer burden and risk for nursing home admission. Anxiety affects up to 40% of patients with PD and may predate motor symptoms by several years. The most common anxiety disorders in PD are panic attacks (often during off periods), generalized anxiety disorder, and simple and social phobias. Psychotic symptoms vary in frequency according to the definition used. If mild forms are included, these affect up to 50% of patients. Visual hallucinations are the most common type. However, hallucinations occur in all sensory domains and delusions of various types are also relatively common. The impact of psychosis is substantial in that it is associated with dementia, depression, earlier mortality, greater caregiver strain, and nursing home placement. Thus, it is crucial to treat these symptoms in order to optimize the management of PD patients. Generally, however, current therapies are inadequate. Medications have improved the prognosis of PD, but also have problematic adverse effects. Since treatment of PD is often unsatisfactory and since cannabis has recently become legal and readily available in Colorado, persons with PD have been trying it. Patients have heard from the internet, support groups and other sources that marijuana is helpful. Most are doing so on their own, without the supervision or even knowledge of their neurologist. In a survey conducted in the spring of 2014 in University of Colorado Hospital Movement Disorders clinic about 5% of 207 PD patients, average age 69, reported using cannabis. In another study Katerina Venderova and colleagues reported that 25% of PD patients had taken cannabis in the General University Hospital in Prague. In the investigators clinics, about 30% of the PD patients have asked doctors during their clinic visits over the past 6 months about cannabis. In an anonymous web-based survey, 72% PD patients reported current or past using medical cannabis, and 48% reducing prescription medication since beginning cannabis use. PD mostly affects the elderly, and affected persons often have cognitive, psychiatric and motor problems, such as being prone to falling. Cannabis is well documented to cause psychosis, anxiety, slowness and incoordination. Studies have also shown that chronic users have structural and functional Central Nervous System (CNS) alterations. Thus, cannabis is expected to be risky in persons with PD. Further, there are many components of cannabis, and the cannabis preparations being sold in Colorado vary widely in composition. There are no definitive data regarding the benefits and risks in of these various preparations in PD. Studies on safety and efficacy are greatly needed to protect this fragile Colorado population. Human trials report that CBD decreases anxiety and causes sedation in healthy individuals, decreases psychotic symptoms in schizophrenia and PD, and improves motor and non-motor symptoms and alleviates levodopa-induced dyskinesia in PD. Given the current literature regarding CBD: possible neuroprotective effect good tolerability, anxiolytic and antipsychotic effects and general lack of information in PD, including its effect on tremor, the investigators feel that it is important to study its use in PD further. The investigators hypothesized that it would reduce tremor, anxiety and psychosis, and would be well tolerated in PD. The Specific Aims are: Primary Specific Aim: To evaluate the efficacy of CBD on motor symptoms in PD, specifically on the motor section of the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS). Secondary Specific Aim: To assess the safety and tolerability of CBD in PD, and to examine the effect of CBD on severity & duration of intractable tremor, night-time sleep, rigidity, emotional dyscontrol, anxiety and pain in PD. Exploratory Analyses: To study the efficacy of CBD on cognition, psychosis, sleep, daytime sleepiness, mood, fatigue, impulsivity, bladder function, other motor and non-motor PD signs, restless legs syndrome and Rapid Eye Movement (REM) sleep behavior disorder and quality of life. The study is a randomized, placebo controlled, double blind parallel design with two treatment arms, each of approximately 2-3 weeks duration. In the 2-3 week treatment phase participants will start study drug and titrate up to the maximum tolerated or targeted dose (2.5 mg/kg/day of CBD). Each participant will have a screening visit, baseline visit within 3 weeks, 1 liver function monitoring visits on 3rd to 5th day of 2.5 mg/kg/day, 2 dose assessment visit (1.25 mg/kg/day and 2.5 mg/kg/day), and a safety visit (6 visits total). Participants will be evaluated on the 3rd to 5th day at each dose level for monitoring liver function and adverse events, as well as changes in medical history and concomitant medications. Participants are called 3 days and 1 week after stopping the study drug to check for signs of withdrawal.

Double blind, randomised placebo-controlled trial [PROTOCOL]
Grade: N/A

NCT, Cannabis Oil for Pain in Parkinson's Disease. https://clinicaltrials.gov/show/NCT03639064 - external site 2018

BACKGROUND AND RATIONALE Pain is a common symptom in PD and is reported in up to 50 % of patients. Pain in PD has been classified as musculoskeletal, dystonic (particularly in OFF periods), radicular and central pain, and is frequently associated with muscle rigidity, postural abnormalities and bradykinesia. Often, the presence of pain in PD is associated with the daily fluctuations in the motor symptoms of PD. In addition, some patients experience 'off-dystonia' which affects the toes and feet, with painful cramps and posturing. The treatment of pain in PD patients with such fluctuating symptoms involves optimizing the dose of levodopa or other dopaminergic drugs to treat the OFF periods. Frequently, the pain does not resolve on altering the PD medication and remains difficult to treat. Cannabis Sativa (marijuana) and its major psychoactive constituent, delta tetrahydrocannabinol(Δ9THC) have been used for centuries to treat pain. The mechanism of action is likely mediated via cannabinoid receptors (CB1 and CB2) in basal ganglia and spinal circuits. Because of these potential therapeutic properties, several synthetic and naturally occurring cannabinoid preparations have been manufactured. Cannabinoids have been demonstrated to alleviate allodynia or hyperalgesia in animal models of pain; the effect on pain modulation may be secondary to CB1 receptors in the amygdala, thalamus, spinal cord and dorsal root ganglion. Several recent clinical studies have demonstrated the potential efficacy of synthetic and naturally occurring cannabinoids in pain. Synthetic cannabinoids such as nabilone and nabiximols are now licensed as add on therapy in multiple sclerosis and advanced cancer for relief of pain. A Canadian systematic review of randomized clinical trials of cannabinoids (cannabis, nabilone, dronabinol and nabiximols) for the treatment of chronic non cancer pain (neuropathic pain, mixed chronic pain, rheumatoid arthritis, fibromyalgia) concluded that cannabinoids are modestly effective. Other cannabinoids found in cannabis sativa include cannabidiol (CBD). CBD potentially lacks a psychoactive effect and appears to act via non-CB receptor mediated actions including ion channels and enzymes. Pre-clinical studies suggest anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform actions. Thus, the advantage of CBD in PD is a potentially lesser risk of cognitive dysfunction and psychosis. Currently, there is an oil preparation (CanniMed® Oil) in Canada, with the advantage of ease of administration. CanniMed® Oil is a mixed oil preparation that contains both Δ9THC and CBD, of varying proportions of Δ9THC (more psychoactive component) and CBD (18:0; 10:10; 1:20 respectively). Investigators of this study have experience in conducting trials using synthetic cannabinoids in movement disorders, including PD. Investigators have demonstrated tolerability, but limited efficacy, of short-term administration of clinically available oral tablet cannabinoids in idiopathic dystonia. More specifically in PD, investigators have assessed nabilone for the treatment of levodopa-induced dyskinesia with documented efficacy. Of interest to the current proposal, in this study, investigators also found an improvement in painful OFF-period limb dystonia in 2 out of 7 subjects. It is unknown if this effect is a specific analgesic effect or related with an anti-dystonia effect. STUDY HYPOTHESIS Despite the major advances in understanding the pathophysiology of the endocannabinoid system, there are many unknowns in the use of cannabinoids for medical purposes. To date, clinical studies with cannabinoids in PD have been inconclusive and the use of cannabinoids remains controversial due to a lack of well-powered confirmatory clinical studies and obvious safety concerns. However, the known efficacy of cannabinoids in reducing pain suggests that PD-related pain may also be a reasonable target for cannabinoids. Combined with the potential ratio ale for reducing dystonia, we hypothesize that cannabinoids could reduce pain in PD, regardless of the PD-specific pain cause. Primary Outcome Safety: Incidence and severity of adverse events - Maximum tolerated dose (MTD) Tolerability: Ability to remain on assigned treatment - Withdrawal rates due to adverse events Secondary Outcomes: Assess change from baseline in the King's Parkinson Disease Pain scale (KPPS). Other Outcomes: Assess change from baseline in frequency and severity of pain, sleep, dystonia and PD motor symptoms, using the following measurement tools: Visual Analogue Scale for Pain MDS-UPDRS part III UDysRS Dystonia part 2 subscores Clinical Global Impression of pain severity (severity and improvement) Epworth Sleepiness Scale

Observational study; cohort study
Grade 2- Moderate

Ferre L, Nuara A, Pavan G, Radaelli M, Moiola L, Rodegher M, et al. Efficacy and safety of nabiximols (Sativex) on multiple sclerosis spasticity in a real-life Italian monocentric study. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2016; 37: 235-42.

144 patients, mean age 50, suffering from treatment resistant moderate-to-severe spasticity due to MS at the San Raffaele Hospital MS centre in Milan treated with nabiximols (Sativex) were followed for up to 48 weeks.

Observational study; open label
Grade 2- Moderate

Haroutounian S, Ratz Y, Ginosar Y, Furmanov K, Saifi F, Meidan R, et al. The effect of medicinal cannabis on pain and quality-of-life outcomes in chronic pain: a prospective open-label study. Clinical Journal of Pain 2016; 32: 1036-43.

206 patients with treatment resistant chronic pain and a mean age of 51 approved for treatment with smoked or edible cannabis by the Israeli Ministry of Health were followed for 6 months.

Observational study; follow up
Grade 2- Moderate

Paolicelli D, Direnzo V, Manni A, D'Onghia M, Tortorella C, Zoccolella S, et al. Long-term data of efficacy, safety, and tolerability in a real-life setting of THC/CBD oromucosal spray-treated multiple sclerosis patients. Journal of Clinical Pharmacology 2016; 56: 845-51.

102 patients at the MS Centre of the University of Bari treated with nabiximols (Sativex) approved for MS spasticity in Italy in 2013 by the Italian Drug Agency (AIFA) were evaluated at the time of commencement and at 3 month intervals thereafter over 40 weeks.

Observational study; open label
Grade 2- Moderate

Hoggart B, Ratcliffe S, Ehler E, Simpson KH, Hovorka J, Lejcko J, et al. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. Journal of Neurology 2015; 262: 27-40.

380 patients with peripheral neuropathic pain associated with diabetes or allodynia entered this study from two parent randomised controlled trials of nabiximols (Sativex) THC:CBD spray over 38 weeks.

Observational study; open label
Grade 2- Moderate
see also [3]

Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, et al. 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 2013; 260: 984-97.

58 patients with MS and central neuropathic pain at multiple sites in the UK, Europe, and Canada who had completed phase 1 of a RCT entered open label and randomised withdrawing phases 2 and 3 of a study of nabiximols over 18 weeks.

Observational study; open label
Grade 2- Moderate
see also [39]

Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. Journal of Pain 2008; 9: 254-64.

28 adults with a mean age of 44 with chronic non-cancer pain recruited at several Harvard Medical School teaching hospital sites self-administered dronabinol (Marinol) in a stepwise dosage schedule over 4 weeks starting at 5mg 2/day with a maximum of 20mg 3/day after participating in a crossover RCT comparing the active treatment with placebo.

Observational study; prospective follow-up
Grade 2- Moderate

Toth C, Au S. A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy. Pain 2008; 138: 657-66.

182 patients with neuropathic pain identified from 408 patients referred for diagnosis and/or management of polyneuropathy were given a range of study medications "chosen in concert with physician and patient" including gabapentinoids, tricyclic antidepressants, anticonvulsants, cannabinoids legally prescribed in Canada including nabilone (Cesamet) in oral capsules (used by 3%) and oromucosal THC/CBD spray (2%), and topical agents.

Observational study; open label extension
Grade 2- Moderate

Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clinical Therapeutics 2007; 29: 2068-79.

63 adult patients with MS aged 27-71 were treated with nabiximols (Sativex) THC:CBD spray in a 2 year extension trial.

Observational study; follow on from crossover RCT
Grade 2- Moderate
see also [41]

Pinsger M, Schimetta W, Volc D, Hiermann E, Riederer F, Polz W. [Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trial]. Wiener klinische Wochenschrift 2006; 118: 327-35 (in German with English abstract).

30 adults in Austria aged 50-63 with chronic refractory pain of musculoskeletal origin who compared nabilone (Cesamet) with placebo in a preceding 14 week crossover study entered a 16 week period with free choice of the study drugs (the active treatment or placebo).

Observational study; open label extension
Grade 2- Moderate

Wade DT, Makela PM, House H, Bateman C, Robson P. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Multiple Sclerosis 2006; 12: 639-45.

137 adult MS patients aged 27-73 with symptoms not controlled satisfactorily using standard drugs were treated with nabiximols (Sativex) THC:CBD spray and followed for an average of 434 days (21-814).

Observational study; open label
Grade 2- Moderate
see also [47]

Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehabilitation 2003; 17: 21-9.

24 outpatients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1) underwent an open label test dosing two week period with THC:CBD before proceeding to a consecutive series of 24 double-blind, randomized, placebo-controlled single-patient cross-over trials comparing several cannabis extract formulations with one another and with placebo.

Observational study; open label
Grade 3- Low

Palmieri B, Laurino C, Vadala M. Short-term efficacy of CBD-enriched hemp oil in girls with dysautonomic syndrome after human papillomavirus vaccination. Israel Medical Association Journal: IMAJ 2017; 19: 79-84.

21 female adolescents and young adults aged 12-24 with severe somatoform and dysautonomic syndrome following HPV vaccination whose families consulted a web-based medical consultation referral network in Modena were given sublingual CBD-rich hemp oil drops at 25mg/kg/day plus supplemental doses to reach a maximum of 150mg/ml CBD/day over 3 months. Study medication was manufactured as a neutroceutical by Elixinol (Broomfield, Colorado).

