Appendices

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Appendix 1. Search strategies……….……. page 2 Appendix 2. Excluded study references and reasons……… page 5 Appendix 3. Trials ongoing or awaiting classification……….. page 15 Appendix 4. Small studies excluded from systematic review …... page 18 Appendix 5. Risk of bias judgements ………... page 23 Appendix 6. Forest plots and change score analyses of secondary

outcomes………..……….... page 48 Appendix 7. Secondary outcomes of analyses for cannabinoids,

cannabis and CBMs, with forest plots………page 62 Appendix 8. Secondary outcomes of analyses by pain conditions, with forest plots……….……page 65

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Appendix 1. Search strategies Medline and Embase

1. Exp Cannabinoids/

2. Exp Cannabis/

3. Cannab* or Marijuana or Marinol or Dronabinol or Nabilone or

Levonantradol or Tetrahydrocannabinol or Cesamet or Delta-9-THC or Delta-9-Tetrahydrocannabinol or Nabiximols or Sativex or Cannabidiol or THC or CBD.mp.

4. Or/1-3

5. Exp therapeutic uses/

6. Exp drug therapy 7. Exp analgesics/

8. ‘Therapeutic use*’ or drug therap* or analgesic*.mp.

9. Or/5-8 10. 4 AND 9

11. Exp medical marijuana/

12. ‘Medicinal marijuana’ or ‘medical marijuana’.mp.

13. ‘Medicinal cannabis’ or ‘medical cannabis’.mp.

14. Or/11-13 15. 10 OR 14 16. Exp Pain/

17. Exp fibromyalgia/

18. Exp arthritis/

19. Exp headache disorders/

20. Fibromyalgia or musculoskeletal pain or dysmenorrhea or neuralgi* or neuropath*.mp.

21. headache* or cephalgi* or cephalalgi* or migrain* or neuropath*.mp.

22. pain or painful.mp.

23. postoperative or 'post operative'.mp.

24. Or/16-23

25. randomized controlled trial.pt.

26. controlled clinical trial.pt.

27. randomized.ab.

28. placebo.ab.

29. drug therapy.fs.

30. randomly.ab.

31. trial.ab.

32. groups.ab.

33. Or/25-32

34. 15 AND 24 AND 33

Medline and Embase (overview review search) 1. Exp Cannabinoids/

2. Exp Cannabis/

Levonantradol or Tetrahydrocannabinol or Cesamet or Delta-9-THC or Delta-9-Tetrahydrocannabinol or Nabiximols or Sativex or Cannabidiol or THC or CBD.mp.

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4. Or/1-3

6. Exp drug therapy 7. Exp analgesics/

8. ‘Therapeutic use*’ or drug therap* or analgesic*.mp.

9. Or/5-8 10. 4 AND 9

12. ‘Medicinal marijuana’ or ‘medical marijuana’.mp.

13. ‘Medicinal cannabis’ or ‘medical cannabis’.mp.

14. Or/11-13 15. 10 OR 14 16. Exp Pain/

18. Exp arthritis/

35. Fibromyalgia or musculoskeletal pain or dysmenorrhea or neuralgi* or neuropath*.mp.

20. headache* or cephalgi* or cephalalgi* or migrain* or neuropath*.mp.

21. pain or painful.mp.

22. postoperative or 'post operative'.mp.

23. Or/16-23

24. meta analysis.pt.

25. (meta‐analys* or meta analys* or metaanalys*).tw,sh.

26. exp meta-analysis as topic/

27. exp meta-analysis/

28. (systematic* adj5 review*).tw,sh.

29. (systematic* adj5 overview*).tw,sh.

30. (quantitativ* adj5 review*).tw,sh.

31. (quantitativ* adj5 overview*).tw,sh.

32. (quantitativ* adj5 synthesis*).tw,sh.

33. (methodologic* adj5 review*).tw,sh.

34. (methodologic* adj5 overview*).tw,sh.

35. (integrative research review* or research integration).tw.

36. Cochrane.ti.

37. Or/25-37

38. 15 AND 24 AND 38

CENTRAL (for both reviews) 1. Exp Cannabinoids/

2. Exp Cannabis/

Levonantradol or Tetrahydrocannabinol or Cesamet or Delta 9 THC or Delta9THC or Delta 9 Tetrahydrocannabinol or

Delta9Tetrahydrocannabinol or Nabiximols or Sativex or Cannabidiol or THC or CBD

4. Or/1-3

6. Exp drug therapy

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7. Exp analgesics/

8. “Therapeutic use*” or drug therap* or analgesic*:ti,ab,kw.

9. Or/5-8 10. 4 AND 9

12. “Medicinal marijuana” or “medical marijuana”:ti,ab,kw.

13. “Medicinal cannabis” or “medical cannabis”:ti,ab,kw.

14. Or/11-13 15. 10 OR 14 16. Exp Pain/

18. Exp arthritis/

36. Fibromyalgia or musculoskeletal pain or dysmenorrhea or neuralgi* or neuropath*:ti,ab,kw.

20. headache* or cephalgi* or cephalalgi* or migrain* or or neuropath*:ti,ab,kw.

21. pain or painful:ti,ab,kw.

22. postoperative or “post operative”:ti,ab,kw.

23. Or/16-23

24. Limit to Cochrane reviews, protocols, trials, and special issues

DARE (for the overview only) 1. Exp Cannabinoids/

2. Exp Cannabis/

Levonantradol or Tetrahydrocannabinol or Cesamet or Delta 9 THC or Delta9THC or Delta 9 Tetrahydrocannabinol or

Delta9Tetrahydrocannabinol or Nabiximols or Sativex or Cannabidiol or THC or CBD

4. Or/1-3

6. Medicinal marijuana or medical marijuana 7. Medicinal cannabis or medical cannabis 8. Or/5-7

9. 4 or 8 10. Exp Pain/

12. Exp arthritis/

37. Fibromyalgia or musculoskeletal pain or dysmenorrhea or neuralgi* or neuropath*

14. headache* or cephalgi* or cephalalgi* or migrain* or or neuropath*.

15. pain or painful

16. postoperative or post operative

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Appendix 2. Excluded study references and reasons

Excluded reference Reason

Abe, S., et al. (2017). "A prospective, randomized study of inhaled prostacyclin versus nitric oxide in patients with residual pulmonary hypertension after pulmonary endarterectomy." General thoracic and cardiovascular surgery 65(3): 153-159.

