Cannabis-Based Medicine for Neuropathic Pain and Spasticity—A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (−0.54–1.38), CBD 0.45 (−0.47–1.38) and THC&CBD 0.16 (−0.75–1.08)), mean spasticity intensity (THC 0.24 (−0.67–1.45), CBD 0.46 (−0.74–1.65), and THC&CBD 0.10 (−1.18–1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98).

[1]  N. Finnerup,et al.  Oral capsules of tetra‐hydro‐cannabinol (THC), cannabidiol (CBD) and their combination in peripheral neuropathic pain treatment , 2022, European journal of pain.

[2]  P. Leutscher,et al.  Safety and effectiveness of cannabinoids to Danish patients with treatment refractory chronic pain—A retrospective observational real‐world study , 2022, European journal of pain.

[3]  K. Jensen,et al.  Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain , 2022, JAMA network open.

[4]  A. Großhennig,et al.  Implications for blinding in clinical trials with THC-containing cannabinoids based on the CANNA-TICS trial , 2022, Frontiers in Neuroscience.

[5]  G. Filippini,et al.  Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis. , 2022, The Cochrane database of systematic reviews.

[6]  A. Oturai,et al.  The Effect of Cannabis-Based Medicine on Neuropathic Pain and Spasticity in Patients with Multiple Sclerosis and Spinal Cord Injury: Study Protocol of a National Multicenter Double-Blinded, Placebo-Controlled Trial , 2021, Brain sciences.

[7]  L. Dreyer,et al.  Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind placebo-controlled trial. , 2021, Pain.

[8]  A. Vigano,et al.  Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process , 2021, Journal of Cannabis Research.

[9]  A. Rice,et al.  Presenting the outputs of the IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia. , 2021, Pain.

[10]  Thailand,et al.  International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia position statement , 2021, Pain.

[11]  B. Fiani,et al.  Current application of cannabidiol (CBD) in the management and treatment of neurological disorders , 2020, Neurological Sciences.

[12]  M. Rowbotham,et al.  Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials. , 2020, Pain.

[13]  Paul A. Harris,et al.  The REDCap consortium: Building an international community of software platform partners , 2019, J. Biomed. Informatics.

[14]  M. Rowbotham,et al.  Cannabinoids, cannabis, and cannabis-based medicine for pain management: a protocol for an overview of systematic reviews and a systematic review of randomised controlled trials , 2019, Pain reports.

[15]  Anup D. Patel,et al.  Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome , 2018, The New England journal of medicine.

[16]  L. Degenhardt,et al.  The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews , 2018, Current Neurology and Neuroscience Reports.

[17]  S. Schimrigk,et al.  Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients , 2017, European Neurology.

[18]  A. Agarwal,et al.  Cannabinoids for spasticity due to multiple sclerosis or paraplegia: A systematic review and meta-analysis of randomized clinical trials. , 2017, Complementary therapies in medicine.

[19]  O. Lennon,et al.  Neuropathic pain prevalence following spinal cord injury: A systematic review and meta‐analysis , 2017, European journal of pain.

[20]  J. Nielsen,et al.  Pain, spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark , 2016, Spinal Cord.

[21]  F. Biering-Sørensen,et al.  Modified Ashworth scale and spasm frequency score in spinal cord injury: reliability and correlation , 2016, Spinal Cord.

[22]  L. Leocani,et al.  Efficacy and safety of nabiximols (Sativex®) on multiple sclerosis spasticity in a real-life Italian monocentric study , 2016, Neurological Sciences.

[23]  Blair H. Smith,et al.  Neuropathic pain: an updated grading system for research and clinical practice , 2016, Pain.

[24]  Penny F Whiting,et al.  Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. , 2015, JAMA.

[25]  G. Nagels,et al.  The Symbol Digit Modalities Test as sentinel test for cognitive impairment in multiple sclerosis , 2014, European journal of neurology.

[26]  R. Pertwee.  Handbook of Cannabis , 2014 .

[27]  W. Notcutt,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 , 2013, Journal of Neurology.

[28]  Barbara Stanley,et al.  The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. , 2011, The American journal of psychiatry.

[29]  C. Pozzilli,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 , 2011, European journal of neurology.

[30]  Ethan B. Russo.  Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects , 2011, British journal of pharmacology.

[31]  C. Collin,et al.  A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis , 2010, Neurological research.

[32]  P. Harris,et al.  Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support , 2009, J. Biomed. Informatics.

[33]  David Cella,et al.  Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. , 2008, The journal of pain : official journal of the American Pain Society.

[34]  T. Nurmikko,et al.  Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial , 2007, PAIN®.

[35]  C. Collin,et al.  Randomized controlled trial of cannabis‐based medicine in spasticity caused by multiple sclerosis , 2007, European journal of neurology.

[36]  T. Friede,et al.  Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis , 2005, Neurology.

[37]  H. J. Hansen,et al.  Sensory function and quality of life in patients with multiple sclerosis and pain , 2005, Pain.

[38]  T. Jensen,et al.  Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial , 2004, BMJ : British Medical Journal.

[39]  Jacques Fermanian,et al.  Development and validation of the Neuropathic Pain Symptom Inventory , 2004, Pain.

[40]  T. Tombaugh.  Trail Making Test A and B: normative data stratified by age and education. , 2004, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.

[41]  D. Goodkin,et al.  Upper extremity function in multiple sclerosis: improving assessment sensitivity with box-and-block and nine-hole peg tests. , 1988, Archives of physical medicine and rehabilitation.

[42]  D. Centonze,et al.  The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases , 2018, Progress in Neurobiology.

[43]  T. Tombaugh,et al.  A comprehensive review of the Paced Auditory Serial Addition Test (PASAT). , 2006, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.