Observational study; retrospective comparison
Grade 3- Low

Shah A, Craner J, Cunningham JL. Medical cannabis use among patients with chronic pain in an interdisciplinary pain rehabilitation program: characterization and treatment outcomes. Journal of Substance Abuse Treatment 2017; 77: 95-100.

48 patients admitted to a 3-week outpatient interdisciplinary chronic pain rehabilitation program were compared on the basis of cannabis use detected in urine; 24 who screened positive for THC were matched with a comparison sample of patients with a negative screen.

Observational study; follow up
Grade 3- Low

Robinson D, Garti A, Yassin M. Cannabis treatment of diabetic neuropathy: treatment effect and change in health over a 6 month period (abstract of conference paper only). Foot and Ankle Surgery 2016; 22: 58.

18 patients with painful neuropathy attending the Rabin Medical Center, Hasharon Hospital, Israel who treated themselves with "natural smoked" Cannabis sativa from government-approved sources were followed over an average of 6 months.

Observational study; prospective multisite
Grade 3- Low

Vermersch P, Trojano M. Tetrahydrocannabinol:cannabidiol oromucosal spray for multiple sclerosis-related resistant spasticity in daily practice. European Neurology 2016; 76: 216-26.

433 patients with a mean age of 50 and drug-resistant MS related spasticity were recruited to a multicentre study of nabiximols (Sativex) as an adjunctive treatment in Italy, Norway and Denmark; 349 participants continued after 1 month, and 281 after 3 months.

Observational study; prospective cohort
Grade 3- Low

Ware MA, Wang T, Shapiro S, Collet JP. Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). Journal of Pain 2015; 16: 1233-42.

431 adults with chronic non-cancer pain from 7 clinics across Canada were treated with herbal cannabis provided by Prairie Plant Systems Inc. (average 12.5% THC) via the patient's preferred delivery method, titrated over a one year trial period upward to the maximum tolerated dose.

Observational study; open label
Grade 3- Low

Lotan I, Treves TA, Roditi Y, Djaldetti R. Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clinical Neuropharmacology 2014; 37: 41-4.

22 patients with Parkinson disease attending the motor disorder clinic of a tertiary medical centre in 2011-2012 were evaluated at baseline and 30 minutes after smoking cannabis they had been licensed to use for medical purposes by the Israeli Ministry of Health as an adjunctive treatment.

Observational study; open label
Grade 3- Low

Bestard JA, Toth CC. An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Practice 2011; 11: 353-68.

249 peripheral neuropathy patients with neuropathic pain in a tertiary care neuromuscular clinic in Calgary were permitted to initiate nabilone (Cesamet) or gabapentin as monotherapy or add one of these to their existing treatment regimen.

Observational study; retrospective chart review
Grade 3- Low

Aggarwal SK, Carter GT, Sullivan MD, ZumBrunnen C, Morrill R, Mayer JD. Characteristics of patients with chronic pain accessing treatment with medical cannabis in Washington State. Journal of Opioid Management 2009; 5: 257-86.

139 chronic pain patients, mean age 47, who received Washington State government medical authorisation to treat themselves with cannabis during 2007-2008 used preparations they procured from various state-approved channels, as the study authors were not licenced to conduct research with cannabis supplied by US federal agencies.

Observational study; open label
Grade 3- Low

Centonze D, Mori F, Koch G, Buttari F, Codeca C, Rossi S, et al. Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2009; 30: 531-4.

20 adult MS patients aged 21-51 with chronic neuropathic pain refractory or intolerant to commonly prescribed medications were treated with nabiximols (Sativex) THC:CBD spray.

Observational study; retrospective chart review
Grade 3- Low
see also [48]

Chung SA, Hossain NK, Blackman AS, Shapiro CM. Can the cannabinoid nabilone help with pain and sleep in fibromyalgia patients? Sleep 2009; 32: A325-A26.

5 female fibromyalgia patients who participated in a 4 week crossover pilot comparing nabilone with placebo continued treatment of 1mg doses on prescription for 1 year.

Observational study; retrospective survey
Grade 3- Low

Weber J, Schley M, Casutt M, Gerber H, Schuepfer G, Rukwied R, et al. Tetrahydrocannabinol (Delta 9-THC) treatment in chronic central neuropathic pain and fibromyalgia patients: results of a multicenter survey. Anesthesiology Research and Practice 2009: 10.1155/2009/827290.

172 chronic central neuropathic pain and fibromyalgia patients were treated with dronabinol supplied by Delta 9 Pharma, Neumarkt, either liquid, capsule, or in combination in increasing doses to an average 7.5mg/day, not exceeding 15mg/day for an average of 217 days.

Observational study; open label
Grade 3- Low

Haroutiunian S, Rosen G, Shouval R, Davidson E. Open-label, add-on study of tetrahydrocannabinol for chronic nonmalignant pain. Journal of Pain & Palliative Care Pharmacotherapy 2008; 22: 213-7.

13 patients with chronic nonmalignant pain at a Jerusalem tertiary pain centre were given orally administered THC.

Observational study; open label/Double-blind parallel RCT
Grade 3- Low

Hagenbach U, Luz S, Ghafoor N, Berger JM, Grotenhermen F, Brenneisen R, et al. The treatment of spasticity with Delta9-tetrahydrocannabinol in persons with spinal cord injury. Spinal Cord 2007; 45: 551-62.

25 patients aged 19-73 with traumatic spinal cord injury at a treatment centre in Basel compared oral dronabinol (Marinol) with rectal THC.

Observational study; open label
Grade 3- Low

Schley M, Legler A, Skopp G, Schmelz M, Konrad C, Rukwied R. Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Current Medical Research and Opinion 2006; 22: 1269-76.

9 fibromyalgia patients were treated with daily oral doses of 2.5–15mg THC with a weekly increase of 2.5mg, as long as no side effects were reported, over 3 months.

Observational study; open label
Grade 3- Low

Attal N, Brasseur L, Guirimand D, Clermond-Gnamien S, Atlami S, Bouhassira D. Are oral cannabinoids safe and effective in refractory neuropathic pain? European Journal of Pain 2004; 8: 173-7.

8 consecutive pain patients with chronic refractory neuropathic pain at the Hopital Ambroise Pare were treated with dronabinol (Marinol) oral capsules containing 2.5mg THC provided by the Agence Francaise de Securite Sanitaire des Produits de Sante.

Observational study; case report
Grade 3- Low

Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmons S, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia 2004; 59: 440-52.

34 adult patients in the UK aged 26-66 with chronic pain recuited from local pain relief clinics or directly referred by hospital consultants and GPs compared cannabis extracts as THC spray with CBD spray, THC:CBD spray and with placebo over 8 weeks.

Observational study; open label
Grade 3- Low

Clermont-Gnamien S, Atlani S, Attal N, Le Mercier F, Guirimand F, Brasseur L. [The therapeutic use of D9-tetrahydrocannabinol (dronabinol) in refractory neuropathic pain]. Presse Medicale 2002; 31: 1840-5 (in French with English abstract).

7 patients with a mean age of 60 suffering from chronic refractory neuropathic pain were treated with dronabinol (Marinol), mean dose of 15mg, titrated up to a maximum dose of 25mg/day for an average duration of 55 days (range 13-128 days).

Observational study; case report
Grade 3- Low

Holdcroft A, Smith M, Jacklin A, Hodgson H, Smith B, Newton M, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997; 52: 483-6.

1 patient with familial Mediterranean fever who presented with chronic relapsing pain and inflammation of gastrointestinal origin was treated with 50mg THC in five doses daily.

Observational study; case report
Grade 3- Low

Martyn CN, Illis LS, Thom J. Nabilone in the treatment of multiple sclerosis. Lancet 1995; 345: 579.

A 45 year old man who asked to be prescribed nabilone (Cesamet) compared nabilone with placebo. The active treatment or placebo was administered every 2nd day for four successive periods lasting 4 weeks each; the starting treatment was randomly allocated and alternated thereafter.

Observational study; case report
Grade 3- Low

Maurer M, Henn V, Dittrich A, Hofmann A. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. European Archives of Psychiatry and Clinical Neuroscience 1990; 240: 1-4.

1 patient with spasticity and pain due to spinal cord injury was treated with 5mg THC orally in sugar cubes, 50mg codeine or placebo in 18 randomised sessions over 5 months.

Observational study; Single-blind, flexible-dose run in phase
Grade 4- Very low
see also [5]

Toth C, Mawani S, Brady S, Chan C, Liu C, Mehina E, et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain 2012; 153: 2073-82.

37 adults, mean age 62, with refractory diabetic peripheral neuropathic pain were initiated on a 4-week flexible-dose single-blind run-in phase to receive adjuvant nabilone as part of an enriched enrolment randomized withdrawal design using exclusion of non-responders before proceeding to a randomised double-blind phase of the study.

Observational study; retrospective survey
Grade 4- Very low

Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. Journal of Pain 2016; 17: 739-44.

244 medical cannabis patients with chronic pain were recruited to the survey from a medical cannabis dispensary in Michigan during 2013-2015; participants mostly (79%) smoked herbal cannabis daily.

observational study; open label
Grade 4- Very low

Gerardi M, Batticciotto A, Talotta R, Ditto M, Atzeni F, Sarzi-Puttini P. Efficacy of cannabis flos in patients with fibromyalgia: a monocentric observational study (abstract of conference paper only). Arthritis and Rheumatology 2016; 68

15 mostly female patients aged 50-54 affected by fibromyalgia were treated with Cannabis sativa flowers (flos) with a potency of 19% THC and 1% CBD in an oral preparation available in Italy to treat chronic pain.

Observational study; case report
Grade 4- Very low

Ko GD, Bober SL, Mindra S, Moreau JM. Medical cannabis - the Canadian perspective. Journal of Pain Research 2016; 9: 735-44.

3 patients with neuropathic low-back pain, fibromyalgia, and MS-related neuropathic pain respectively, aged 49, 57, and 67 were administered Cannabis sativa by vaporiser over 60 days. The respective doses were 1g/day of strain containing 9% THC and 13% CBD; 1.5g/day 5% THC: 8% CBD for 2 weeks escalated by mixing existing supply in equal parts with 12% THC; and 1g/day 2.5% THC: 5% CBD upgraded to 9% THC: 13% CBD.

Observational study; compassionate use trial
Grade 4- Very low

Cimas-Hernando I, Pato-Pato A, Lorenzo-Gonzalez JR, Rodriguez-Constenla I. [Assessment of the effectiveness and safety of Sativex in compassionate use]. Revista de Neurologica 2015; 60: 202-6 (in Spanish with English abstract).

10 adult patients in Vigo, Spain with neuropathic pain and spasticity from causes other than multiple sclerosis were treated with nabiximols (Sativex) for 6 months through a compassionate use protocol for pathologies beyond permitted indications.

Observational study; cohort study
Grade 4- Very low

Degenhardt L, Lintzeris N, Campbell G, Bruno R, Cohen M, Farrell M, et al. Experience of adjunctive cannabis use for chronic non-cancer pain: findings from the Pain and Opioids IN Treatment (POINT) study. Drug and Alcohol Dependence 2015; 147: 144-50.

649 cannabis users who participated in a study of 1514 people in Australia prescribed pharmaceutical opioids for chronic non-cancer pain reported on frequency of their use of illicit cannabis as a self-prescribed adjunctive treatment.

Observational study; patient survey
Grade 4- Very low

Gurevich T, Chleider LBL, Rosenberg A, Knaani J, Baruch Y, Djaldetti R. Effect of medical cannabis in Parkinson's disease: survey of patient experiences (abstract of meeting paper only). Movement Disorders 2015; 30: S88-S89.

39 adults with Parkinson's disease with a mean age of 63 granted medical cannabis treatment licenses by the Israeli Ministry of Health were surveyed after 17-19 months.

Observational study; cross-sectional
Grade 4- Very low

Bonn-Miller MO, Boden MT, Bucossi MM, Babson KA. Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. American Journal of Drug and Alcohol Abuse 2014; 40: 23-30.

217 community-based adults aged 18-74 currently receiving cannabis for a physical or mental health condition reported using cannabis for a medical condition for an average period of ten years. Participants used cannabis obtained from a San Francisco dispensary.

Observational study; retrospective chart review
Grade 4- Very low

Cameron C, Watson D, Robinson J. Use of a synthetic cannabinoid in a correctional population for posttraumatic stress disorder-related insomnia and nightmares, chronic pain, harm reduction, and other indications: a retrospective evaluation. Journal of Clinical Psychopharmacology 2014; 34: 559-64.

104 male prison inmates with serious mental illness in a secure psychiatric treatment centre in Ottawa were prescribed nabilone (Cesamet) in capsule or powder form with water, mean final dosage of 4mg daily for a mean duration of 11 weeks.

Observational study; open label
Grade 4- Very low

Eisenberg E, Ogintz M, Almog S. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study. Journal of Pain & Palliative Care Pharmacotherapy 2014; 28: 216-25.

10 patients aged 25-69 suffering from chronic neuropathic pain who were on a stable analgesic regimen including medicinal cannabis were given pharmaceutical cannabis flos (Bedrocan, Veendam, The Netherlands; 19.9% THC, 0.1% CBD, and 0.2% cannabinol (CBN)).

Observational study; patient survey
Grade 4- Very low

Notcutt W, Phillip C, Hughe J, Lacoux P, Vijayakulasingam V, Baldock L. A retrospective description of the use of nabilone in UK clinical practice – extension study: poster presented at the British Pain Society Annual Scientific Meeting. Multiple Sclerosis Journal 2014; 20: 468.

250 patients at several UK centres prescribed nabilone (Cesamet) from 2005-2013 were analysed retrospectively for a mean observation period of 31 months. 48 patients had been prescribed nabilone off-label for MS, the most common distinct condition in the sample.

Observational study; patient survey
Grade 4- Very low

Storr M, Devlin S, Kaplan GG, Panaccione R, Andrews CN. Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn's disease. Inflammatory Bowel Diseases 2014; 20: 472-80.