Not pain

Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV- associated sensory neuropathy: A randomized placebo-controlled trial. Neurology. 2007; 68(67):515–521. 2007. [PubMed: 17296917]

N<30 analysis

Aragona, M., et al. (2009). "Psychopathological and cognitive effects of therapeutic cannabinoids in multiple clerosis: A double- blind, placebo controlled, crossover study." Clinical

Neuropharmacology 32(1): 41-47.

No pain outcome

Beaulieu, P. (2006). "Effects of nabilone, a synthetic cannabinoid, on postoperative pain." Canadian journal of anaesthesia = Journal canadien d'anesthesie 53(8): 769-775.

N<30 analysis Blake, D. R., et al. (2006). "Preliminary assessment of the efficacy,

tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis."

Rheumatology (Oxford, England) 45(1): 50-52.

N<30 analysis

Brooks BR, Thisted RA, Appel SH, Bradley WG, Olney RK, Berg JE, et al. Treatment of pseudobulbar affect in ALS

with dextromethorphan/quinidine: A randomized trial.

Neurology 2004;63(8):1364–70. [PUBMED: 15505150]

No pain outcome

Buggy, D. J., et al. (2003). "Lack of analgesic efficacy of oral delta- 9-tetrahydrocannabinol in postoperative pain." Pain 106(1-2): 169- 172.

N<30 analysis Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, Parkin SG,

Fox P, Wright D, Hobart J, Zajicek JP: Cannabis for dyskinesia in Parkinson disease: a randomized doubleblind crossover study.

Neurology 2004; 63:1245–1250.

No pain outcome

Chung SA, Hossain NK, Blackman AS, Shapiro CM. Can the cannabinoid nabilone help with pain and sleep in fibromyalgia patients? Sleep 2009;32:A325–6.

Conference abstract Cobellis, L., et al. (2011). "Effectiveness of the association

micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study." European journal of obstetrics, gynecology, and reproductive biology 158(1): 82-86.

N<30 analysis

Collin, C., et al. (2007). "Randomized controlled trial of cannabis- based medicine in spasticity caused by multiple sclerosis."

European Journal of Neurology 14(3): 290-296.

Not pain

Conte A, Bettolo CM, Onesti E, et al. Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis. Eur J Pain.

2009;13:472–477.

Experimental pain

Costiniuk, C. T., et al. (2019). "Oral cannabinoids in people living with HIV on effective antiretroviral therapy: CTN PT028-study

Not pain

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protocol for a pilot randomised trial to assess safety, tolerability and effect on immune activation." BMJ open 9(1).

Cote, M., et al. (2016). "Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial." The Annals of otology, rhinology, and laryngology 125(4): 317-324.

N<30 analysis

Cremon C, Stanghellini V, Barbaro MR, et al. Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome.

Alimentary pharmacology & therapeutics. 2017;45(7):909-922.

No pain outcome

De Trane, S., et al. (2017). "THC: CBD (Nabiximols) has a

beneficial effect on resistant MS related spasticity and reduces the need for Intrathecal baclofen." Multiple Sclerosis Journal 23(3 Supplement 1): 1012-1013.

Conference abstract

de Vries M, Van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, Van Goor H. Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. British journal of clinical pharmacology.

2016;81(3):525-537.

N<30 analysis

De Vries M, Van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, Van Goor H. Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo- controlled Study. Clin Gastroenterol Hepatol 2017;15:1079–86.e4.

N<30 analysis

de Vries, M., et al. (2016). "Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study." Clinical gastroenterology and

hepatology (no pagination).

N<30 analysis

Eckstein, F., et al. (2018). "Intra-articular sprifermin reduces

cartilage loss in addition to increasing cartilage gain independent of femorotibial location: A post-hoc analysis of a randomized,

placebo-controlled phase ii clinical trial." Osteoarthritis and Cartilage 26(Supplement 1): S294.

Conference abstract

Ellis, R. J., et al. (2009). "Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial."

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34(3): 672-680.

N<30 analysis

Evangelista, M., et al. (2018). "Ultra-micronized

palmitoylethanolamide effects on sleep-wake rhythm and neuropathic pain phenotypes in patients with carpal tunnel

syndrome: An open-label, randomized controlled study." CNS and Neurological Disorders - Drug Targets 17(4): 291-298.

No pain outcome

Farag, A. A., et al. (2013). "Single-blind randomized controlled trial of surfactant vs hypertonic saline irrigation following endoscopic endonasal surgery." International forum of allergy & rhinology 3(4):

276â€•280.

Not pain

Ferre, L., et al. (2016). "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 37(2): 235-242.

No pain outcome

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Fitzcharles, M. A., et al. (2009). "The effects of nabilone on

insomnia in fibromyalgia: Results of a randomized controlled trial."

Arthritis and Rheumatism 60(SUPPL. 10): 1429.

No pain outcome Fox P, Bain PG, Glickman S et al. The effect of cannabis on tremor

in patients with multiple sclerosis. Neurology 2004;62:1105-9.

Not pain Freeman RM, Adekanmi O,Waterfield MR,Waterfield AE,Wright D,

Zajicek J. The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-

controlled trial (CAMS-LUTS). Int Urogynecol J Pelvic Floor Dysfunct. 2006;17(6):636-641. doi:10.1007/s00192-006-0086-x

No pain outcome

Germini, F., et al. (2017). "N-of-1 Randomized Trials of Ultra- Micronized Palmitoylethanolamide in Older Patients with Chronic Pain." Drugs & aging 34(12): 941-952.

N<30 analysis Giammusso, B., et al. (2017). "The efficacy of an association of

palmitoylethanolamide and alpha-lipoic acid in patients with chronic prostatitis/chronic pelvic pain syndrome: A randomized clinical trial." Archivio Italiano di Urologia e Andrologia 89(1): 17-21.

N<30 analysis

Grunberg, S. M., et al. (2012). "Randomized double-blind evaluation of dronabinol for the prevention of chemotherapy- induced nausea." Journal of Clinical Oncology 30(15 SUPPL. 1).

Conference abstract Guillaud J, Legagneux F, Paulet C, Leoni J, Lassner J. Essai du

l_evonantradol pour l’analg_esie postop_eratoire. Cahiers d’Anesth_esiologie 1983; 31: 243–8.

N<30 per arm Hagenbach, U., et al. (2007). "The treatment of spasticity with

Delta9-tetrahydrocannabinol in persons with spinal cord injury."

Spinal cord 45(8): 551-562.

N<30 analysis Hobart, J. C. and J. P. Zajicek (2012). "Cannabis as a symptomatic

treatment for MS: Clinically meaningful MUSEC to the stiffness and walking problems of people with MS." Multiple Sclerosis 18(4 SUPPL. 1): 247.

