Pain - randomised controlled trials and other studies

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3 October 2017
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Randomised controlled trials

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.

Other studies

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.