319 consecutive patients with IBD seen in the University of Calgary from July 2008 to March 2009 reported self-medication with cannabis, mostly smoked; none used the sublingual spray legally allowed for specific indications in Canada.

Observational study; prospective cohort
Grade 4- Very low

Ravikoff Allegretti J, Courtwright A, Lucci M, Korzenik JR, Levine J. Marijuana use patterns among patients with inflammatory bowel disease. Inflammatory Bowel Diseases 2013; 19: 2809-14.

292 patients with inflammatory bowel disease at an academic medical center in Massachusetts were surveyed regarding use of smoked cannabis, source not stated; US state of study site permitted medical cannabis use for some indications but not the one under study at the time of publication.

Observational study; patient survey
Grade 4- Very low

Fiz J, Duran M, Capella D, Carbonell J, Farre M. Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life. PLoS ONE 2011; 6: e18440.

56 adult patients in Barcelona with treatment resistant fibromyalgia were recruited by advertisement to compare a sample of medical cannabis users (28) with those who did not use cannabis for their symptoms (28).

Observational study; cohort study
Grade 4- Very low

Haroutiunian S, Ratz Y, Rosen G, Ezra Y, Livay R, Davidson E. Evaluation of pain and health-related quality of life outcomes in chronic pain patients treated with cannabis (abstract of conference paper only). European Journal of Pain Supplements 2011; 5: 277.

42 patients with a mean age of 49 and chronic pain who received individual approval for use of herbal cannabis by the Israeli Ministry of Health were surveyed after 3-6 months.

Observational study; patient survey
Grade 4- Very low

Martinez-Rodriguez JE, Munteis E, Carreno M, Blanco Y, Roquer J, Abanades S, et al. Cannabis use in Spanish patients with multiple sclerosis: fulfilment of patients' expectations? Journal of the Neurological Sciences 2008; 273: 103-7.

175 MS patients attending 2 university-based neurology clinics in Barcelona were surveyed regarding their use of cannabis for medical or recreational purposes.

Observational study; open label pilot
Grade 4- Very low
see also [97]

Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Multiple Sclerosis 2004; 10: 425-33.

21 adult patients aged 18-65 with advanced MS and refractory lower urinary tract symptoms were recruited to an open label study to self-administer THC:CBD spray for 8 weeks, then THC-only spray (2.5mg/spray) for a further 8 weeks to establish preferred formulation and dose.

Observational study; open label extension
Grade 4- Very low
see also [96]

Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Multiple Sclerosis 2004; 10: 425-33.

11 adult patients with advanced MS and refractory lower urinary tract symptoms who participated in an open label dose establishing study entered a long-term trial extension for a mean of 27 months; all patients chose to take the THC-only spray, reportedly for greater efficacy.

Observational study; case report
Grade 4- Very low

Rudich Z, Stinson J, Jeavons M, Brown SC. Treatment of chronic intractable neuropathic pain with dronabinol: case report of two adolescents. Pain Research & Management 2003; 8: 221-4.

2 adolescents with complex regional pain syndrome and depression at a tertiary treatment centre in Toronto were given dronabinol (Marinol) at starting doses of 5mg/day with 5mg increments to maximum doses of 20 and 25mg/day and followed over 2 to 5 years respectively.

Observational study; patient survey
Grade 4- Very low

Ware MA, Doyle CR, Woods R, Lynch ME, Clark AJ. Cannabis use for chronic non-cancer pain: results of a prospective survey. Pain 2003; 102: 211-6.

209 consecutive chronic non-cancer patients were recruited to an anonymous survey over 6 weeks in 2001 from the pain management unit, Queen Elizabeth II Health Sciences Center, Nova Scotia (32 used cannabis for pain; 40 were recreational users). Participants reported use of various preparations (herbal, hashish, oil) but not whether they were sourced illicitly or via Health Canada supply or medical licence to grow.

Open-label, prospective, single-arm trial
Open-label, prospective, single-arm trial Grade 3- Low

Lahat, A., Lang, A., & Ben-Horing, S. (2012). Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study. Digestion, 85, 1-8.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) patients suffer from significant morbidity and diminished life quality. The plant cannabis is beneficial in various gastrointestinal diseases, stimulating appetite and causing weight gain. Our aims were to assess whether treatment with inhaled cannabis improves quality of life, disease activity and promotes weight gain in these patients. METHODS: Patients with long-standing IBD who were prescribed cannabis treatment were included. Two quality of life questionnaires and disease activity indexes were performed, and patient's body weight was measured before cannabis initiation and after 3 months' treatment. RESULTS: Thirteen patients were included. After 3 months' treatment, patients reported improvement in general health perception (p = 0.001), social functioning (p = 0.0002), ability to work (p = 0.0005), physical pain (p = 0.004) and depression (p = 0.007). A schematic scale of health perception showed an improved score from 4.1 ± 1.43 to 7 ± 1.42 (p = 0.0002). Patients had a weight gain of 4.3 ± 2 kg during treatment (range 2-8; p = 0.0002) and an average rise in BMI of 1.4 ± 0.61 (range 0.8-2.7; p = 0.002). The average Harvey-Bradshaw index was reduced from 11.36 ± 3.17 to 5.72 ± 2.68 (p = 0.001). CONCLUSIONS: Three months' treatment with inhaled cannabis improves quality of life measurements, disease activity index, and causes weight gain and rise in BMI in long-standing IBD patients.

Open-label trial
Grade 3- Low

Schimrigk, S., Marziniak, M., Neubauer, C., Kugler, E. M., Werner, G., & Abramov-Sommariva, D. (2017). Dronabinol is a safe long-term treatment option for neuropathic pain patients. European Neurology, 78, 320-329.

Treatment of neuropathic pain (NP) symptoms associated with multiple sclerosis (MS) is frequently insufficient. Yet, cannabis is still rarely offered for treatment of pain. This clinical trial aimed at showing the positive benefit-risk ratio of dronabinol. Two hundred forty MS patients with central NP entered a 16-weeks placebo-controlled phase-III study followed by a 32-weeks open-label period. One hundred patients continued therapy for overall up to 119 weeks. Primary endpoint was change of pain intensity on the 11-point Numerical Rating Scale over a 16-weeks treatment period. Safety was assessed on the basis of adverse reactions (ARs), signs of dependency and abuse. Pain intensity during 16-weeks dronabinol and placebo treatment was reduced by 1.92 and 1.81 points without significant difference in between (p = 0.676). Although the proportion of patients with ARs was higher under dronabinol compared to placebo (50.0 vs. 25.9%), it decreased during long-term use of dronabinol (26%). No signs of drug abuse and only one possible case of dependency occurred. The trial results demonstrate that dronabinol is a safe long-term treatment option.

Open-label trial with long-term follow-up
Grade 3- Low

Schimrigk, S., Marziniak, M., Neubauer, C., Kugler, E. M., Werner, G., & Abramov-Sommariva, D. (2017). Dronabinol is a safe long-term treatment option for neuropathic pain patients. European Neurology, 78, 320-329.

Treatment of neuropathic pain (NP) symptoms associated with multiple sclerosis (MS) is frequently insufficient. Yet, cannabis is still rarely offered for treatment of pain. This clinical trial aimed at showing the positive benefit-risk ratio of dronabinol. Two hundred forty MS patients with central NP entered a 16-weeks placebo-controlled phase-III study followed by a 32-weeks open-label period. One hundred patients continued therapy for overall up to 119 weeks. Primary endpoint was change of pain intensity on the 11-point Numerical Rating Scale over a 16-weeks treatment period. Safety was assessed on the basis of adverse reactions (ARs), signs of dependency and abuse. Pain intensity during 16-weeks dronabinol and placebo treatment was reduced by 1.92 and 1.81 points without significant difference in between (p = 0.676). Although the proportion of patients with ARs was higher under dronabinol compared to placebo (50.0 vs. 25.9%), it decreased during long-term use of dronabinol (26%). No signs of drug abuse and only one possible case of dependency occurred. The trial results demonstrate that dronabinol is a safe long-term treatment option.

Observational study; single arm clinical trial
Grade 3 - low

Poli, P. Crestani, F. Salvadori, C. Valenti, I. Sannino, C. Medical Cannabis in Patients with Chronic Pain: Effect on Pain Relief, Pain Disability, and Psychological aspects. A Prospective Non randomized Single Arm Clinical Trial. Clinica Terapeutica 2018; 169: https://dx.doi.org/10.7417/T.2018.2062 - external site

BACKGROUND: There is an increasing interest in the medical use of cannabis, particularly in the treatment of chronic pain.
OBJECTIVES: The aim is to evaluate the effects of cannabis use and the associated benefits reported by patients with various chronic pain diagnoses. MATERIAL AND METHODS: A total of 338 patients with different chro- nic pain conditions were treated with a Cannabis Flos 19% decoction for 12 months, in addition to their pharmacological therapy. Baseline levels for pain medications, pain intensity, pain disability, anxiety and depression were recorded at 1, 3, 6 and 12 months.
RESULTS: Pain intensity records a statistically significant reduction from Baseline to 12 months follow up (X2 61.375; P<0,001); the improvements from Baseline to 12 months follow up are also recorded in pain disability (X2 39.423; P<0,001) and in anxiety and depression symptoms (X230.362; P<0,001; X227.786; P<0,001).
CONCLUSIONS: Our study suggest that Cannabis therapy, as an adjunct a traditional analgesic therapy, can be an efficacious tool to make more effective the management of chronic pain and its consequences on functional and psychological dimension. Further randomized, controlled trials are needed to confirm our conclusions.

Observational study; prospective cohort
Grade 3 - low

Poli, P. Frigerio, G. Salvadori, C. Sannino, C. Neurostimulation therapy integrated with medical cannabis: A new way for the management of chronic neuropathic pain? Pain Practice 2018; 18 (Supplement 1)

Objectives: The aim of this observational study is to asses if the integrated use of Medical Cannabis and Neurostimulation therapy can be leads to a greater improvement on chronic neuropathic pain than Neurostimulation therapy alone. Method(s): A group of subjects with chronic neuropathic pain treated with Neurostimulation therapy (N. 35; age 55 +/- 13) was compared with a group of subjects (n.40; age 66 +/- 13) affected by various kind of chronic neuropathic pain treated with Neurostimulation therapy integrated with Medical Cannabis assumption. Our investigations have concerned Pain intensity, measured with Visual Analogue Scale, and psychological dimension, measured with Hospital Anxiety and Depression Scale (HADS) at Baseline and at 3 months follow up. Result(s): Statistical analyses revealed that in Medical Cannabis and Neurostimulation group Pain Intensity Difference (DVAS) in the period between Baseline and 3 months follow up is greater and statistically significant than the Pain Intensity Difference measured in Neurostimulation group (t (74)= 2.21; p < 0.05). Pearson correlations highlights a significant statistically link between variable Age and variable Pain intensity Difference only in Neurostimulation group (r =-0.81; n = 75; p = 0.002) HADS-D and HADS TOT registered a greater significant reduction in the Medical Cannabis and Neurostimulation group than in Neurostimulation group (t(74)= 2.71 p < 0.05; t(74)=3.95 p < 0.05) Conclusion(s): Our results suggest a better response on chronic neuropathic pain from integrated therapy, Neurostimulation and Medical Cannabis, than from Neurostimulation therapy alone.

Observational study; prospective cohort
Grade 3 - low

Poli, P. Salvadori, C. Sannino, C. Effects of cannabis-based drugs on chronic neuropathic pain: Comparison between italian and dutch medical cannabis variety. Pain Practice 2018; 18 (Supplement 1)

Objectives: Cannabis Flos variety Bediol^R and Italian Cannabis based drug FM2^R are, in Italy, Cannabis based drugs that contain a more balanced ratio between THC and CBD and therefore are frequently used in complex painful disorder in order to obtain pain relief. Method(s): The aim of this study is to assess if there are significative differences between Bediol^R and FM2^R effects on chronic neuropathic pain. In this observational prospective study, a group of subjects with chronic neuropathic pain using Bediol^R (N. 57) has been compared with another group affected by chronic neuropathic pain using FM2 (N.59) at Baseline, three months follow up and six months follow up. Variables compared were pain intensity (VAS), frequence of side effects, frequence in the use of traditional analgesic drugs; Psychopatological dimensions were evaluated with Hospital Anxiety and Depression Scale (HADS). Result(s): Statistical analyses demonstrate that subjects treated with FM2 recorded less adverse effects (x = 5.78; p < 0.05) and less use of traditional analgesic drug (% = 6.24; p < 0.05) compared to those treated with Bediol at 6 months. No statistically significant differences were found in Pain Intensity. Depression and anxiety symptoms show a greater reduction in FM2^R group than Bediol^R group at six months follow up (t = 2.27; p < 0.05; t = 3.53: p < 0.05). Conclusion(s): Our study suggest faster adaptability and greater tolerance of the organism to FM2, ^R treatment compared to Bediol^R treatment, with a reduction in the use of traditional analgesic drugs and greater improvement of psychological conditions. Further studies are needed to confirm our conclusions.