Conference abstract

Huggins, J. P., et al. (2012). "An efficient randomised, placebo- controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates

endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee." Pain 153(9): 1837- 1846.

N<30 across 4 arms

Hunter, D., et al. (2018). "Synthetic transdermal cannabidiol for the treatment of knee pain due to osteoarthritis." Osteoarthritis and Cartilage 26(Supplement 1): S26.

Conference abstract Irving, P. M., et al. (2018). "A Randomized, Double-blind, Placebo-

controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis."

Inflammatory Bowel Diseases 24(4): 714-724.

Not pain

Issa, M. A., et al. (2014). "The subjective psychoactive effects of oral dronabinol studied in a randomized, controlled crossover clinical trial for pain." The Clinical journal of pain 30(6): 472-478.

No pain outcome Jain AK, Ryan JR, McMahon FG, Smith G. Evaluation of

intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 1981; 21: 320S–6S.

N<30 analysis

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Karst, M., et al. (2003). "Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial." JAMA 290(13): 1757-1762.

N<30 analysis Katsinelos, P., et al. (2008). "Combination of endoprostheses and

oral ursodeoxycholic acid or placebo in the treatment of difficult to extract common bile duct stones." Digestive and Liver Disease 40(6): 453-459.

Not pain

Katsinelos, P., et al. (2017). "Impact of nitroglycerin and glucagon administration on selective common bile duct cannulation and prevention of post-ERCP pancreatitis." Scandinavian journal of gastroenterology 52(1): 50-55.

Not pain

Kavia, R. B. C., et al. (2010). "Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis." Multiple Sclerosis 16(11): 1349-1359.

No pain outcome Killestein J, Hoogervorst EL, Reif M, et al. Safety, tolerability, and

efficacy of orally administered cannabinoids in MS. Neurology.

2002;58(9):1404â€•1407.

No pain outcome Kramm, T., et al. (2005). "Inhaled iloprost to control residual

pulmonary hypertension following pulmonary endarterectomy."

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 28(6): 882-888.

Not pain

Levin, D. N., et al. (2016). "A randomized controlled trial of

nabilone for the prevention of postoperative nausea and vomiting in elective surgery." Anesthesia and analgesia 122(5): S463â€•.

Conference abstract Lus, G., et al. (2017). ""Taste", a pilot study: Palatability and oral

cavity tolerability of Sativex and possible improvement measures in multiple sclerosis patients with resistant spasticity." Multiple

Sclerosis Journal 23(3 Supplement 1): 996-997.

No pain outcome

Lynch, M. E., et al. (2014). "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 47(1): 166-173.

N<30 analysis

Marini, I., et al. (2012). "Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of

temporomandibular joint inflammatory pain." Journal of orofacial pain 26(2): 99-104.

N<30 analysis

Markova, J. (2017). "Sativex as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity double blind randomized clinical trial." Multiple Sclerosis Journal 23(3 Supplement 1): 990.

Conference abstract

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):1-4.

N<30 analysis

Meininger V, Bensimon G, Bradley WG, Brooks BR, Douillet P, Eisen A A, et al. Efficacy and safety of xaliproden

in amyotrophic lateral sclerosis: Results of two phase III trials. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2004;5(2):107–17. [PUBMED: 15204012]

Not pain

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Murina, F., et al. (2013). "Vestibulodynia: synergy between palmitoylethanolamide + transpolydatin and transcutaneous electrical nerve stimulation." Journal of lower genital tract disease 17(2): 111-116.

No pain outcome

Narang S, Gibson D,Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9(3): 254-264.

N<30 analysis Nicolodi, M., et al. (2017). "Therapeutic use of cannabinoids-dose

finding, effects and pilot data of effects in chronic migraine and cluster headache." European Journal of Neurology 24(Supplement 1): 287.

Conference abstract

Niederle, N., et al. (1986). "Crossover comparison of the antiemetic efficacy of nabilone and alizapride in patients with

nonseminomatous testicular cancer receiving cisplatin therapy."

Klinische Wochenschrift 64(8): 362-365.

No pain outcome

Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. A placebo- controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex (nabiximols). Multiple Sclerosis Journal. 2012;18(2):219-228.

No pain outcome

Notcutt W, Price M, Miller R, et al. Initial experiences with

medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia. 2004;59(5):440-452.

N<30 analysis Noyes, R., Brunk, F., Baram, D., & Canter, A. (1975a). Analgesic

effect of delta-9 tetrahydrocannabinol. Journal of Clinical Pharmacology, 15, 139–143.

N<30 analysis Olanow, C. W., et al. (2006). "TCH346 as a neuroprotective drug in

Parkinson's disease: a double-blind, randomised, controlled trial."

Lancet Neurology 5(12): 1013-1020.

Not pain

Opioid modulation of cannabis-induced analgesia and subjective effects in cannabis smokers. Drug and alcohol dependence.

2017;Conference: 2016 Annual Meeting of the College on Problems of Drug Dependence, CPDD 2016. United States.

171(pp e44â€•e45).

Conference abstract

Orefice N, Calabrese M, Carotenuto A, et al. A double-blind, randomized, versus-placebo study of palmitoylethanolamide in relapsing-remitting multiple sclerosis. Multiple Sclerosis. 2014;20(1 SUPPL. 1):114-115.

No pain outcome

Pini LA, Guerzoni S, Cainazzo MM, Ferrari A, Sarchielli P, Tiraferri I, Ciccarese M, Zappaterra M (2012) Nabilone for the treatment of medication overuse headache: results of a preliminary double- blind, active-controlled, randomized trial. J Headache Pain 13:677–

684

N<30 analysis

Pinsger, M. (2012). "Benefit of an Add-On-Treatment with a synthetic cannabinomimeticum on patients with chronic back pain- a randomized controlled trial." European Spine Journal 21(11):

2366.

Conferene abstract

Pomeroy, M., et al. (1986). "Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-

No pain outcome

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induced emesis." Cancer Chemotherapy and Pharmacology 17(3):

285-288.

Pooyania, S., et al. (2010). "A Randomized, Double-Blinded, Crossover Pilot Study Assessing the Effect of Nabilone on

Spasticity in Persons With Spinal Cord Injury." Archives of Physical Medicine and Rehabilitation 91(5): 703-707.

No pain outcome

Rawal, R. B., et al. (2015). "Post-operative budesonide irrigations for patients with polyposis: a blinded, randomized controlled trial."

Rhinology 53(3): 227-234.

Not pain

Reichenbach, Z. W., et al. (2015). "A 4-week pilot study with the cannabinoid receptor agonist dronabinol and its effect on metabolic parameters in a randomized trial." Clinical therapeutics 37(10):

2267-2274.

