Cannabinoids and an anti-inflammatory diet for the treatment of neuropathic pain after spinal cord injury (The CATNP Study): study protocol for a randomized controlled trial

Abstract

Study design

Multicenter, randomized, double-blind, placebo controlled, clinical trial.

Objective

The objective of this paper is to evaluate the effectiveness of cannabinoids and an anti-inflammatory diet, alone and in combination, for the management of neuropathic pain (NP) after spinal cord injury (SCI).

Setting

Two Canadian SCI rehabilitation centers.

Methods

A sample of 144 individuals with SCI will receive either an anti-inflammatory diet, cannabinoids or a placebo for 6 weeks. Following this, a combined effect of these treatments will be evaluated for a further 6 weeks. The primary outcome measure will be the change in NP as assessed by the numeric rating scale (NRS). Secondary outcomes will include changes in inflammation, mood, sleep, spasticity, cost-effectiveness, and function.

Conclusion

This study will assess the efficacy of an anti-inflammatory diet and cannabinoids (individually and in combination) for the treatment of NP following SCI. Results may reveal a cost-effective, side-effect free intervention strategy which could be utilized for the long-term management of NP following SCI.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Timeline.
Fig. 2: Schematic of study design.

Data availability

The data sets used and/or analyzed during the current study are available from the corresponding author on request.

References

  1. 1.

    Siddall PJ, Loeser JD. Pain following spinal cord injury. Spinal Cord. 2001;39:63–73. https://doi.org/10.1038/sj.sc.3101116.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Henwood P, Ellis JA. Chronic neuropathic pain in spinal cord injury: the patient’s perspective. Pain Res Manag. 2004;9:39–45. https://doi.org/10.1155/2004/863062.

    Article  PubMed  Google Scholar 

  3. 3.

    Ashton JC, Milligan ED. Cannabinoids for the treatment of neuropathic pain: clinical evidence. Curr Opin Investig Drugs. 2008;9:65–75.

    CAS  PubMed  Google Scholar 

  4. 4.

    Cardenas DD, Jensen MP. Treatments for Chronic Pain in Persons With Spinal Cord Injury: A Survey Study 2005:109–17.

  5. 5.

    Corroon JM, Mischley LK, Sexton M. Cannabis as a substitute for prescription drugs—a cross-sectional study. J Pain Res. 2017;10:989–98. https://doi.org/10.2147/JPR.S134330.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Bruce D, Brady JP, Foster E, Shattell M. Preferences for medical marijuana over prescription medications among persons living with chronic conditions: alternative, complementary, and tapering uses. J Alter Complement Med. 2018;24:146–53. https://doi.org/10.1089/acm.2017.0184.

    Article  Google Scholar 

  7. 7.

    Reiman A, Welty M, Solomon P. Cannabis as a substitute for opioid-based pain medication: patient self-report. Cannabis Cannabinoid Res. 2017;2:160–6. https://doi.org/10.1089/can.2017.0012.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Eisenstein M. Medical marijuana: showdown at the cannabis corral. Nature. 2015;525:S15–7. https://doi.org/10.1038/525S15a.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    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. https://doi.org/10.1212/01.wnl.0000176753.45410.8b.

    Article  PubMed  Google Scholar 

  10. 10.

    Nielsen S, Germanos R, Weier M, Pollard J, Degenhardt L, Hall W, et al. The use of cannabis and cannabinoids in treating symptoms of multiple sclerosis: a systematic review of reviews. Curr Neurol Neurosci Rep. 2018;18:8. https://doi.org/10.1007/s11910-018-0814-x.

    Article  PubMed  Google Scholar 

  11. 11.

    Fine PG, Rosenfeld MJ. Cannabinoids for neuropathic pain. Curr Pain Headache Rep. 2014;18:451. https://doi.org/10.1007/s11916-014-0451-2.

    Article  PubMed  Google Scholar 

  12. 12.

    Guy SD, Mehta S, Casalino A, Côté I, Kras-Dupuis A, Moulin DE, et al. The CanPain SCI clinical practice guidelines for rehabilitation management of neuropathic pain after spinal cord: recommendations for treatment. Spinal Cord. 2016;54:S14–23. https://doi.org/10.1038/sc.2016.90.

    Article  PubMed  Google Scholar 

  13. 13.