Observational study; retrospective chart review
Grade 4 -Very low

Abuhasira, R. Ron, A. Sikorin, I. Novack, V. Medical cannabis for older patients-treatment protocol and initial results. Journal of Clinical Medicine 2019; 8 (11) (no pagination): http://dx.doi.org/10.3390/jcm8111819 - external site

Older adults may benefit from cannabis treatment for various symptoms such as chronic pain, sleep difficulties, and others, that are not adequately controlled with evidence-based therapies. However, currently, there is a dearth of evidence about the efficacy and safety of cannabis treatment for these patients. This article aims to present a pragmatic treatment protocol for medical cannabis in older adults. We followed consecutive patients above 65 years of age prospectively who were treated with medical cannabis from April 2017 to October 2018. The outcomes included treatment adherence, global assessment of efficacy and adverse events after six months of treatment. During the study period, 184 patients began cannabis treatment, 63.6% were female, and the mean age was 81.2 +/- 7.5 years (median age-82). After six months of treatment, 58.1% were still using cannabis. Of these patients, 33.6% reported adverse events, the most common of which were dizziness (12.1%) and sleepiness and fatigue (11.2%). Of the respondents, 84.8% reported some degree of improvement in their general condition. Special caution is warranted in older adults due to polypharmacy, pharmacokinetic changes, nervous system impairment, and increased cardiovascular risk. Medical cannabis should still be considered carefully and individually for each patient after a risk-benefit analysis and followed by frequent monitoring for efficacy and adverse events. Copyright © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Observational study; retrospective chart review
Grade 4 -Very low

Abuhasira, R. Schleider, L. B. Mechoulam, R. Novack, V. Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. European Journal of Internal Medicine 2018; 49: https://dx.doi.org/10.1016/j.ejim.2018.01.019 - external site

INTRODUCTION: There is a substantial growth in the use of medical cannabis in recent years and with the aging of the population, medical cannabis is increasingly used by the elderly. We aimed to assess the characteristics of elderly people using medical cannabis and to evaluate the safety and efficacy of the treatment.
METHODS: A prospective study that included all patients above 65years of age who received medical cannabis from January 2015 to October 2017 in a specialized medical cannabis clinic and were willing to answer the initial questionnaire. Outcomes were pain intensity, quality of life and adverse events at six months.
RESULTS: During the study period, 2736 patients above 65years of age began cannabis treatment and answered the initial questionnaire. The mean age was 74.5+/-7.5years. The most common indications for cannabis treatment were pain (66.6%) and cancer (60.8%). After six months of treatment, 93.7% of the respondents reported improvement in their condition and the reported pain level was reduced from a median of 8 on a scale of 0-10 to a median of 4. Most common adverse events were: dizziness (9.7%) and dry mouth (7.1%). After six months, 18.1% stopped using opioid analgesics or reduced their dose.
CONCLUSION: Our study finds that the therapeutic use of cannabis is safe and efficacious in the elderly population. Cannabis use may decrease the use of other prescription medicines, including opioids. Gathering more evidence-based data, including data from double-blind randomized-controlled trials, in this special population is imperative.

Observational study; patient survey
Grade 4 -Very low

Balash, Y. Bar-Lev Schleider, L. Korczyn, A. D. Shabtai, H. Knaani, J. Rosenberg, A. Baruch, Y. Djaldetti, R. Giladi, N. Gurevich, T. Medical Cannabis in Parkinson Disease: Real-Life Patients' Experience. Clinical Neuropharmacology 2017; 40: https://dx.doi.org/10.1097/WNF.0000000000000246 - external site

BACKGROUND: The use of medical cannabis (MC) is controversial. Support for its benefits is based on small clinical series.
OBJECTIVE: The aim of this study was to report the results of a standardized interview study that retrospectively assessed the effects of MC on symptoms of Parkinson disease (PD) and its adverse effects in patients treated for at least 3 months. METHODS: The survey used telephone interviews using a structured questionnaire based on subjective global impressions of change for various parkinsonian symptoms and yes/no questions on adverse effects.
RESULTS: Forty-seven nondemented patients with PD (40 men) participated. Their mean age was 64.2 +/- 10.8 years, mean disease duration was 10.8 +/- 8.3 years, median Hoehn and Yahr (H&Y) was stage III. The duration of MC use was 19.1 +/- 17.0 months, and the mean daily dose was 0.9 +/- 0.5 g. The delivery of MC was mainly by smoking cigarettes (38 cases, 80.9%). Effect size (r) improvement for falls was 0.89, 0.73 for pain relief, 0.64 for depression, 0.64 for tremor, 0.62 for muscle stiffness, and 0.60 for sleep. The most frequently reported adverse effects from MC were cough (34.9%) in those who used MC by smoking and confusion and hallucinations (reported by 17% each) causing 5 patients (10.6%) to stop treatment.
CONCLUSIONS: Medical cannabis was found to improve symptoms of PD in the initial stages of treatment and did not cause major adverse effects in this pilot, 2-center, retrospective survey. The extent of use and the reported effects lend support to further development of safer and more effective drugs derived from Cannabis sativa.

Observational study; retrospective chart review
Grade 4 -Very low

Bargnes, V. Hart, P. Gupta, S. Mechtler, L. Safety and efficacy of medical cannabis in elderly patients: A retrospective review in a neurological outpatient setting. Neurology. Conference: 71st Annual Meeting of the American Academy of Neurology, AAN 2019; 92

Objective: To evaluate medical cannabis' (MC) efficacy and adverse effects (AE) in patients 75 years of age or older. Background(s): MC has become a popular treatment option among patients with chronic disorders, with currently 2.1 million Americans utilizing MC. Research is required to observe the effect of MC in an elderly population that has an 80% prevalence of >=1 chronic disorders. Design/Methods: A retrospective chart review was conducted in patients >=75 years of age, who utilized New York State's Medical Marijuana Program's cannabis. Patients were certified and followed in a neurologic outpatient setting within DENT Neurologic Institute in Buffalo, NY. Result(s): With an average age of 81 years (range 75-102), 204 patients (129=female 75=male) were included in the study. The average exposure time to MC was 16.8+/-12.1 weeks. At stable doses, following personalized changes in cannabinoid doses, 34% reported AE. AE that resolved after change in dosage, were present in 13%. The most common AE were somnolence (13%), disequilibrium (7%), and gastrointestinal disturbance (7%). Euphoria was observed in 3% of patients. Symptomatic benefit was appreciated in 69%, with relief in chronic pain (49%), sleep (18%), neuropathy (15%), and anxiety (10%) most common. Opioid pain medication was reduced on MC treatment in 32%. Seven patients (3.4%) discontinued due to AE. A balanced tetrahydrocannabinol to cannabidiol tincture (1:1) was the most commonly reported formulation among patients who reported no side effects. Conclusion(s): MC is a well-tolerated treatment with improvement noted in chronic pain, sleep, neuropathy, and anxiety in patients >=75 years of age. AE that resolved on dosage adjustment were noted in 13% of patients. A balanced 1:1 THC to CBD oral tincture was most commonly used in achieving these results. Randomized, placebo-controlled studies are required to further investigate AE, with an emphasis on somnolence and disequilibrium, optimal dosing, tolerability, and efficacy.

Observational study; retrospective chart review
Grade 4 -Very low

Bellnier, T. Brown, G. Ortega, T. Insull, R. A preliminary evaluation of the effcacy, safety, and costs associated with the treatment of chronic pain with medical marijuana in the elderly. Consultant Pharmacist 2017; 32 (10): http://dx.doi.org/10.4140/TCPn.2017.577 - external site

OBJECTIVE/PURPOSE: To evaluate the efficacy and safety of medical marijuana (MM) as a treatment for chronic pain in community-dwelling elderly. METHOD(S): Institutional Review Board approval was given to conduct this retrospective chart review. All patients meeting inclusion criteria were included and served as their own controls. The EQ-5D quality of life, Pain Quality Assessment Scale (PQAS) factor analysis, GAD-7 Anxiety and PHQ-9 Depression were used to measure clinical outcomes. Records were reviewed for 3 months prior to MM initiation (Pre) and 3 months post exposure to MM use (Post). Kruskal-Wallis for analysis of variance and Wilcoxon signed rank test for significance were used. RESULT(S): 36 ambulatory patients were identified with a diagnosis of chronic pain. Patient demographics included: age 71+/-7 (65-86), 100% Caucasian, 27 females, 9 males, duration of illness 18 +/-7 years. Clinical outcome: EQ-5D (Pre 31-Post 62, P<.0001), PQAS Paroxysmal (Pre 7.72-Post 2.04, P<.0001), Surface (Pre 5.20-Post 1.59, P<.0001), Deep (Pre 6.87-Post 3.03, P<.0001), Unpleasant (Pre "miserable"-Post "annoying", P<.0001), GAD-7 Anxiety (Pre 4.81-Post 2.83, P<.0001), and PHQ-9 Depression (Pre 3.97-Post 3.57, P<.001) Service utilization: pain medication cost (Pre $363.90-Post $238.40, P<.05). Safety: morphine equivalents (Pre 69.94-Post 18.65, P<.05). Adverse effects were reported in 9% of subjects. CONCLUSION(S): The present study provides evidence that medical marijuana in community-dwelling elderly is effective, well tolerated and cost-effective for chronic pain. A randomized placebo controlled clinical trial is warranted to further evaluate the role of medical marijuana in the treatment of chronic pain in the elderly.

Observational study; patient survey
Grade 4 -Very low

Bergamaschi, V. Konrad, G. Battaglia, M. A. Brichetto, G. Efficacy and discontinuation of nabiximols in patients with multiple sclerosis: A real-life study. Multiple Sclerosis Journal 2018; 24 (2 Supplement): http://dx.doi.org/10.1177/1352458518798592 - external site

Introduction: Over the last decade, clinical experience with nabiximols in managing MS-related spasticity is growing steadily. The efficacy and safety of nabiximols in clinical trials is well established however real-life observational studies are still lacking. The aim of this study is to evaluate in a real-life context the self-reported efficacy and reasons for discontinuation of treatment with nabiximols in patients with MS (PwMS) followed at the Italian MS Society Rehabilitation Centre, Genoa, Italy. Method(s): 224 PwMS were recruited consecutively among those followed for rehabilitative treatment in a five months period from 1 January 2018 to 1 March 2018. PwMS were asked to compile a self-reported questionnaire on: the use of nabiximols (currently or in the past), self-perceived satisfaction and perceived efficacy on five domains (movement control, fatigue, pain, urinary symptoms and other symptoms), side effects, reasons for discontinuation, therapy duration, day dosage. Result(s): Out of 224 PwMS, 146 were females, 78 males, mean EDSS 5.9 + 1.8; mean age 58.3 + 11.2; 76 pwMS (33.9% of the total sample) were treated with nabiximols; 37 PwMS (48.7%) were still using it, 39 (51.3%) subjects were discontinuing the drug for different reasons. The 37 subjects that were still assuming nabiximols reported: 81.1% a self-perceived improvement, 13.5% were uncertainty and 5.4% no improvements. Subjects that showed an improvement reported a one-domain improvement in 46.7% of cases, two domains improvement in 30% of cases, three domains in 13.3% of cases and four domains improvement in 10% of cases. Domains that were perceived as more impacted by the drug were: movement control 35.7%; pain 21.4%; fatigue 19.6%; bladder control 12.5%; other symptoms 10.7%. Reasons for discontinuation were: drug not effective for 14 subjects (35.9%); side effects for 25 subjects (64.1%). Conclusion(s): This real-world study confirms nabiximols efficacy in the treatment of MS-related symptoms and, therefore, on relevant functional domains such as movement control, fatigue, pain and urinary function. The discontinuation percentage is in line with other studies published in literature showing that it is necessary to improve response-to-drug predictors' algorithms in order to avoid the cost of long term uneffective treatments.

Observational study; patient survey
Grade 4 -Very low

Boehnke, K. F. Scott, J. R. Litinas, E. Sisley, S. Williams, D. A. Clauw, D. J. Pills to Pot: Observational Analyses of Cannabis Substitution Among Medical Cannabis Users With Chronic Pain. Journal of Pain 2019; 20: http://dx.doi.org/10.1016/j.jpain.2019.01.010 - external site

Chronic pain is common, costly, and challenging to treat. Many individuals with chronic pain have turned to cannabis as an alternative form of pain management. We report results from an ongoing, online survey of medical cannabis users with chronic pain nationwide about how cannabis affects pain management, health, and pain medication use. We also examined whether and how these parameters were affected by concomitant recreational use, and duration of use (novice: <1 year vs experienced: >=1 year). There were 1,321 participants (59% female, 54% >=50 years old) who completed the survey. Consistent with other observational studies, approximately 80% reported substituting cannabis for traditional pain medications (53% for opioids, 22% for benzodiazepines), citing fewer side effects and better symptom management as their rationale for doing so. Medical-only users were older (52 vs 47 years old; P < .0001), less likely to drink alcohol (66% vs 79%, P < .0001), and more likely to be currently taking opioids (21% vs 11%, P < .0001) than users with a combined recreational and medical history. Compared with novice users, experienced users were more likely to be male (64% vs 58%; P < .0001), take no concomitant pain medications (43% vs 30%), and report improved health (74% vs 67%; P = .004) with use. Given that chronic pain is the most common reason for obtaining a medical cannabis license, these results highlight clinically important differences among the changing population of medical cannabis users. More research is needed to better understand effective pain management regimens for medical cannabis users. Perspective(s): This article presents results that confirm previous clinical studies suggesting that cannabis may be an effective analgesic and potential opioid substitute. Participants reported improved pain, health, and fewer side effects as rationale for substituting. This article highlights how use duration and intentions for use affect reported treatment and substitution effects. Copyright © 2019 the American Pain Society

Observational study; retrospective cohort
Grade 4 -Very low

Bulbul, A. Mino, E. A. Khorsand-Sahbaie, M. Lentkowski, L. Opioid dose reduction and pain control with medical cannabis. Journal of Clinical Oncology. Conference 2018; 36: http://dx.doi.org/10.1200/JCO.2018.36.34_suppl.189 - external site

Background: The use of medical cannabis (MC) for palliation of symptoms is on the rise in cancer and rheumatological patients. Whether there is a potential for opioid dose reduction (ODR) and or quality of life improvements (QOL) is unclear. Method(s): A retrospective cohort was evaluated to understand the pattern of care and QOL outcomes with MC use across rural multidisciplinary practices in New Mexico. MC use (> 1 mo.), EMR interrogation, urine toxicology screening were used to identify patients. QOL questionnaire included a graded pain scale. Morphine equivalent (ME) dose was used to estimate changes in opioid dose. ODR was defined as any reduction of baseline opioid dose. A chi-square was performed to evaluate associations. Result(s): A total of 133 patients were identified between Jan 2017- May 2017. (M/F) 65/68; median age of 53 (range 20 - 84). Nineteen percent (25/133) had a cancer diagnosis. Pain score improved in 80 % of patients with cancer and in 75% (64/89) of non-cancer patients (x2 0.24 p = 0.62). ODR was achieved in 41% (54/133) of all patients on MC. Of these, 63% (34/54) had a 25% ODR and 37% (20/54) had 26% or more ODR (x2 12.8 p = 0.002). In cancer patients, a 25% ODR was achieved in 73% (x2 0.51 p = 0.771). All patients (15/15) using MC and high dose opioid (morphine equivalent <= 50 mg/day) had some ODR. Coadjuvant NSAIDs with MC improved pain score in 67% of all cases vs 33% among non-NSAID cohort (x2 10.7 p = 0.001). ODR was achieved in 32% of patients with active depression vs 68% of patients without (x2 0.044 p = 0.83). Conclusion(s): In this rural cohort, MC use led to ODR in 41% of all patients. Depression was a negative predictor of ODR. NSAID use facilitated ODR. It will be important to assess MC toxicity before considering this intervention. This study did not include toxicity data due to the retrospective nature of this study and its inherent limitations. Prospective data are needed to confirm these findings.