No pain outcome

Rintala, D. H., et al. (2010). "Effect of dronabinol on central neuropathic pain after spinal cord injury: a pilot study." American journal of physical medicine & rehabilitation 89(10): 840-848.

N<30 analysis Rog, D. J., et al. (2007). "Oromucosal delta9-

tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year

extension trial." Clinical therapeutics 29(9): 2068-2079.

Open label extension with one group after Rog 2005 Ruthirakuhan, M., et al. (2017). "A randomized, placebo-controlled,

cross-over trial investigating nabilone as a treatment for agitation in patients with moderate-to-severe Alzheimer's disease: blinded, interim safety results." Alzheimer's & dementia 13(7): P1254â€•.

Conferene abstract

Scelsa SN, MacGowan DJL, Mitsumoto H, Imperato T, LeValley AJ, Liu MH, et al. A pilot, double-blind, placebocontrolled

trial of indinavir in patients with ALS. Neurology 2005;64(7):1298–300. [PUBMED: 15824372]

Not pain

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(1):128-130.

N<30 analysis

Serpell, M. G., et al. (2013). "Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis." Journal of neurology 260(1): 285-295.

Follow-up single arm trial after Collin 2007 Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the

treatment of pain in fibromyalgia. J Pain 2008;9:164–73. N<30 analysis Song, T. J., et al. (2011). "Paclitaxel-eluting covered metal stents

versus covered metal stents for distal malignant biliary obstruction:

A prospective comparative pilot study." Gastrointestinal Endoscopy 73(4): 727-733.

Not pain

Staquet M, Gantt C, Machin D. Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther. 1978 Apr;23(4):397-401.

N<30 analysis Strasser, F., et al. (2006). "Comparison of orally administered

cannabis extract and delta-9- tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: A

Not pain

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multicenter, phase III, randomized, double-blind, placebo- controlled clinical trial from the Cannabis-In-Cachexia-Study- Group." Journal of Clinical Oncology 24(21): 3394-3400.

Svendsen, K. B., et al. (2004). "Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial." BMJ (Clinical research ed.) 329(7460): 253.

N<30 analysis

Tanaka, K., et al. (2019). "Efficacy and Safety of a Weekly Cyclophosphamide-Bortezomib-Dexamethasone Regimen as Induction Therapy Prior to Autologous Stem Cell Transplantation in Japanese Patients with Newly Diagnosed Multiple Myeloma: A Phase 2 Multicenter Trial." Acta Haematologica 141(2): 111-118.

Not pain

Tomassini V, Onesti E, Tinelli E, et al. Assessing the

neurophysiological effects of cannabinoids on spasticity in multiple sclerosis. J Neurosci Rehabil. 2014;1(2):1-13. doi:10.17653/2374- 9091.SS0005

Not pain

Toth, C., et al. (2012). "A randomized, double-blind, placebo controlled, parallel assignment, flexible dose, efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain." Pain Research and Management 17(3): 194- 195.

Conference abstract

Toth, C., et al. (2012). "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 153(10): 2073-2082.

N<30 analysis

Turcott, J. G., et al. (2018). "The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 26(9): 3029-3038.

Not pain

Turcotte, D. A., et al. "A randomized, double-blinded, placebo- controlled study evaluating the efficacy and safety of nabilone as an adjunctive to gabapentin in managing multiple sclerosis-induced neuropathic pain: An interim analysis." Pain Research and

Management 15(2): 99.

N<30 analysis

Turcotte, D. A., et al. (2011). "Randomized, double-blinded, placebo-controlled study evaluating the efficacy and safety of nabilone adjunctive to gabapentin in managing multiple sclerosis- induced neuropathic pain." European Journal of Pain Supplements 5(1): 240-241.

Conferene abstract

Turcotte, D., et al. (2011). "A randomised, double-blinded, placebo- controlled study evaluating the efficacy and safety of nabilone as an adjunctive to gabapentin in managing multiple sclerosisinduced neuropathic pain." Multiple Sclerosis 17(10 SUPPL. 1): S475-S476.

Conferene abstract

Turcotte, D., et al. (2013). "A randomized, double-blinded, placebo- controlled study evaluating efficacy and tolerability of nabilone as an adjunctive to gabapentin in the management of multiple

sclerosis-induced neuropathic pain." Multiple Sclerosis 19(11 SUPPL. 1): 112.

Conferene abstract

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Turcotte, D., et al. (2015). "Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial." Pain medicine (Malden, Mass.) 16(1):

149-159.

Conferene abstract

Turner, S., et al. (2017). "Safety, efficacy and tolerability of oromucosal tetrahydrocannabinol/cannabidiol therapy to reduce spasticity in children and adolescents. results of a multicentre, double blind placebo controlled trial." Developmental Medicine and Child Neurology 59(Supplement 4): 12-13.

Conference abstract

Vachov. M, Novotn. A, Mares J, et al. A multicentre, double-blind, randomised, parallel-group, placebocontrolled study of effect of long-term Sativex. treatment on cognition and mood of patients with spasticity due to multiple sclerosis. J Mult Scler (Foster City).

2014;1(2):1-8. doi:10.4172/jmso.1000122

No pain outcome

van Amerongen G, Kanhai K, Baakman AC, et al. Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Î”9- tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. Clinical therapeutics. 2018;40(9):1467â€•1482.

N<30 analysis

van de Donk, T., et al. (2019). "An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia." Pain 160(4): 860-869.

N<30 analysis Vaney, C., et al. (2004). "Efficacy, safety and tolerability of an

orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: A randomized, double-blind,

placebo-controlled, crossover study." Multiple Sclerosis 10(4): 417- 424.

No pain outcome

Wada 1982, Double blind randomised crossover trial of nabilone vs placebo in cancer

Not pain 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. Mult Scler.

2004;10(4):434-441. doi:10.1191/1352458504ms1082oa

Not pain

Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study todetermine whether whole-plant cannabis extracts can improve intractable neurogenicsymptoms. Clin Rehabil. 2003;17:21–29.

N<30 analysis

Wallace M, Atkinson J, Gouaux B, Marcotte T, Umlauf A. Effect of smoked cannabis on painful diabetic peripheral neuropathy.

Journal of Pain. 2013;14(4 SUPPL. 1):S62.

Conferene abstract Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH.

Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. The journal of pain : official journal of the American Pain Society.

2015;16(7):616-627.

N<30 analysis

Ware MA, Ducruet T, Robinson AR. Evaluation of herbal cannabis characteristics by medical users: a randomized trial. Harm

reduction journal. 2006;3:32.

