A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain

Figures & data

Table 1 European Federation of Neurological Societies Recommended Treatment for Common Neuropathic Pain Conditions

Condition	First Line	Second or Third Line
Diabetic neuropathic pain	Duloxetine Gabapentin Pregabalin Tricyclic antidepressants Venlafaxine extended release	Opioids Tramadol^†
Post-herpetic neuralgia	Gabapentin Pregabalin Tricyclic antidepressants Lidocaine plasters^§	Capsaicin Opioids
Classical trigeminal neuralgia	Carbamazepine Oxcarbazepine	Surgery
Central pain	Gabapentin Pregabalin Tricyclic antidepressants	Cannabinoids (multiple sclerosis) Lamotrigine Opioids Tramadol (spinal cord injury)

Notes: Adapted with permission from Attal N, Cruccu G, Baron R, et al. European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113–e88.³² †Tramadol may be considered first line in patients with acute exacerbations of pain especially in combination with acetaminophen. ^§Lidocaine is recommended in elderly patients.

Figure 1 Role of the endocannabinoid system in the control of pain at peripheral, spinal, and supraspinal levels. Cannabinoid receptor activity inhibits the ascending nociceptive transmission, activates the inhibitory descending pathway, and modifies the emotional component of pain. CB₁R, Cannabinoid type 1 receptor; CB₂R, Cannabinoid type 1 receptor. Reproduced with permission from Maldonado R, Baños JE, Cabañero D. The endocannabinoid system and neuropathic pain. Pain. 2016;157(Suppl 1):S23–S32. Available from: https://insights.ovid.com/article/00006396-201602001-00005.⁴⁰

Table 2 Randomized Clinical Trials and Extension Studies of THC:CBD Oromucosal Spray (Nabiximols) in Neuropathic Pain

Reference	Neuropathic Pain Study	Randomized/Entered Extension Study, n	Completed, n	Treatment Duration	Change in Pain 0–10 NRS for THC:CBD Oromucosal Spray (Nabiximols) vs Placebo	p-value
[^Citation87]	Multiple sclerosis	66	64	4 weeks	–2.7 vs –1.4 (Δ 1.3)	0.005
[^Citation88]	Multiple sclerosis (open-label extension of^Citation87	63	34 (1 year) 28 (2 years)	2 years	–2.9^†	N/A
[^Citation89]	Multiple sclerosis	339	297	14 weeks	–1.93 vs –1.76 (Δ 0.17)	0.47
[^Citation90]	Multiple sclerosis or other defects of neurological function	70	63	3 weeks	–1.3 vs –0.9 (Δ 0.4)^§	0.33
[^Citation92]	Spinal cord injury	116	106	3 weeks	–0.74 vs –0.69 (∆ 0.05)	0.71
[^Citation93]	Brachial plexus avulsion	48	45	2 weeks	Δ –0.58 vs placebo^§	0.005
[^Citation94]	Allodynia	125	105	5 weeks	–1.48 vs –0.52 (Δ 0.97)	0.004
[^Citation95]	Allodynia	246	173	14 weeks	Δ –0.34 vs placebo	0.139
[^Citation96]	Diabetes	297	230	14 weeks	–1.67 vs –1.55 (∆ 0.12)	0.63
[^Citation97]	Allodynia or diabetes (open-label extension of^Citation95,Citation96	380 (176 allodynia, 204 diabetes)	234 (100 allodynia, 134 diabetes)	38 weeks	–2.7 vs baseline^‡	N/A
[^Citation98]	Chemotherapy-induced	18	16	6 weeks	–1.25 vs –0.44 (Δ 0.81)	0.29

Notes: ^†Mean pain 0–10 NRS score in patients completing 2 years’ follow-up; ^§0–10 Box Scale score; ^‡Pain 0–10 NRS score decreased over time from a mean of 6.9 points (baseline in the parent studies) to a mean of 5.5 points (end of parent studies), to a mean of 4.2 points (end of open-label treatment) in remaining patients.

Abbreviation: NRS, numerical rating scale.

Figure 2 Proportion of patients with chronic pain (neuropathic 62.1%; mixed 31.1%; nociceptive 6.8%) reporting ≥50% improvement from baseline in Aggregated 9-Factor Symptom Relief (ASR-9) scores after 12 weeks’ treatment with THC:CBD oromucosal spray (nabiximols). Data from Ueberall et al (2019).¹⁰¹

Abbreviations: PIX, pain intensity index; mPDI, modified pain disability index; MQHFF, Marburg Questionnaire on Habitual Health Findings; SF12PCS, Short Form 12-item Health Survey physical component score; SF12MCS, Short Form 12-item Health Survey mental component score; DASS, Depression, Anxiety, Stress Scale.

Attal N, Cruccu G, Baron R, et al. European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113–e88. doi:10.1111/j.1468-1331.2010.02999.x

 PubMed Web of Science ®Google Scholar

Maldonado R, Baños JE, Cabañero D. The endocannabinoid system and neuropathic pain. Pain. 2016;157(Suppl 1):S23–S32. doi:10.1097/j.pain.0000000000000428

 Web of Science ®Google Scholar

Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65:812–819. doi:10.1212/01.wnl.0000176753.45410.8b

 PubMed Web of Science ®Google Scholar

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. Clin Ther. 2007;29:2068–2079. doi:10.1016/j.clinthera.2007.09.013

 PubMed Web of Science ®Google Scholar

Langford RM, Mares J, Novotna A, 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. J Neurol. 2013;260:984–997. doi:10.1007/s00415-012-6739-4

 PubMed Web of Science ®Google Scholar

ClinicalTrials.gov. A study to evaluate the effects of cannabis based medicine in patients with pain of neurological origin. Available from: https://clinicaltrials.gov/ct2/show/NCT01606176. Accessed January 18, 2020.

 Google Scholar

ClinicalTrials.gov. A study of cannabis based medicine extracts and placebo in patients with pain due to spinal cord injury. Available from: https://clinicaltrials.gov/ct2/show/results/NCT01606202. Accessed January 18, 2020.

 Google Scholar

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. doi:10.1016/j.pain.2004.09.013

 PubMed Web of Science ®Google Scholar

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;133:210–220. doi:10.1016/j.pain.2007.08.028

 PubMed Web of Science ®Google Scholar

Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014;18:999–1012. doi:10.1002/j.1532-2149.2013.00445.x

 PubMed Web of Science ®Google Scholar

ClinicalTrials.gov. A double blind, randomized, placebo controlled, parallel group study of Sativex in the treatment of subjects with pain due to diabetic neuropathy. Available from: https://clinicaltrials.gov/ct2/show/NCT00710424. Accessed January 18, 2020.

 Google Scholar

Hoggart B, Ratcliffe S, Ehler E, 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. J Neurol. 2015;262:27–40. doi:10.1007/s00415-014-7502-9

 Web of Science ®Google Scholar

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. J Pain Symptom Manage. 2014;47:166–173. doi:10.1016/j.jpainsymman.2013.02.018

 PubMed Web of Science ®Google Scholar

Ueberall MA, Essner U, Mueller-Schwefe GH. Effectiveness and tolerability of THC:CBD oromucosal spray as add-on measure in patients with severe chronic pain: analysis of 12-week open-label real-world data provided by the German Pain e-Registry. J Pain Res. 2019;12:1577–1604. doi:10.2147/JPR.S192174

 PubMed Web of Science ®Google Scholar