Observational study; prospective cohort
Grade 4 -Very low

Campbell, G. Hall, W. D. Peacock, A. Lintzeris, N. Bruno, R. Larance, B. Nielsen, S. Cohen, M. Chan, G. Mattick, R. P. Blyth, F. Shanahan, M. Dobbins, T. Farrell, M. Degenhardt, L. Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study. The lancet. Public Health 2018; 3: https://dx.doi.org/10.1016/S2468-2667(18)30110- - external site5

BACKGROUND: Interest in the use of cannabis and cannabinoids to treat chronic non-cancer pain is increasing, because of their potential to reduce opioid dose requirements. We aimed to investigate cannabis use in people living with chronic non-cancer pain who had been prescribed opioids, including their reasons for use and perceived effectiveness of cannabis; associations between amount of cannabis use and pain, mental health, and opioid use; the effect of cannabis use on pain severity and interference over time; and potential opioid-sparing effects of cannabis. METHODS: The Pain and Opioids IN Treatment study is a prospective, national, observational cohort of people with chronic non-cancer pain prescribed opioids. Participants were recruited through community pharmacies across Australia, completed baseline interviews, and were followed up with phone interviews or self-complete questionnaires yearly for 4 years. Recruitment took place from August 13, 2012, to April 8, 2014. Participants were asked about lifetime and past year chronic pain conditions, duration of chronic non-cancer pain, pain self-efficacy, whether pain was neuropathic, lifetime and past 12-month cannabis use, number of days cannabis was used in the past month, and current depression and generalised anxiety disorder. We also estimated daily oral morphine equivalent doses of opioids. We used logistic regression to investigate cross-sectional associations with frequency of cannabis use, and lagged mixed-effects models to examine temporal associations between cannabis use and outcomes.
FINDINGS: 1514 participants completed the baseline interview and were included in the study from Aug 20, 2012, to April 14, 2014. Cannabis use was common, and by 4-year follow-up, 295 (24%) participants had used cannabis for pain. Interest in using cannabis for pain increased from 364 (33%) participants (at baseline) to 723 (60%) participants (at 4 years). At 4-year follow-up, compared with people with no cannabis use, we found that participants who used cannabis had a greater pain severity score (risk ratio 1.14, 95% CI 1.01-1.29, for less frequent cannabis use; and 1.17, 1.03-1.32, for daily or near-daily cannabis use), greater pain interference score (1.21, 1.09-1.35; and 1.14, 1.03-1.26), lower pain self-efficacy scores (0.97, 0.96-1.00; and 0.98, 0.96-1.00), and greater generalised anxiety disorder severity scores (1.07, 1.03-1.12; and 1.10, 1.06-1.15). We found no evidence of a temporal relationship between cannabis use and pain severity or pain interference, and no evidence that cannabis use reduced prescribed opioid use or increased rates of opioid discontinuation. INTERPRETATION: Cannabis use was common in people with chronic non-cancer pain who had been prescribed opioids, but we found no evidence that cannabis use improved patient outcomes. People who used cannabis had greater pain and lower self-efficacy in managing pain, and there was no evidence that cannabis use reduced pain severity or interference or exerted an opioid-sparing effect. As cannabis use for medicinal purposes increases globally, it is important that large well designed clinical trials, which include people with complex comorbidities, are conducted to determine the efficacy of cannabis for chronic non-cancer pain.
FUNDING: National Health and Medical Research Council and the Australian Government.

Observational study; prospective cohort
Grade 4 -Very low

Capano, A. Weaver, R. Burkman, E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgraduate Medicine. 2019; : http://dx.doi.org/10.1080/00325481.2019.1685298 - external site

Context: Chronic pain is highly prevalent in most of the industrialized nations around the world. Despite the documented adverse effects, opioids are widely used for pain management. Cannabinoids, and specifically Cannabidiol, is proposed as an opioid alternative, having comparable efficacy with better safety profile. Objective(s): We aim to investigate the impact of full hemp extract cannabidiol (CBD) on opioid use and quality of life indicators among chronic pain patients. Method(s): An initial sample of 131 patients was recruited from a private pain management center's investigative population. Ninety-seven patients completed the 8-week study. The primary inclusion criteria included patients between 30 and 65 years old with chronic pain who have been on opioids for at least 1 year. Data were collected at three different time points: baseline, 4, and 8 weeks. Opioid and other medication use were evaluated via the medication and psychiatric treatment receipt. Improvement was evaluated using four indices: Pain Disability Index (PDI-4); Pittsburgh Sleep Quality Index (PSQI), Pain Intensity and Interference (PEG); and Patient Health Questionnaire (PHQ-4). Result(s): Over half of chronic pain patients (53%) reduced or eliminated their opioids within 8 weeks after adding CBD-rich hemp extract to their regimens. Almost all CBD users (94%) reported quality of life improvements. The results indicated a significant relationship between CBD and PSQI (p = 0.003), and PEG (p = 0.006). There was a trend toward improvement but no significant relationship between CBD use and PHQ and PDI. Conclusion(s): CBD could significantly reduce opioid use and improve chronic pain and sleep quality among patients who are currently using opioids for pain management. Key Message: This is a prospective, single-arm cohort study for the potential role of cannabinoids as an alternative for opioids. The results indicate that using the CBD-rich extract enabled our patients to reduce or eliminate opioids with significant improvement in their quality of life indices. Copyright © 2019, © The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Observational study; retrospective chart review
Grade 4 -Very low

Casarett, D. J. Beliveau, J. N. Arbus, M. S. Benefit of Tetrahydrocannabinol versus Cannabidiol for Common Palliative Care Symptoms. Journal of Palliative Medicine 2019; 22: http://dx.doi.org/10.1089/jpm.2018.0658 - external site

Objectives: To determine the relative contributions of tetrahydrocannabinol (THC) and cannabidiol (CBD) to patients' self-ratings of efficacy for common palliative care symptoms. Design(s): This is an electronic record-based retrospective cohort study. Model development used logistic regression with bootstrapped confidence intervals (CIs), with standard errors clustered to account for multiple observations by each patient. Setting(s): This is a national Canadian patient portal. Participant(s): A total of 2,431 patients participated. Main Outcome Measure(s): Self-ratings of efficacy of cannabis, defined as a three-point reduction in neuropathic pain, anorexia, anxiety symptoms, depressive symptoms, insomnia, and post-traumatic flashbacks. Result(s): We included 26,150 observations between October 1, 2017 and November 28, 2018. Of the six symptoms, response was associated with increased THC:CBD ratio for neuropathic pain (odds ratio [OR]: 3.58; 95% CI: 1.32-9.68; p = 0.012), insomnia (OR: 2.93; 95% CI: 1.75-4.91; p < 0.001), and depressive symptoms (OR: 1.63; 95% CI: 1.07-2.49; p = 0.022). Increased THC:CBD ratio was not associated with a greater response of post-traumatic stress disorder (PTSD)-related flashbacks (OR: 1.43; 95% CI: 0.60-3.41; p = 0.415) or anorexia (OR: 1.61; 95% CI: 0.70-3.73; p = 0.265). The response for anxiety symptoms was not significant (OR: 1.13; 95% CI: 0.77-1.64; p = 0.53), but showed an inverted U-shaped curve, with maximal benefit at a 1:1 ratio (50% THC). Conclusion(s): These preliminary results offer a unique view of real-world medical cannabis use and identify several areas for future research. Copyright 2019 David J. Casarett et al.

Observational study; case series
Grade 4 -Very low

Chelliah, M. P. Zinn, Z. Khuu, P. Teng, J. M. C. Self-initiated use of topical cannabidiol oil for epidermolysis bullosa. Pediatric Dermatology 2018; 35: https://dx.doi.org/10.1111/pde.13545 - external site

Epidermolysis bullosa is a rare blistering skin disorder that is challenging to manage because skin fragility and repeated wound healing cause itching, pain, limited mobility, and recurrent infections. Cannabidiol, an active cannabinoid found in cannabis, is postulated to have anti-inflammatory and analgesic effects. We report 3 cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa in an observational study. One patient was weaned completely off oral opioid analgesics. All 3 reported faster wound healing, less blistering, and amelioration of pain with cannabidiol use. Although these results demonstrate promise, further randomized, double-blind clinical trials are necessary to provide scientific evidence of our observed benefits of cannabidiol for the treatment of epidermolysis bullosa.

Observational study; patient survey
Grade 4 -Very low

Crowley, K. de Vries, S. T. Moreno-Sanz, G. Self-reported effectiveness and safety of Trokie Lozenges: A standardized formulation for the buccal delivery of cannabis extracts. Frontiers in Neuroscience 2018; 12 (AUG) (no pagination): http://dx.doi.org/10.3389/fnins.2018.00564 - external site

Therapeutic use of cannabinoids, the main active ingredients of Cannabis sativa L., is often hindered by their limited bioavailability and undesirable psych activity. We conducted an observational study in December 2016 and another one in February 2018 to investigate respectively: (i) the effectiveness of Trokie lozenges, a standardized formulation containing cannabis extracts, to deliver cannabinoids via buccal absorption and (ii) its long-term safety. Participants were members of the Palliative Care Corporation health clinic, registered California cannabis patients, and had a diagnosis of chronic non-cancer pain. For the effectiveness study, 49 participants were asked to self-report pain perception before and after 1-12 weeks of taking Trokie lozenges, using an 11-point pain intensity numeric rating scale (PI-NRS). A mean reduction in PI-NRS score of 4.9 +/- 2.0 points was observed. Onset of analgesia typically varied between 5 and 40 min, which seems consistent with, at least partial, buccal absorption. In the safety study, 35 participants were asked to complete a questionnaire about adverse events (AEs) associated with Trokie lozenges. AEs were reported by 16 subjects (46%), the most common being dizziness/unsteadiness (N = 7), bad taste (N = 5), and throat irritation/dry mouth (N = 4). None of the self-reported AEs resulted in a serious medical situation and most of them had limited impact on daily functions. Despite the AEs, 90% of participants reported being "satisfied" or "very satisfied" with the product. These observations suggest that buccal administration of standardized extracts via Trokie lozenges may represent an efficacious and safe approach to cannabis administration. Copyright © 2018 Crowley, de Vries and Moreno-Sanz.

Observational study; prospective cohort
Grade 4 -Very low

De Trane, S. Buchanan, K. Keenan, L. Simeoni, S. O'Brien, L. Stevenson, V. Farrell, R. THC: CBD (Nabiximols) has a beneficial effect on resistant MS related spasticity and reduces the need for Intrathecal baclofen. Multiple Sclerosis Journal 2017; 23 (3 Supplement 1): http://dx.doi.org/10.1177/1352458517733228 - external site

Objective: To evaluate the efficacy of THC: CBD Nabiximols as add on treatment for people with moderate to severe MS related spasticity as an alternative to Intrathecal Baclofen Therapy (ITB). Method(s): Subjects were identified prospectively from the NHNN complex spasticity service. Nabiximols was offered to subjects with moderate to severe spasticity failing 2 or more first line treatments. Baseline data included demographics, current treatment, Numerical Rating Scale (NRS) for spasticity and Multiple Sclerosis Spasticity Scale-88 (MSSS-88). Patients underwent a 4 weeks trial of THC: CBD with a telephone review at 2 weeks. Subjects were deemed Clinical Responders (CR) if they reported >=20% improvement in NRS from baseline. Partial Responders (PR) were those reporting benefit not meeting CR threshold. Subjects were reviewed at 6 monthly intervals. NRS was repeated at 6-month intervals; MSSS-88 at 12-month intervals. Non-Responders (NR) were offered other treatments including proceeded with ITB. Result(s): 137 subjects trialled THC:CBD from January 2011 to December 2016. Baseline mean NRS was 7.2 [10-3], MSSS-88 was 253/352 (walkers) 231/312 (non-walkers). After 4 weeks 44 (32%) were NR and stopped treatments, 10 proceeded with ITB. Of 93 (68%) who reported benefits 53 were CR, 40 were PR with benefits related to spasticity, bladder control, pain and sleeping. Median time to discontinuation was 12.1 months. Of 137 40 remain on treatment. Mean change NRS in CR was -3.4 (p< 0.001), PR and NR did not show significant changes in NRS. Mean change MSSS-88 in CR in ambulatory was -57, vs CR nonambulatory -39.4. PR, NR did not show significant change. 27 patients proceeded to ITB during the follow up period. Response on NRS and MSSS-88 were strongly correlated (R=0.67, p< 0.001). Mean dose was 8 sprays and was in line with literature. SEs (48%) were generally mild and resolved within a few days even when treatment was continued. 10% of the total withdrew treatment due to SEs. 1 suicide was recorded. Conclusion(s): THC:CBD provided symptomatic relief in people with treatment resistant spasticity (response rate at 4 weeks = 68%) delaying or avoiding the need to proceed to ITB with 27 having an ITB pump implanted. Strict vigilance is required to identify any pattern of mood disturbance or suicide risk.