No pain outcome Ware, M. A., et al. (2010). "Smoked cannabis for chronic

neuropathic pain: a randomized controlled trial." CMAJ : Canadian

N<30 analysis

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Medical Association journal = journal de l'Association medicale canadienne 182(14): E694-701.

Ware, M. A., et al. (2010). "The effects of nabilone on sleep in fibromyalgia: Results of a randomized controlled trial." Anesthesia and Analgesia 110(2): 604-610.

N<30 analysis Ware, M., et al. (2009). "The effects of nabilone on sleep in

fibromyalgia: Results of a randomized controlled trial." Journal of Rheumatology 36(11): 2607.

No pain outcome Weber M, Goldman B, Truniger S. Tetrahydrocannabinol (THC) for

cramps in amyotrophic lateral sclerosis: a randomised, double- blind crossover trial. J Neurol Neurosurg Psychiatry

2010;81(10):1135-40. {not pain, and small???)

Not pain

Werth, V. P., et al. (2018). "A phase 2 study of safety and efficacy of lenabasum (JBT-101), a cannabinoid receptor type 2 agonist, in refractory skinpredominant dermatomyositis." Annals of the

rheumatic diseases 77: 763â€•.

Not pain

Werth, V. P., et al. (2018). "Safety and efficacy of lenabasum in refractory skin-predominant dermatomyositis subjects treated in an open label extension of trial JBT101-DM-001." Annals of the

Rheumatic Diseases 77(Supplement 2): 1111-1112.

Not pain

Wissel, J., et al. (2006). "Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial." Journal of neurology 253(10): 1337-1341.

N<30 analysis

Wollmer, M. A., et al. (2012). "Facing depression with botulinum toxin: a randomized controlled trial." Journal of psychiatric research 46(5): 574â€•581.

Not pain

Wong, B. S., et al. (2011). "Pharmacodynamic effects of dronabinol, a non-selective cannabinoid receptor agonist, on colonic sensory and motor functions in irritable bowel syndrome."

Gastroenterology 140(5 SUPPL. 1): S2.

Conference abstract

Xu, Y. J., et al. (2014). "Effect of thoracic epidural anaesthesia on serum vascular endothelial growth factor C and cytokines in patients undergoing anaesthesia and surgery for colon cancer."

British journal of anaesthesia 113 Suppl 1: i49-55.

Not pain

Yamamoto, R., et al. (2016). "Ursodeoxycholic acid after bile duct stone removal and risk factors for recurrence: A randomized trial."

Journal of Hepato-Biliary-Pancreatic Sciences 23(2): 132-136.

Not pain

Yassin, M., et al. (2019). "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 and experimental rheumatology 37 Suppl 116(1): 13-20.

No pain outcome

Zadikoff C, Wadia PM, Miyasaki J, et al. Cannabinoid, CB1 agonists in cervical dystonia: Failure in a phase IIa randomized controlled trial. Basal Ganglia. 2011;1(2):91-95.

N<30 analysis Zajicek, J., et al. (2009). "Cannabis extract in the treatment of

muscle stiffness and other symptoms in multiple sclerosis - Results of the MUSEC study." Multiple Sclerosis 15(9 Suppl. S): S274.

Conference abstract

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Zajicek, J., et al. (2013). "Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): A randomised, placebo- controlled trial." The Lancet Neurology 12(9): 857-865.

Not pain

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Appendix 3. Trials ongoing or awaiting classification None of the trials in this table had results available

Trial

registration

Recruitmen t status

First entered Rando mised N

Pain condition

Number of trial arms

CBM type Control group

Funder

ACTRN1261 0000783022

Not yet recruiting

Sep-10 100 Kidney failure 2 Nabiximols Placebo Unknown

ACTRN1261 6001104448

Completed Aug-16 320 Knee

osteoarthritis

3 ZygelTM

(ZYN002 CBD Gel), not currently a CBM

Placebo Zynerba

Pharmaceutical s Inc.

ACTRN1261 8001220257

Not yet recruiting

Jul-18 144 Cancer 2 Cannabinoids Placebo National Health

and Medical Research Council EUCTR2017-

003574-13- DK /

NCT0369383 3

Recruiting Mar-18 160 Hand

osteoarthritis and psoriatic arthritis

2 Cannabidiol Placebo Aalborg

University

Hospital dept. of reumatology

EUCTR2006- 003655-20- GB

Prematurely ended

Nov-06 218 Post-herpetic

neuralgia

2 Nabiximols Placebo GW Pharma

EUCTR2006- 001133-18- GB

Completed Completed 03/2007

105 Post-op pain, dental

surgery

2 Cannabinor Placebo Pharmos Corp

(16)

EUCTR- 2007- 007873-22

Completed Completed 12/2011

60 Chronic pain 2 Nabilone Ibuprofen AZIENDA

OSPEDALIERA POLICLINICO DI MODENA EUCTR2011-

001739-21-IT

Ongoing Mar-12 188 Cancer 2 Nabiximols Unknown

(don't think it is placebo)

Ricerca Corrente

EUCTR2012- 000730-19- NL

Prematurely ended

Mar-12 68 Chronic

pancreatitis

2 Namisol Placebo EFRO,

Radboud University Nijmegen Medical Centre NCT0228328

1

Unknown Nov-14 200 Post-op pain 4 Nabiximols (high

and low dose)

Placebo and Paracetamol + midazolam + placebo

Hadassah Medical Organisation, GW Pharma NCT0289259

1

Recruiting Sep-16 100 Back and

neck pain

3 Cannabis (THC

medium dose)

Placebo and oxycodone

Unknown

NCT0333750 3

Recruiting Nov-17 160 Chronic pain 4 THC/CBD 1:1

ration; THC/CBD 1:2 ration; high CBD/trace THC

Placebo Sante

Cannabis; Tetra Bio-Pharma

NCT0376385 1

Not yet recruiting

Dec-18 420 Cancer 3 THC/CBD 1:1

ratio low (1mg each) and high (2.5mg each)

Placebo Tetra Bio- Pharma

NCT0363559 3

Not yet recruiting

Aug-18 309 Chronic non-

cancer pain

3 CBD; CBD/THC Placebo Hamilton Health

Sciences Corporation

(17)

NCT0367597 1

Not yet recruiting

Sep-18 220 Knee

replacement

2 Cannabidiol Placebo Unknown

(18)

Appendix 4. Small studies excluded from systematic review As part of the search for RCTs evaluating cannabinoid, cannabis, and CBM effects on pain, we excluded 39 trials because they included <30 participants post-treatment. Of the 39 studies excluded on the basis of size alone, 22 had a crossover design, 16 parallel group, and on an enriched enrolment

randomised withdrawal (EERW) design. Pain was a primary outcome in 36, and all had a pain outcome. Three were not blind, and four were probably not double blind.

Overall 794 patients were treated with 12 types of cannabinoid, cannabis, and CBM over periods ranging from less than a day to 84 days. The largest

number of patients treated with any one CBM was 180 treated with nabilone, and almost half were treated with nabilone or THC). In each case, though, a wide range of conditions was treated with each of these drugs. The number of conditions treated ranged from one to seven, and 17 of the 39 studies

(360/794 patients) claimed a beneficial effect for a cannabinoid, cannabis, and CBM.

Table 1. Small trials of cannabinoids, cannabis, and CBM

Drug

Number of

studies

Patients treated with CBM

Number of conditions treated

Days (range)

Claim effect

Cannabidiol 1 9 1 56 0

Cannabis extract 4 93 4 1-28 2

CT3 1 21 1 7 0

Dronabinol 3 53 3 1-56 2

EPC002A 1 12 1 28 0

Levonantradol 2 90 1 1 0

Nabilone 8 180 7 1-63 5

Nabiximols 4 89 3 7-84 2

NIB 1 15 1 1 1

Palmitoylethanolamide 4 65 3 7-84 2

PF-04457845 1 19 1 14 0

THC 9 148 7 1-51 3

Eighteen different pain conditions were treated in the trials, though arguably neuropathic pain and painful diabetic neuropathy could be taken together. The largest number of patients treated with a cannabinoid, cannabis, or CBM was for acute pain, with 130; for only eight of the 18 conditions more than 50 patients had been treated with a cannabinoid, cannabis, or CBM, often split between a variety of conditions.

Table 3 also shows the number of trials claiming a beneficial effect with cannabinoid, cannabis, or CBM. Neuropathic pain and painful diabetic neuropathy taken together as seven trials stand out as possibly showing a

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signal for efficacy. Of the seven trials, one was single dose, three were two weeks or less, and three lasted four weeks or longer. Of these, one of two trials of nabiximols with (30 patients treated with CBM in total) claimed effect, as did one EERW trial with nabilone (26 treated patients).

Table 2. Pain conditions treated

Condition Number

of studies

Number of CBM

Number of patients

Claim effect

Acute pain 4 4 80 0

Analgesic overuse headache 1 1 29 1

Cancer pain 3 3 53 1

Cervical dystonia 1 1 9 0

Chronic abdominal pain 3 1 74 0

Chronic non-cancer pain 3 3 61 1

Fibromyalgia 3 2 69 1

HIV neuropathy 1 1 24 1

Motor neurone disease 1 1 13 1

MS associated pain 3 3 51 2

Neurological diagnosis 1 1 24 0

Neuropathic pain 4 4 83 3

Osteoarthritis 1 1 19 0

Painful diabetic neuropathy 3 3 57 2

Pelvic pain 2 1 43 1

Rheumatoid arthritis 1 1 31 1

Spinal cord injury 3 2 12 1

Temporomandibular disorder 1 1 12 1

Conclusions

These studies can offer very little in the way of insight into cannabinoid, cannabis, or CBM efficacy in any pain condition. It is not only that the studies are themselves small. If they had investigated the same drug in the same or similar condition, with the same outcomes, over the same period of time, there might well be an argument for examining them in some way attempting some form of analysis. Given the array of cannabinoid, cannabis, and CBM used, the wide range of doses, and broad range of pain conditions, duration, and outcomes reported, no sensible analysis is possible. Nor would these studies contribute meaningfully to any analysis in the main systematic review.

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References of excluded studies

[1]. Abrams, D. I., et al. (2007). "Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial."

Neurology 68(7): 515-521.

[2]. Beaulieu, P. (2006). "Effects of nabilone, a synthetic cannabinoid, on postoperative pain." Canadian journal of anaesthesia = Journal canadien d'anesthesie 53(8): 769-775.

[3]. Blake, D. R., et al. (2006). "Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis." Rheumatology (Oxford, England) 45(1): 50-52.

[4]. Buggy, D. J., et al. (2003). "Lack of analgesic efficacy of oral delta-9- tetrahydrocannabinol in postoperative pain." Pain 106(1-2): 169-172.

[5]. Cobellis, L., et al. (2011). "Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study." European journal of obstetrics, gynecology, and reproductive biology 158(1): 82-86.

[6]. Cote, M., et al. (2016). "Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial." The Annals of otology, rhinology, and laryngology 125(4): 317-324.

[7]. de Vries M, Van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, Van Goor H. Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. British journal of clinical pharmacology. 2016;81(3):525- 537.

[8]. De Vries M, Van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, Van Goor H. Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study.

Clin Gastroenterol Hepatol 2017;15:1079–86.e4.

[9]. de Vries, M., et al. (2016). "Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo- controlled Study." Clinical gastroenterology and hepatology (no pagination).

[10]. Ellis, R. J., et al. (2009). "Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial."

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34(3): 672-680.

[11]. Germini, F., et al. (2017). "N-of-1 Randomized Trials of Ultra- Micronized Palmitoylethanolamide in Older Patients with Chronic Pain." Drugs & aging 34(12): 941-952.

[12]. Giammusso, B., et al. (2017). "The efficacy of an association of palmitoylethanolamide and alpha-lipoic acid in patients with chronic prostatitis/chronic pelvic pain syndrome: A randomized clinical trial."

Archivio Italiano di Urologia e Andrologia 89(1): 17-21.

[13]. Guillaud J, Legagneux F, Paulet C, Leoni J, Lassner J. Essai du levonantradol pour l’analgesie postoperatoire. Cahiers

d’Anesthesiologie 1983; 31: 243–8.

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[14]. Hagenbach, U., et al. (2007). "The treatment of spasticity with Delta9- tetrahydrocannabinol in persons with spinal cord injury." Spinal cord 45(8): 551-562.

[15]. Huggins, J. P., et al. (2012). "An efficient randomised, placebo- controlled clinical trial with the irreversible fatty acid amide hydrolase- 1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee." Pain 153(9): 1837-1846.

[16]. Jain AK, Ryan JR, McMahon FG, Smith G. Evaluation of

intramuscular levonantradol and placebo in acute postoperative pain.

J Clin Pharmacol 1981; 21: 320S–6S.

[17]. Karst, M., et al. (2003). "Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial."

JAMA 290(13): 1757-1762.

[18]. Lynch, M. E., et al. (2014). "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 47(1): 166-173.

[19]. Marini, I., et al. (2012). "Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain." Journal of orofacial pain 26(2): 99-104.

[20]. 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):1-4.