Observational study; case study
Grade 4 -Very low

Dini, E. Cafalli, M. De Luca, C. Baldacci, F. Gori, S. Bonuccelli, U. Case report: Chronic migraine successfully treated with cannabinoids. Journal of Headache and Pain. Conference: 12th European Headache Federation Congress and the 32nd National Congress of the Italian Society for the Study of Headaches. Italy. 2018; 19: http://dx.doi.org/10.1186/s10194-018-0900-0 - external site

Introduction. The use of Cannabis sativa plant for medical purposes dates back to ancient times. Due to their strong analgesic action, cannabinoids are still used for symptomatic and prophylactic treatment in many pain conditions. Phytocannabinoids such as THC (DELTA-9- tetrahydrocannabinol) and CBD (cannabidiol), are effective in reducing pain and inflammatory damages, causing also plastic changes in brain areas implicated in pain transmission¹. Empirical evidences suggest the utility of cannabinoids in treating migraine, but no controlled trials are available². Case Report. A 48-year-old man presented last July to headache outpatient clinic. He referred, since he was a young boy, recurring headache with unilateral, switching side, pulsating pain, associated with nausea/vomiting, photophobia and phonophobia; the pain exacerbates with routine physical activity. In his past medical history, he reported Chronic lymphocytic leukemia in hematological follow-up. A recent brain MRI scan was performed and resulted normal. The neurological examination of the patient was also normal. For the past two years the headache frequency has been >20 days/month, with indomethacin overuse. Along this period, the patient underwent prophylactic treatment with propranolol and flunarizine, both ineffective. Detoxification with dexamethasone was prescribed, along with prophylactic treatment with amitriptyline up to 30 mg/days. This therapy, although well tolerated, resulted ineffective in reducing headache frequency and intensity, so it was discontinued by the patient after 3 months. In November he started a prophylactic treatment, prescribed by a specialist from Analgesic Treatment Centre, with a galenic formulation of THC 6.5% and CBD 8%, 10 drops orally bid, with reduction in migraine frequency: 0-1 days/month in the last 4 months, as he reported during the last month headache outpatient clinic evaluation. Discussion. Cannabinoids are a promising weapon in treating migraine, due to their analgesic, antiemetic and anti-inflammatory action. Supporting literature is limited to case reports and laboratory studies1. Further researches, especially randomized clinical trials, are needed to determine specific posology and prescription3, since low doses of cannabinoids lower migraine pain, while higher doses exacerbate it. Moreover, an important question to investigate in cannabinoids use for chronic pain syndromes, is the development of physical reliance and tolerance. CBD, unlike THC, does not have psychoactive effects, so a path for CBD-based drugs should also be explored. Formal approval of cannabinoids drugs for a certain number of medical conditions, may encourage further scientific research to establish effectiveness and safety of these compounds in migraine treatment, to uncover potential therapeutic effects still unknown.

Observational study; case series
Grade 4 -Very low

Flachenecker, P. Sacca, F. Vila, C. Variability of multiple sclerosis spasticity symptoms in response to THC:CBD oromucosal spray: Tracking cases through clinical scales and video recordings. Case Reports in Neurology 2018; 10: http://dx.doi.org/10.1159/000490376 - external site

Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune demyelinating disease of the central nervous system. Patients exhibit heterogeneous patterns of disabling symptoms, including spasticity. In the majority of patients with MS spasticity, it and its associated symptoms contribute to disability, interfere with performance of everyday activities, and impair quality of life. Even under treatment with oral antispasticity drugs, about a third of patients continue to experience spasticity of moderate to severe intensity, underscoring the need for additional treatment options. The efficacy of tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray as add-on therapy in patients with refractory MS spasticity has been demonstrated in clinical trials and observational studies. To gain insight into patients' response to treatment at the individual level, in-depth changes from baseline in various clinical scales and video-assessed parameters were evaluated in patients with resistant MS spasticity before and after 1 month of treatment with THC:CBD oromucosal spray. All 6 patients showed >=20% improvement in the spasticity Numerical Rating Scale (i.e., were initial responders to treatment), but displayed individual variability in other spasticity-related parameters. Improved Modified Ashworth Scale scores were observed in 5 cases, with a reduction of -2/-3 points in lower limb scores for 1 patient who also showed benefit in terms of a more stable gait but modest improvement in the timed 10-meter walk test (10MWT). Improvement in the 10MWT (or 25-foot walk test) was noted in 4 of the 6 cases. THC:CBD oromucosal spray also improved upper limb function as indicated by faster 9-Hole Peg Test results. Copyright © 2018 The Author(s).

Observational study; patient survey
Grade 4 -Very low

Forray, A. Bozzo, J. Cole, J. Spodick, J. Roberts, J. D. Marijuana use in adults with sickle cell disease. Drug and Alcohol Dependence 2017; 171: http://dx.doi.org/10.1016/j.drugalcdep.2016.08.187 - external site

Aims: Sickle cell disease (SCD) is an inherited disorder characterized by the unpredictable onset of pain that is often severe and may become chronic. Anecdotal reports suggest that some adults with SCD smoke marijuana for pain relief and other medicinal purposes. To date the use of marijuana among adults with sickle cell disease in the United States has not been evaluated. The purpose of this project was to estimate the prevalence, frequency, and rationale for marijuana use among adults with SCD. Method(s): Over a period of two months all patients receiving care at a hospital-based adult sickle cell clinic were asked to complete a one-page, self-report anonymous survey about marijuana use. In addition, over a 20-month period we reviewed the results of random urine toxicology screens routinely conducted in the clinic for patients receiving prescriptions for opioid pain medication. Result(s): All approached clinic patients (n = 59) participated in the survey (34% men; 66% women). 40% (n = 24) of respondents endorsed use in the last two years (65% men; 29% women). Reported frequency of use was approximately evenly distributed among 4 frequency categories: less than monthly, monthly, weekly, and daily. Daily use was more common among men. Among users, a majority endorsed all 5 "medical" reasons for marijuana use: pain, anxiety, mood, sleep, and appetite. Nearly one-third reported using marijuana "to get high". 75% reported that marijuana allowed use of less opiate pain medication. Of 121 adults engaged in the clinic, 57 underwent urine toxicology screening that included testing for marijuana. For those tested the median number of tests was 2, and 28% tested positive for marijuana at least once. Conclusion(s): Marijuana use is common among adults with sickle cell disease. Most users report use primarily for medicinal reasons; a minority acknowledge recreational use. These findings are timely and highly relevant given the increasing interest and social and legal acceptance of marijuana as a medical treatment for pain and other disorders.

Observational study; patient survey
Grade 4 -Very low

Garone, A. Martini, A. Arrigoni, E. Schweiger, V. Parolini, M. Polati, E. Treatment of fibromyalgia cannabinoid treatment in fibromyalgia. Clinical and Experimental Rheumatology 2019; 37 (1 Supplement 116):

Aim of the study. Therapy with cannabinoids has shown a beneficial effect in the treatment of different pathological conditions. We wanted to observe if they are able to improve quality of life and to control pain also in fibromyalgic patients. Method. We reviewed outcomes of 15 patients followed by our center affected by fibromyalgia, which started cannabinoids as an addon therapy. We proposed three questionnaires (FIQ, McGill pain questionnaire, PSQUI), to which patients were asked to answer on a basis of three months, for an observation period of six months. All patients were treated by cannabinoid in oil extraction and doses may vary from patient to patient with the aim to achieve the maximum tolerable daily dose in two administration. Results. We collected data from 15 patients. From the analysis of the results we saw a 13,15% drop down of the mean value of the FIQ and 14,15% decrease of the McGill pain questionnaires in the first 3 months of observation, with a consequent stabilization of the pain's perception to T2. Analysis of the results of PSQUI showed a 41% improvement of the mean value at T2. Conclusion. Cannabinoids have shown to increase sleep quality while their effect on pain or quality of life is still uncertain. Our main limitation is the small sample and moreover our patients have a lot of difficulties in getting a stable supply of the chosen cannabinoid. Anyway, a bigger sample is needed for a definite conclusion. (Figure Preseted).

Observational study; prospective cohort
Grade 4 -Very low

Grao-Castellote, C. Torralba-Collados, F. Gonzalez, L. M. Giner-Pascual, M. [Delta-9-tetrahydrocannabinol-cannabidiol in the treatment of spasticity in chronic spinal cord injury: a clinical experience]. Revista de Neurologia 2017; 65:

INTRODUCTION: Spasticity in chronic spinal cord injury is a condition that can have negative repercussions on the patient's quality of life. Its treatment is complex and sometimes the outcome is insufficient. Cannabinoids have recently been used in multiple sclerosis to successfully treat spasticity that is refractory to other therapies.
AIM: To quantify the clinical response of a group of patients with spastic chronic spinal cord injury to the orally administered drug delta-9-tetrahydrocannabinol-cannabidiol (Sativex ) as medication for use in special situations.
PATIENTS AND METHODS: The research consists of a six-month observational study in patients with chronic spinal cord injuries with refractory spasticity. The variables collected were: modified Ashworth scale, Penn spasm frequency scale, Numeric Rating Scale, and Visual Analogue Scale for pain. Additionally, clinical variables and side effects of the treatment were also collected.
RESULTS: Fifteen patients took part in this study. A significant improvement was observed on three of the scales recorded: modified Ashworth scale (z = -2.97; p = 0.003), Penn spasm frequency scale (z = -2.76; p = 0.006) and Numeric Rating Scale (z = -3.21; p = 0.001). The use of the drug was withdrawn in two patients due to side effects.
CONCLUSIONS: Sativex can be considered an alternative in patients with spasticity associated with chronic spinal cord injury for whom other therapeutic measures have been insufficient. Further studies need to be conducted before the use of this drug can be recommended and so as to define a complete profile of its long-term side effects.

Observational study; patient survey
Grade 4 -Very low

Hawley, L. A. Ketchum, J. M. Morey, C. Collins, K. Charlifue, S. Cannabis Use in Individuals With Spinal Cord Injury or Moderate to Severe Traumatic Brain Injury in Colorado. Archives of Physical Medicine and Rehabilitation 2018; 99: http://dx.doi.org/10.1016/j.apmr.2018.02.003 - external site

Objectives: To describe the prevalence of cannabis use in an adult sample with spinal cord injury (SCI) or traumatic brain injury (TBI) in Colorado, and to describe the self-reported reasons and side effects of cannabis use in this sample. Design(s): Mixed-methods observational study, using focus group data and telephone survey. Setting(s): Community. Participant(s): Colorado adults who sustained SCI or moderate to severe TBI and received services through Craig Hospital. Intervention(s): None. Main Outcome Measure(s): Survey. Result(s): Focus group participants identified issues that were then included in the survey development. Seventy percent of the 116 participants surveyed reported cannabis use before their injury (67% SCI, 74% TBI) and 48% reported use after their injury (53% SCI, 45% TBI). Overall, the most common reason for use was recreational (67%), followed by reducing stress/anxiety (62.5%) and improving sleep (59%). Among the respondents with SCI, the most common reasons for use were to reduce spasticity (70%), recreation (63%), and to improve sleep (63%). Among those with TBI, reasons endorsed were recreational (72%), reducing stress/anxiety (62%), and improving sleep (55%). Smoking was the most common method of use. Conclusion(s): A majority of this sample reported using cannabis before injury, and approximately half reported using cannabis after injury. Both groups reported recreational use, whereas the group with SCI also highly endorsed using cannabis to address chronic medical conditions. Clinicians should be aware of the high prevalence of cannabis use in these populations and the impact such use may have on the individual's medical management. Further research in this area is needed. Copyright © 2018 American Congress of Rehabilitation Medicine

Observational study; patient survey
Grade 4 -Very low

Hugos, C. Rice, J. Cameron, M. Cannabis use in people with MS and spasticity: A cross-sectional analysis. Multiple Sclerosis Journal 2019; 25 (7): http://dx.doi.org/10.1177/1352458519844447 - external site

Objective: To describe cannabis use in subjects with MS and spasticity. Background(s): Spasticity affects over 80% of people with MS, impacting activity, participation and quality of life. 2014 systematic reviews found pharmaceutical cannabinoids (oral or oral-mucosal spray containing tetrahydrocannabinol [THC] with or without cannabidiol [CBD]) reduce patient-reported spasticity. These products are not available in the US, but marijuana is medically (1998) and recreationally (2014) legal in Oregon. Here we describe cannabis use in subjects in Portland, Oregon, with MS and self-reported spasticity enrolling in a randomized controlled rehabilitation trial for spasticity. Design/Methods: Subjects reported cannabis use, route of administration, frequency of use and perceived benefits. They also reported use of prescribed medications for spasticity. Here we report data from the first 50 subjects, with an additional 20-30 to be reported at the meeting. Result(s): In 50 subjects (42 females and 8 males), 36% (18/50) used cannabis. Of these, some reported one route of administration: 17% (3/18) topical, 6% each (1/18) tincture or smoking. All others reported multiple routes of administration including 61% (11/18) edibles, 44% (8/18) topical, 33% (6/18) tinctures, 28% each (5/18) smoking or vaping. Of current cannabis users, 33% (3/18) use between weekly and monthly, 22% (4/18) use between daily and weekly, 22% (4/18) use daily, and 39% (7/18) use multiple times per day. 78% (14/18) reported cannabis being somewhat or very helpful for spasticity and 89% (16/18) reported similar benefit for pain. 72% (13/18) reported also using at least one prescribed medication for spasticity, with baclofen being the most common (56%, 10/18). Conclusion(s): In Oregon, USA, where medical and recreational marijuana are legal but pharmaceutical cannabinoids are not available, approximately 1/3 of people with MS and spasticity report using cannabis. Most find cannabis somewhat to very helpful for spasticity and pain, use multiple routes of administration, and also use prescribed antispasticity medications.

Observational study; case study
Grade 4 -Very low

Lim, J. Z. Abdelrahim, S. Alam, U. Wilding, J. P. Mon, A. Therapeutic effect of improved glycaemic control with concomitant use of cannabis oil. Diabetic Medicine 2019; 36 (Supplement 1): http://dx.doi.org/10.1111/dme.13883 - external site

Introduction: Animal-based and some human studies identified potential benefits of cannabis oil use for diabetes. Medicines and Healthcare products Regulatory Agency (MHRA) approved Sativex (50-50 mix of tetrahydrocannabinol and cannabidiol) for use in the United Kingdom (UK) for multiple sclerosis. From 1st November, doctors will be able to prescribe cannabis products in the UK for epilepsy and chronic pain. This will likely result in an increase in use of cannabis oil in clinical practice, especially as chronic pain is common in diabetes. We report a case of marked improvement in glycaemic and blood pressure control with cannabis oil use in a patient with Type 2 diabetes. Case report: A 67-year-old gentleman with Type 2 diabetes for over 30 years with ischaemic heart disease, hypertension, peripheral neuropathy and congestive cardiac failure was diagnosed with a primary progressive form of multiple sclerosis, aged 61. Sativex (cannabis oil), specifically licensed to treat muscular spasms and stiffness in multiple sclerosis, was used under supervision of a neurologist in the private sector. Weight 90kg with body mass index (BMI) of 29.5kg/m². After three months on Sativex, the patient reported relief from neuropathic pain. Glycaemic control improved; HBA1C (88 to 75MMOL/MOL) and capillary glucose (12-14mmol/l to 4-6mmol/l) improved without any hypoglycaemiaor change inbasal-bolus insulin (126units daily). Blood pressure improved from 152/98mm Hg to 99/62mm Hg without any change in antihypertensives. Conclusion(s): Improved blood pressure and glycaemic control could result from pain relief, better concordance or a direct effect of cannabis oil on glucose metabolism; further study in controlled trials is warranted. Acknowledgement: Obesity and Endocrinology Research Group.

Observational study; retrospective chart review
Grade 4 -Very low

Mechtler, L. Bargnes, V. Hart, P. McVige, J. Saikali, N. Medical cannabis for chronic migraine: A retrospective review. Neurology. Conference: 71st Annual Meeting of the American Academy of Neurology, AAN 2019; 92:

Objective: To examine the effects of medical cannabis (MC) on chronic migraine (CM). Background(s): New York State (NYS) authorized cannabis for medically certified patients in 2015. No guidelines exist for the use of MC in CM patients. The limited body of literature for MC leaves providers underequipped and patients vulnerable. Design/Methods: This retrospective chart review of patients with CM, per International Classification of Headache Disorders Third Edition, examined 316 patients >=21 years of age with at least one month of MC through DENT Neurologic Institute. Result(s): On NYS MC, 88.3% (279) patients reported improvement in their headache profile with an average MC exposure of 22.4+/-17.5 weeks. The average monthly migraine frequency change was significant with 42.1% decrease (24.9+/-7.16 to 16.1+/-10.7, p<0.0001). Over half of the patients (171) reported improvement in their headache frequency, with 55.0% (111) experiencing >=50% reduction of headache days. Sleep improvement was noted in 38.3% (121), anxiety improvement in 30.7% (97), and mood improvement in 24.7% (78). Opioid medications for CM-related pain were reduced in 50% (14) after an average of 5.6 years of opioid use. Adverse effects (AE) were reported in 23.1% (73) with 4 (1.3%) discontinuing due to AE. Patients taking a 20:1 ratio (tetrahydrocannabinol to cannabidiol) reported significantly higher occurrence of overall headache profile improvement than patients on a 1:1 ratio (p=0.039) and headache medication reduction (p=0.0059, RR 3.12). A high to low ratio carried a RR of 3.40 for mood improvement, with similar RR observed for anxiety (3.01) and sleep (2.17) improvements. There was no significant difference in AE among high to low, equal, or low to high ratios. Conclusion(s): MC may play a safe role in CM management by helping to improve headache profile, anxiety, sleep, mood, and opioid reduction. Prospective studies are required to examine the role of MC in CM within a placebo-controlled environment.

Observational study; retrospective chart review
Grade 4 -Very low

Mechtler, L. Hart, P. Bargnes, V. Saikali, N. Medical cannabis treatment in patients with trigeminal neuralgia. Neurology. Conference: 71st Annual Meeting of the American Academy of Neurology, AAN 2019; 92:

Objective: The purpose of this study is to assess medical cannabis' (MC) efficacy, reported adverse effects (AE), and dosages used in the treatment of patients with trigeminal neuralgia (TN). Background(s): Few treatments currently exist for the treatment of TN, and almost half of patients become refractory to those medications with limited and often invasive recommendations for symptom control. A growing amount of evidence suggests that MC may be effective in alleviating neuropathic pain, making MC a potentially valuable treatment option for TN. Design/Methods: A retrospective chart review of patients with TN that were treated with MC through the New York State Medical Marijuana Program was conducted in Buffalo, New York. Result(s): Of 42 patients (32=female 10=male) included in the study, 81% reported improvement in their TN symptoms. AE were reported in 40%, and two discontinued because of AE. The most common side effects were fatigue, somnolence, nausea, and dizziness. Of patients who reported >=50% improvement in TN symptoms, 69% used one product and 50% used a 1:1 ratio of tetrahydrocannabinol to cannabidiol. Of patients reporting opioid use at the beginning of MC treatment, 50% were able to reduce their opioid consumption on MC. Conclusion(s): This study found that MC is well tolerated in the treatment of TN, with the 81% of patients reporting improvement and 50% of patients reducing opioid consumption with MC. The most common efficacious dosage for these patients is a 1:1 ratio of THC to CBD. These results suggest that MC is a useful part of a comprehensive pain management plan for patients with TN, but future randomized placebo-controlled trials are needed.

Observational study; prospective cohort
Grade 4 -Very low

Merlin, J. S. Long, D. Becker, W. C. Cachay, E. R. Christopolous, K. A. Claborn, K. R. Crane, H. M. Edelman, E. J. Lovejoy, T. I. Mathews, W. C. Morasco, B. J. Napravnik, S. O'Cleirigh, C. Saag, M. S. Starrels, J. L. Gross, R. Liebschutz, J. M. Marijuana Use Is Not Associated with Changes in Opioid Prescriptions or Pain Severity among People Living with HIV and Chronic Pain. Journal of Acquired Immune Deficiency Syndromes 2019; 81: http://dx.doi.org/10.1097/QAI.0000000000001998 - external site

Background: People living with HIV (PLWH) commonly report marijuana use for chronic pain, although there is limited empirical evidence to support its use. There is hope that marijuana may reduce prescription opioid use. Our objective was to investigate whether marijuana use among PLWH who have chronic pain is associated with changes in pain severity and prescribed opioid use (prescribed opioid initiation and discontinuation). Method(s): Participants completed self-report measures of chronic pain and marijuana use at an index visit and were followed up for 1 year in the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). Self-reported marijuana use was the exposure variable. Outcome variables were changes in pain and initiation or discontinuation of opioids during the study period. The relationship between exposure and outcomes was assessed using generalized linear models for pain and multivariable binary logistic regression models for opioid initiation/discontinuation. Result(s): Of 433 PLWH and chronic pain, 28% reported marijuana use in the past 3 months. Median pain severity at the index visit was 6.3/10 (interquartile range 4.7-8.0). Neither increases nor decreases in marijuana use were associated with changes in pain severity, and marijuana use was not associated with either lower odds of opioid initiation or higher odds of opioid discontinuation. Conclusion(s): We did not find evidence that marijuana use in PLWH is associated with improved pain outcomes or reduced opioid prescribing. This suggests that caution is warranted when counseling PLWH about potential benefits of recreational or medical marijuana. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Observational study; retrospective chart review
Grade 4 -Very low

Myers, B. Geist, T. Hart, P. Aladeen, T. Begley, A. Westphal, E. S. Floarea, S. Rainka, M. Mechtler, L. Medical cannabis in the treatment of parkinson's disease. Neurology. Conference: 71st Annual Meeting of the American Academy of Neurology, AAN 2019; 92:

Objective: The study aims to evaluate medical cannabis' (MC) efficacy and adverse effects (AE) in treatment of Parkinson's disease (PD) symptoms. Background(s): Thirty U.S. states have legislation allowing prescription of medical cannabis (MC). Previous research suggests possible benefits of cannabinoids in treating PD symptoms including tremor, rigidity and dyskinesia; however, more research is needed. Design/Methods: A retrospective analysis including patients diagnosed with idiopathic PD and treated with MC through the NYS Medical Marijuana Program was conducted. Result(s): Sixty-two (43=Male, 20=Female) patients aged 71+/-10 years were included. Primary indication for MC treatment included PD (71%), chronic pain (25%), cancer (2%), and neuropathy (2%). Seventy-seven percent (N=48) reported improvement in PD motor symptoms, most commonly in tremor and spasticity; improvements in rigidity, gait instability, dyskinesia and bradykinesia were also noted. Of patients reporting chronic pain, 85% reported decreased pain with MC therapy. Twenty-five patients were taking an opioid at MC therapy initiation, and a significant proportion (48%, p=0.002) either discontinued or reduced the opioid during treatment. Over half of patients also reported improvement in non-motor PD symptoms, including sleep disturbance, anxiety, depressed mood, and nausea. Forty-four percent of patients reported AE, most commonly somnolence (N=15), followed by disorientation (N=8) and dizziness (N=4). AE were transient or resolved with dose adjustment in 41% of these patients. MC was tolerated well in this population, with only 4 patients (6.4%) discontinuing due to AE. Conclusion(s): The study finds that, typically in combination with other PD therapies, MC is a well-tolerated option to improve both motor and non-motor symptoms in PD patients, and may be helpful in relieving some AE of PD medications such as nausea or insomnia. Commonly observed side effects of MC included somnolence and dizziness. Future randomized placebo controlled trials are necessary to verify efficacy, AE profiles, dosage information, and long-term effects of MC on PD.

Observational study; retrospective cohort
Grade 4 -Very low

Ngan, T. Y. T. Litt, M. Eguzo, K. Thiel, J. A. Patient Outcomes Following Initiation of Medical Cannabis in Women with Chronic Pelvic Pain. Journal of Minimally Invasive Gynecology 2019; 26 (7 Supplement): http://dx.doi.org/10.1016/j.jmig.2019.09.751 - external site

Study Objective: The aim is to evaluate the efficacy and side effects of medical cannabis for chronic pelvic pain (CPP). Design(s): We conducted a retrospective cohort study between 2012 and 2018. Setting(s): N/A Patients or Participants: Three gynecologists specialized in pelvic pain who prescribe medical marijuana in their practice for analgesia participated. Only patients with CPP were included. Intervention(s): 3 grams of medical cannabis daily was prescribed. Measurements and Main Results: A descriptive analysis assessing patient baseline characteristics was performed. The usage of medical cannabis was recorded. Patient outcomes following initiation of medical cannabis were studied. Primary outcome was pain response; secondary outcomes were side effects and resulting patterns of opioid use. Chi-square test was used to compare association between different variables. P-value of <0.05 was considered significant. A total of 135 women, with mean age of 35.4 years old, were prescribed medical cannabis. 92.6% were premenopausal. 8.9% underwent hysterectomy. 48.2%, 60.0% and 57% tried at least one type of NSAID, opioid, or neuromodulator respectively. The route of cannabis administration was documented in 38 charts. Some patients used more than one formulation. 25 patients used cannabis oil, 10 ingested edibles, 9 vaporized cannabis and 6 smoked marijuana. Change in pain was documented in 82 cases: 79 experienced improvements, and 3 reported no change. No patient had worsening of pain. Of the patients who had improvement, 39 reduced their opioids use. Side effects were reported by 9 patients-the most common being headache. No significant relationship between patient baseline characteristics and change in pain was found. Conclusion(s): This is the first study reporting use of medical cannabis in CPP. Medical cannabis is a safe treatment with minimal side effects that can improve CPP and reduce opioids use. Future studies evaluating the pharmacokinetics and optimal regimen in the management of CPP are needed. Copyright © 2019

Observational study; patient survey
Grade 4 -Very low

Nugent, S. M. Yarborough, B. J. Smith, N. X. Dobscha, S. K. Deyo, R. A. Green, C. A. Morasco, B. J. Patterns and correlates of medical cannabis use for pain among patients prescribed long-term opioid therapy. General Hospital Psychiatry 2018; 50: https://dx.doi.org/10.1016/j.genhosppsych.2017.11.001 - external site

OBJECTIVE: Little is known about co-occurring long-term opioid therapy (LTOT) and medical cannabis use. We compared characteristics of patients prescribed LTOT who endorsed using medical cannabis for pain to patients who did not report cannabis use.
METHOD: Participants (n=371) prescribed LTOT completed self-report measures about pain, substance use, and mental health.
RESULTS: Eighteen percent of participants endorsed using medical cannabis for pain. No significant differences were detected on pain-related variables, depression, or anxiety between those who endorsed medical cannabis use and those who did not. Medical cannabis users had higher scores of risk for prescription opioid misuse (median=17.0 vs. 11.5, p<0.001), rates of hazardous alcohol use (25% vs. 16%, p<0.05), and rates of nicotine use (42% vs. 26%, p=0.01). Multivariable analyses indicated that medical cannabis use was significantly associated with risk of prescription opioid misuse (beta=0.17, p=0.001), but not hazardous alcohol use (aOR=1.96, 95% CI=0.96-4.00, p=0.06) or nicotine use (aOR=1.61, 95% CI=0.90-2.88, p=0.11).
CONCLUSION: There are potential risks associated with co-occurring LTOT and medical cannabis for pain. Study findings highlight the need for further clinical evaluation in this population. Future research is needed to examine the longitudinal impact of medical cannabis use on pain-related and substance use outcomes.