[21]. Narang S, Gibson D,Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain.

2008;9(3): 254-264.

[22]. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies.

Anaesthesia. 2004;59(5):440-452.

[23]. Noyes, R., Brunk, F., Baram, D., & Canter, A. (1975a). Analgesic effect of delta-9 tetrahydrocannabinol. Journal of Clinical

Pharmacology, 15, 139–143.

[24]. Pini LA, Guerzoni S, Cainazzo MM, Ferrari A, Sarchielli P, Tiraferri I, Ciccarese M, Zappaterra M (2012) Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. J Headache Pain 13:677–684 [25]. Rintala, D. H., et al. (2010). "Effect of dronabinol on central

neuropathic pain after spinal cord injury: a pilot study." American journal of physical medicine & rehabilitation 89(10): 840-848.

[26]. 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(1):128-130.

[27]. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain 2008;9:164–73.

[28]. Staquet M, Gantt C, Machin D. Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther. 1978 Apr;23(4):397-401.

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[29]. Svendsen, K. B., et al. (2004). "Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial." BMJ (Clinical research ed.) 329(7460): 253.

[30]. Toth, C., et al. (2012). "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 153(10): 2073-2082.

[31]. Turcotte, D., et al. (2015). "Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial." Pain medicine (Malden, Mass.) 16(1): 149-159.

[32]. van Amerongen G, Kanhai K, Baakman AC, et al. Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Î”9-

tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis.

Clinical therapeutics. 2018;40(9):1467â€•1482.

[33]. van de Donk, T., et al. (2019). "An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia." Pain 160(4): 860-869.

[34]. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study todetermine whether whole-plant cannabis extracts can improve intractable neurogenicsymptoms. Clin Rehabil.

2003;17:21–29.

[35]. Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. The journal of pain : official journal of the American Pain Society. 2015;16(7):616- 627.

[36]. Ware, M. A., et al. (2010). "Smoked cannabis for chronic neuropathic pain: a randomized controlled trial." CMAJ : Canadian Medical

Association journal = journal de l'Association medicale canadienne 182(14): E694-701.

[37]. Ware, M. A., et al. (2010). "The effects of nabilone on sleep in fibromyalgia: Results of a randomized controlled trial." Anesthesia and Analgesia 110(2): 604-610.

[38]. Wissel, J., et al. (2006). "Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial." Journal of neurology 253(10): 1337-1341.

[39]. Zadikoff C, Wadia PM, Miyasaki J, et al. Cannabinoid, CB1 agonists in cervical dystonia: Failure in a phase IIa randomized controlled trial.

Basal Ganglia. 2011;1(2):91-95.

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Appendix 5. Risk of bias judgements of included studies Study reference: Andresen 2016

Risk of bias Judgement Comment

Random sequence generation

Low risk “assignment to treatment was randomized via a computer-generated randomization list with a homogeneous block size of 4 done by Epitech Group SpA, and patients were allocated consecutively.”

Allocation concealment

Low risk “Patients were allocated consecutively”

Blinding of participants and personnel

Low risk Identical pills

Blinding of outcome assessment

Low risk Identical pills

Incomplete outcome data

Low risk BOCF used (see supplementary materials)

Selective reporting

Low risk Protocol was pre-registered (NCT01851499).

All outcomes were reported.

Size High risk ≤50 participants/arm

Study reference: Ball 2015

Low risk “Participants were assigned via a secure computer-generated randomisation system to receive oral Δ9-THC (dronabinol) or matched placebo capsules for 36 months in a 2 : 1 active-to-placebo ratio.”

Low risk “The randomisation allocation sequence was generated by an independent statistician using a stochastic minimisation algorithm and

balanced according to EDSS score, study site and disease type (PPMS or SPMS) with a random component. During the study, the independent statistician made periodic

checks of the allocation ratios according to the minimisation factors, to ensure that the

(24)

randomisation schedule was performing as intended.”

Low risk “Participants and all other personnel directly involved in the study were blinded to treatment allocation. Placebo treatment consisted of identically matched sesame oil capsules such that dronabinol and placebo capsules were indistinguishable.”

High risk Replaced missing data using multiple imputation.

Selective reporting

High risk Protocol was pre-registered

(ISRCTN62942668). Only stiffness and pain included in pre-registration, but more

outcomes included in manuscript.

Requested data but did not receive a response.

Size Unclear risk 50-199 participants/arm

Study reference: Berman 2004

Low risk "Patients were randomly allocated by a computer-generated list to the six possible sequences of receiving the three study medications."

Low risk "Although the treatment sequence was

blinded, sealed code break envelopes, one for each patient, containing information on the treatment sequence were available if necessary."

Unclear risk No description provided.

(25)

Low risk Few dropouts.

Selective reporting

Low risk Protocol was pre-registered (NCT01606189).

Requested data but email bounced.

Study reference: Bradford 2017

Low risk "Each patient was assigned a unique identification number at the beginning of the study via interactive response technology (IRT)."

Allocation concealment Unclear risk No description provided.

Low risk “To maintain patient blinding during the placebo run-in period and during the single-blind period, patients were

unaware of whether they received active ASP8477 or matching placebo tablets.

Drug assignment during the

placebo run-in, single-blind, and double- blind periods were performed via IRT, and all tablets (ASP8477 and

placebo) looked identical. For the three- week, double-blind period, patients were randomized using IRT in a 1:1 ratio to receive placebo or to continue on the ASP8477 regimen.”

Low risk “To maintain patient blinding during the placebo run-in period and during the single-blind period, patients were

unaware of whether they received active ASP8477 or matching placebo tablets.

Drug assignment during the

(26)

placebo run-in, single-blind, and double- blind periods were performed via IRT, and all tablets (ASP8477 and

placebo) looked identical. For the three- week, double-blind period, patients were randomized using IRT in a 1:1 ratio to receive placebo or to continue on the ASP8477 regimen.”

Low risk Time to treatment failure assessed.

Imputation not an issue.

Selective reporting High risk Protocol was pre-registered

(NCT02065349) but additional outcomes reported in manuscript.

Study reference: Collins 2010

Unclear risk “Each actuation of placebo delivered 100 ml of vehicle containing excipients plus colourants.” No blinding description provided.

Unclear risk Used LOCF rather than BOCF in ITT analyses.

Selective reporting Unclear risk Although authors refer to treatment protocol throughout manuscript, there is not accessible pre-registered protocol available.

(27)

Requested data but email rejected.

Study reference: Corey-Bloom 2012

Low risk “Pre-rolled cannabis and placebo

cigarettes with identical appearances and weight were provided by the National Institute of Drug Abuse."

Low risk “Pre-rolled cannabis and placebo

cigarettes with identical appearances and weight were provided by the National Institute of Drug Abuse."

Unclear risk Sensitivity analysis using 'worst case scenario' but only assumed patients who withdrew would not have shown any treatment effect.

Selective reporting Unclear risk No protocol or registration with manuscript.

Study reference: EUCTR2004-002530-20

Risk of bias Judgement Comment

(28)

Selective reporting High risk Not published.

Study reference: Faig-Marti 2017

Low risk “Group P was given a placebo with exactly the same appearance twice a day for the same period.”

Unclear risk No imputation method reported.

Selective reporting Unclear risk No protocol or pre-registration.

Study reference: Fallon 2017

Unclear risk “Following 1:1 randomization to either Sativex oral mucosal spray (THC (27 mg/mL): CBD (25 mg/mL)) or matching placebo.” Although stated for study 1, nothing stated for study 2.

(29)

Unclear risk Used ITT but not method of imputation.

Selective reporting Low risk Pre-registered (NCT01361607 /

NCT01424566) and outcomes reported Size Unclear risk 50-199 participants/arm

Study reference: Frank 2008

Low risk “Treatment was allocated by random

permuted blocks of 10, stratified by centre."

Allocation concealment Low risk “Code breaking envelopes were kept in each hospital pharmacy and each was used for only one patient. The code was disclosed only to the requesting doctor who was not involved in the study.”

Low risk “The pharmacy at St Mary’s Hospital supplied identical white capsules containing 250 μg nabilone or 30 mg dihydrocodeine.”

Unclear risk No imputation method reported.

Selective reporting Low risk ISRCTN (ISRCTN15330757) registration and outcomes are reported.

Study reference: Guida 2010

Low risk "Selected patients were assigned, by means of random sequence generation

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by computer, to the three treatment groups described in the protocol."

Allocation concealment Unclear risk No description provided Blinding of participants

and personnel

Unclear risk Study was blinded but the methods by which this was achieved was not described.

Low risk Very little missing data (<5%)

Size Low risk ≥200 participants/arm

Study reference: Jochimsen 1978

Low risk "The test preparations, in identical-

appearing capsules, were given at least I hr after breakfast"

Low risk "The test preparations, in identical-

appearing capsules, were given at least I hr after breakfast"

Low risk Few dropouts

Study reference: Johnson 2010

(31)

Allocation concealment Unclear risk No description provided of whether drugs were matched.

Unclear risk No description provided of whether drugs were matched.

Unclear risk No description provided of how data were imputed.

Selective reporting High risk Trial was pre-registered (NCT00674609) and included all outcomes but quality of life findings not reported.

Study reference: Kalliomaki 2013

Low risk Patients received solution and tablet each time, one of which was placebo.

Low risk No dropouts

Selective reporting High risk Trial was pre-registered (NCT00659490) but not all outcomes (e.g., max pain of jaw movement, jaw pain when received rescue meds) are reported in manuscript.

Study reference: Langford 2013

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Risk of bias Judgement Comment Random sequence

generation

Low risk “Randomization occurred using a pre- determined computer-generated

randomization code in which treatment allocation was stratified by center, and used randomly permuted blocks of variable sizes.”

Unclear risk "Patients, investigators, and those assessing the data were therefore blinded to the patients’ treatment allocation.” No method of blinding provided.

Unclear risk "Patients, investigators, and those assessing the data were therefore blinded to the patients’ treatment allocation." No method of blinding provided.

Selective reporting Low risk Trial was pre-registered (NCT00391079) and all outcomes were reported.

Study reference: Leocani 2015

Unclear risk Unclear how they handled dropouts.

(33)

Selective reporting Low risk Trial was pre-registered (NCT01538225).

Study reference: Levin 2017

Low risk “An epidemiologist not directly involved in either the execution of the study or the analysis of the study results prepared a computer-generated restricted

randomization schedule with a 1:1 allocation ratio and randomly varying block sizes.”

Allocation concealment Low risk “An epidemiologist not directly involved in either the execution of the study or the analysis of the study results prepared a computer-generated restricted

randomization schedule with a 1:1 allocation ratio and randomly varying block sizes. To maintain allocation concealment, the research pharmacy used sequentially numbered sealed opaque envelopes to assign and prepare the study drug or placebo for each

enrolled patient in sequence on the day of surgery.”

Low risk “To ensure blinding, the nabilone and placebo pills were identical in

appearance. All study investigators, study coordinators, participants, clinicians, and data analysts were blinded to group allocation for the duration of the study.”

Low risk “To ensure blinding, the nabilone and placebo pills were identical in

appearance. All study investigators, study coordinators, participants, clinicians, and

(34)

data analysts were blinded to group allocation for the duration of the study.”

Low risk Few missing data

Selective reporting High risk Trial was pre-registered (NCT02115529).

However, secondary outcome of number of antiemetic rescue medications not listed as an outcome in methods.

Study reference: Lichtman 2018

Low risk “Eligible patients were randomized 1:1 to receive nabiximols oral mucosal spray or matching placebo.”

Selective reporting Low risk Trial was pre-registered (NCT01262651) and outcomes matched between pre- registered report and manuscript.

Requested data and was referred onto GW Pharmaceuticals who would not provide data beyond what is reported on clinicaltrials.gov

Study reference: Markova 2017

(35)

High risk Used LOCF rather than BOCF in ITT analyses

Selective reporting Low risk Trial was pre-registered (2015-004451- 40) and outcomes matched between pre- registered report and manuscript.

Appendices

Contents

34. 15 AND 24 AND 33

38. 15 AND 24 AND 38

Appendix 2. Excluded study references and reasons

Trial

ACTRN1261 8001220257

EUCTR2006- 001133-18- GB

Table 1. Small trials of cannabinoids, cannabis, and CBM

Table 2. Pain conditions treated

Conclusions

Appendix 5. Risk of bias judgements of included studies Study reference: Andresen 2016

Study reference: Ball 2015

Study reference: Berman 2004

Study reference: Bradford 2017

Study reference: Collins 2010

Study reference: Corey-Bloom 2012

Risk of bias Judgement Comment

Study reference: Faig-Marti 2017

Study reference: Fallon 2017

Study reference: Frank 2008

Study reference: Guida 2010

Study reference: Jochimsen 1978

Study reference: Johnson 2010

Study reference: Kalliomaki 2013

Study reference: Langford 2013

Study reference: Leocani 2015

Study reference: Levin 2017

Study reference: Lichtman 2018

Study reference: Markova 2017

Study reference: NCT00710424

Study reference: NCT01606202

Study reference: NCT01606176