Observational study; case series
Grade 4 -Very low

Palace, Z. J. Reingold, D. A. Medical Cannabis in the Skilled Nursing Facility: A Novel Approach to Improving Symptom Management and Quality of Life. Journal of the American Medical Directors Association 2019; 20: http://dx.doi.org/10.1016/j.jamda.2018.11.013 - external site

Throughout the millennia, the cannabis plant has been utilized as a recognized therapy for pain relief and symptom management. Following the Prohibition-era stigmatization and criminalization of all forms of cannabis of the early 20th century, there has been a recent nationwide and worldwide resurgence in interest and use of the cannabinoid compounds extracted from the cannabis plant, that is, medical cannabis. Although at the Federal level, cannabis remains a Schedule I substance, 31 states have already decriminalized possession and use of medical cannabis for specific diagnoses. It is noteworthy that many of these indicated diagnoses are prevalent in the skilled nursing facility (SNF). This creates regulatory concerns as SNFs and other healthcare facilities must maintain compliance with Federal laws, while balancing the individual resident's rights to utilize medical cannabis where indicated. The authors developed an innovative program that affords their residents the ability to participate in a state-approved medical cannabis program while remaining compliant with Federal law. As medical cannabis use becomes more widespread and accepted, clinicians providing medical care in healthcare facilities will encounter residents who may benefit from and request this alternative therapy. Studies examining older adults that are utilizing medical cannabis legally have demonstrated significant decreases in prescription medication use, most notably a reduction in opioid analgesic usage. As such, medical cannabis should be viewed as an additional option in the clinician's toolbox of therapeutic interventions for symptom relief. Copyright © 2018 AMDA - The Society for Post-Acute and Long-Term Care Medicine

Observational study; patient survey
Grade 4 -Very low

Phatak, U. P. Rojas-Velasquez, D. Porto, A. Pashankar, D. S. Prevalence and Patterns of Marijuana Use in Young Adults With Inflammatory Bowel Disease. Journal of Pediatric Gastroenterology & Nutrition 2017; 64: https://dx.doi.org/10.1097/MPG.0000000000001474 - external site

OBJECTIVES: Recent studies in adults report symptom relief with marijuana use in patients with inflammatory bowel disease (IBD). We assessed the prevalence, pattern, effects, and adverse effects of marijuana use in young adults with IBD.
METHODS: We conducted a prospective questionnaire survey study at a pediatric IBD clinic. All patients (18-21 years of age) answered anonymous questionnaires about demographics, IBD, medications, and marijuana use.
RESULTS: Fifty-three patients (mean age 18.7 years, 32 boys) were enrolled. Thirty-seven patients (70%) reported using marijuana currently or in the past. There was no statistically significant difference between the users and nonusers of marijuana regarding demographics, disease activity, or medications. Despite prolonged use of marijuana, 70% of patients did not discuss it with their gastroenterologists. Twenty-four patients used marijuana medicinally for IBD symptoms in addition to medical therapy. Although majority found marijuana to be moderately/very helpful, complete relief of symptoms such as abdominal pain, poor appetite, nausea, and diarrhea was seen in 29%, 37%, 14%, and 10% of patients, respectively. Only half of patients reported knowledge of possible adverse effects of marijuana and 19% of patients reported mild neuropsychiatric adverse effects. Overall, 98% of patients supported legalization of marijuana and 85% were interested in using medical marijuana if it became legally available.
CONCLUSIONS: We found a high rate of marijuana use in our cohort of young adults with IBD. Majority of users report symptom improvement but do not inform physicians. Future well-controlled studies are necessary to assess role of marijuana in IBD therapy.

Observational study; patient survey
Grade 4 -Very low

Pires, C. Lachiewicz, M. A pilot survey of marijuana use and self-reported benefit in women with chronic pelvic pain. Pain Medicine (United States) 2018; 19 (4): http://dx.doi.org/10.1093/pm/pny044 - external site

Introduction: The use of marijuana has been reported with various pain syndromes. However, there has been no systematic evaluation of marijuana use among women with chronic pelvic pain (CPP). We hypothesize that the prevalence of marijuana use is higher in patients with CPP compared to the general population and that CPP patients report an improvement in their pain symptoms with marijuana use. Method(s): Patients were identified via amedical record query of commonly used CPT codes for pelvic pain. Patients were contacted via phone to confirm CPP diagnosis and emailed an anonymous online survey. Setting(s): Tertiary care academic medical center Results: Fifty-one patients who screened positive for CPP were emailed; 43 responded for a response rate of 84.3%. Three respondents did not meet inclusion criteria. Twenty of 40 (50%) patients reported previous or current use of marijuana. Ten of 20 (50%) current or previous users reported using marijuana for CPP; and 10/10 (100%) reported that it was very helpful or gave complete relief. 35/38 support legalization of medical marijuana and 35/40 patients would consider being in a clinical trial of medical marijuana to treat CPP. Conclusion(s): This pilot study demonstrates that patients with CPP are self-treating with marijuana and finding this to be an effective intervention. Clinical trials are needed in this area to evaluate the efficacy and safety of marijuana use for CPP.

Observational study; prospective cohort
Grade 4 -Very low

Ron, A. Abuhasira, R. Novack, V. Establishment of a specialized geriatric clinic providing medical cannabis. Journal of the American Geriatrics Society 2019; 67 (Supplement 1): http://dx.doi.org/10.1111/jgs.15898 - external site

Introduction: There is a substantial growth in the use of medical cannabis in recent years and with the aging of the population, medical cannabis (MC) is increasingly used by the elderly for a plethora of possible indications. In 2017, NiaMedic has established a specialized geriatric clinic providing MC therapy within the comprehensive geriatric platform. We aimed to assess the characteristics of elderly people treated with MC and to evaluate the safety and efficacy of the treatment. Method(s): A prospective study that included all patients above 65 years of age receiving MC from January 2017 to October 2018. Outcomes were pain intensity, changes in medicine regimens and adverse events at six months. Result(s): We enrolled 184 patients above 65 years of age. The mean age of patients was 81.9+/-7.5 years and 63.6% were females. The most common indication for treatment was pain (76.9%). After six months of treatment, 93.8% of the respondents reported improvement in their condition, the reported pain level was reduced from a median of 10 on a scale of 0-10 to a median of 3 (p=0.001) and 34.8% reported an improvement in their appetite, while 27.1% of the patients stopped treatment with MC. Most common adverse events were: dizziness (14.1%), somnolence (13.0%) and dry mouth (6.5%). After six months, 46.9% stopped using opioid analgesics or reduced their dose. Conclusion(s): Therapeutic use of cannabis is safe and efficacious in the elderly population. Cannabis use may decrease the use of other prescription medicines, including opioids. Gathering more evidence-based data, including data from double-blind randomized-controlled trials, in this special population, is imperative.

Observational study; prospective cohort
Grade 4 -Very low

Sagy, I. Schleider, L. B. L. Abu-Shakra, M. Novack, V. Safety and efficacy of medical cannabis in fibromyalgia. Annals of the Rheumatic Diseases 2019; 78 (Supplement 2): http://dx.doi.org/10.1136/annrheumdis-2019-eular.111 - external site

Background: Although chronic pain is a well-established indication for medical cannabis therapy, there is scarce evidence to support the role of medical cannabis in the treatment of fibromyalgia. Objective(s): The aim of the study was to investigate the characteristics, safety and effectiveness of medical cannabis therapy for fibromyalgia. Method(s): A prospective study with 6 months follow-up period based on fibromyalgia patients who were willing to answer questionnaire in a specialized medical cannabis clinic between 2015 and 2017. Result(s): Among the 367 fibromyalgia patients the mean age was 52.9 +/-15.1, of whom 301 (82.0%) were women. 28 patients (7.6%) stopped the treatment prior to the six months follow-up. The six months response rate was 70.8%. Pain intensity (scale 0-10) reduced from a median of 9.0 at baseline to 5.0 (p<0.001), and 194 patients (81.1%) achieved treatment response. In a multivariate analysis age above 60 years (Odds ratio [OR] 0.34, 95% C.I 0.16-0.72), concerns about cannabis treatment (OR 0.36, 95% C.I 0.16-0.80), spasticity (OR 2.26, 95% C.I 1.08-4.72) and previous use of cannabis (OR 2.46 95% C.I 1.06-5.74) were associated with treatment outcome. The most common adverse effects were mild and included dizziness (7.9%), dry mouth (6.7%) and gastrointestinal symptoms (5.4%). Conclusion(s): Medical cannabis appears to be safe and effective alternative for the treatment of fibromyalgia symptoms. Standardization of treatment compounds and regimens are required.

Observational study; patient survey
Grade 4 -Very low

Schorn, M. Krashin, D. Mannava, A. Belaskova, S. Murinova, N. Marijuana use in headache in a university-based headache clinic. Neurology. Conference: 71st Annual Meeting of the American Academy of Neurology, AAN 2019; 92:

Objective: Our objective was to examine prevalence and experience of patients who self-reported marijuana use for headache pain management in a University-based headache clinic Background: Despite increased interest in marijuana use, there is paucity of research for headache disorders. Marijuana is legal in Washington and multiple states of the USA. Design/Methods: All new patients at a tertiary headache clinic complete a patient intake questionnaire prior to the first visit. This questionnaire contains a section on marijuana use. After seeing the patient face-to-face, clinicians update the database with the headache diagnosis using IHS-3 criteria. Then, a detailed IRB approved questionnaire is sent to patients which includes additional questions about marijuana frequency of use, perceived effectiveness, side effects, age of first use, and safety perception. Result(s): Only 437 patients out of 4386 patients surveyed prior to intake identified trying marijuana. More than 75% of the patients had diagnoses of chronic migraine (315, 77.6%). 215 reported that they tried using marijuana daily for headache prevention, 85.6% of them were currently still taking marijuana daily, 60% found it helpful. From our detailed survey responses of 244 patients, the average frequency of use was 15 days per month. 148 (69.8%) found it helpful. The majority were not able to abort headache fully (19, 10.9% were able to fully relieve pain). Most patients reported reduction in the pain severity (112, 64.4%). Participants also reported using marijuana for other conditions commonly comorbid with migraine: sleep (137, 57.6%), anxiety (107, 45%), mood (63, 26.5%), nausea (85, 35.3%), and other pain (147, 61.8%). Conclusion(s): Results suggest that marijuana use for headache treatment is generally uncommon (10% of survey participants). Most patients who have tried marijuana for headache reported some relief of pain, but rare full relief of headache. Many questions remain, including type and frequency of cannabis use. Randomized controlled studies are needed.

Observational study; patient survey
Grade 4 -Very low

Stillman, M. Capron, M. Mallow, M. Ransom, T. Gustafson, K. Bell, A. Graves, D. Utilization of medicinal cannabis for pain by individuals with spinal cord injury. Spinal cord series and cases 2019; 5: http://dx.doi.org/10.1038/s41394-019-0208-6 - external site

Study design: A cross-sectional multi-center study using an on-line survey addressing utilization, knowledge, and perceptions of medicinal cannabis (MC) by people with spinal cord injury (SCI). Objective(s): To characterize differences between current (CU), past (PU), and never users (NU) of MC with SCI; to determine why people with SCI use MC; to examine reports of MCs' efficacy and tolerability by individuals with SCI. Setting(s): Three academic medical centers in the United States. Method(s): Comparison of demographic and attitudinal differences between CU, PU, and NU and differences in the groups' reports of pain, health, and quality of life (QOL). Evaluation of utilization patterns and perceived efficacy of MC among CU and PU and reports of side effects of MC versus prescription medications. Data were analyzed using either Chi Square, distribution-free exact statistics, or t-tests for continuous data. Result(s): Among a nationwide sample (n=353) of individuals with SCI, NU were less likely than CU and PU to believe that cannabis ought to be legalized and more likely to endorse risks of use. Current users and PU reported greater pain interference in daily life than did NU, but there were no between group differences in QOL or physical or emotional health. Current users and PU took MC to address pain (65.30%), spasms (63.30%), sleeplessness (32.70%), and anxiety (24.00%), and 63.30% reported it offered "great relief" from symptoms. Participants reported that MC is more effective and carries fewer side effects than prescription medications. Conclusion(s): Medicinal cannabis is an effective and well-tolerated treatment for a number of SCI-related symptoms. Copyright © The Author(s), under exclusive licence to International Spinal Cord Society 2019

Observational study; single-group cross-over trial
Grade 4 -Very low

Yassin, M. Oron, A. Robinson, D. Effect of adding medical cannabis to analgesic treatment in patients with low back pain related to fibromyalgia: an observational cross-over single centre study. Clinical & Experimental Rheumatology 2019; 37 Suppl 116:

OBJECTIVES: Low back pain (LBP) occurs in many patients with fibromyalgia (FM). The current study aimed to assess the possible pain and function amelioration associated with medical cannabis therapy (MCT) in this setting.
METHODS: 31 patients were involved in an observational cross-over study. The patients were screened, treated with 3 months of standardised analgesic therapy (SAT): 5 mg of oxycodone hydrochloride equivalent to 4.5 mg oxycodone and 2.5 mg naloxone hydrochloride twice a day and duloxetine 30 mg once a day. Following 3 months of this therapy, the patients could opt for MCT and were treated for a minimum of 6 months. Patient reported outcomes (PRO's) included: FIQR, VAS, ODI and SF-12 and lumbar range of motion (ROM) was recorded using the modified Schober test.
RESULTS: While SAT led to minor improvement as compared with baseline status, the addition of MCT allowed a significantly higher improvement in all PRO's at 3 months after initiation of MCT and the improvement was maintained at 6 months. ROM improved after 3 months of MCT and continued to improve at 6 months.
CONCLUSIONS: This observational cross-over study demonstrates an advantage of MCT in FM patients with LBP as compared with SAT. Further randomised clinical trial studies should assess whether these results can be generalised to the FM population at large.