    Allison DJ, Thomas A, Beaudry K, Ditor DS. Targeting inflammation as a treatment modality for neuropathic pain in spinal cord injury: a randomized clinical trial. J Neuroinflammation. 2016;13:152. https://doi.org/10.1186/s12974-016-0625-4.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Vučkovic S, Srebro D, Vujovic KS, Vučetic Č, Prostran M. Cannabinoids and pain: new insights from old molecules. Front Pharmacol. 2018;9. https://doi.org/10.3389/fphar.2018.01259.

  15. 15.

    Samad TA, Sapirstein A, Woolf CJ. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med. 2002;8:390–6. https://doi.org/10.1016/S1471-4914(02)02383-3.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Hartrick CT, Kovan JP, Shapiro S. The numeric rating scale for clinical pain measurement: a ratio measure? Pain Pract. 2003;3:310–6. https://doi.org/10.1111/j.1530-7085.2003.03034.x.

    Article  PubMed  Google Scholar 

  17. 17.

    Krause SJ, Backonja M-M. Development of a neuropathic pain questionnaire. Clin J Pain. 2003;19:306–14.

    Article  Google Scholar 

  18. 18.

    Widerström-Noga E, Biering-Sørensen F, Bryce TN, Cardenas DD, Finnerup NB, Jensen MP, et al. The international spinal cord injury pain basic data set (version 2.0). Spinal Cord. 2014;52:282–6. https://doi.org/10.1038/sc.2014.4.

    Article  PubMed  Google Scholar 

  19. 19.

    Ferguson L, Scheman J. Patient global impression of change scores within the context of a chronic pain rehabilitation program. J Pain. 2009;10:S73. https://doi.org/10.1016/j.jpain.2009.01.258.

    Article  Google Scholar 

  20. 20.

    McCaffery M, Beebe A. Pain: Clinical Manual for Nursing Practice. Mosby, St. Louis. 1989.

  21. 21.

    McCaffery M, Beebe A. Pain: clinical manual for nursing practicePain: clinical manual for nursing practice. Nurs Stand. 1994;9:55. https://doi.org/10.7748/ns.9.11.55.s69.

    Article  Google Scholar 

  22. 22.

    Miller WC, Anton HA, Townson AF. Measurement properties of the CESD scale among individuals with spinal cord injury. Spinal Cord. 2008;46:287–92. https://doi.org/10.1038/sj.sc.3102127.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Morfeld M, Petersen C, Krüger-Bödeker A, von Mackensen S, Bullinger M. The assessment of mood at workplace—psychometric analyses of the revised Profile of Mood States (POMS) questionnaire. Psychosoc Med. 2007;4:Doc06.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Shahid A, Wilkinson K, Marcu S, Shapiro CM. Leeds Sleep Evaluation Questionnaire (LSEQ). In: STOP, THAT one hundred other sleep scales. New York: Springer; 2011. pp. 211–3. https://doi.org/10.1007/978-1-4419-9893-4_48.

  25. 25.

    Adams MM, Ginis KAM, Hicks AL. The spinal cord injury spasticity evaluation tool: development and evaluation. Arch Phys Med Rehabil. 2007;88:1185–92. https://doi.org/10.1016/j.apmr.2007.06.012.

    Article  PubMed  Google Scholar 

  26. 26.

    Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D. et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727–36. https://doi.org/10.1007/s11136-011-9903-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Golicki D, Niewada M, Karlińska A, Buczek J, Kobayashi A, Janssen MF, et al. Comparing responsiveness of the EQ-5D-5L, EQ-5D-3L and EQ VAS in stroke patients. Qual Life Res. 2015;24:1555–63. https://doi.org/10.1007/s11136-014-0873-7.

    Article  PubMed  Google Scholar 

  28. 28.

    Bouwmans C, Krol M, Severens H, Koopmanschap M, Brouwer W, Roijen Van LH. The iMTA Productivity Cost Questionnaire: a standardized instrument for measuring and valuing health-related productivity losses. Value Heal. 2015;18:753–8. https://doi.org/10.1016/j.jval.2015.05.009.

    Article  Google Scholar 

  29. 29.

    Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006;67:1792–800. https://doi.org/10.1212/01.wnl.0000244422.45278.ff.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    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. Eur J Pain. 2014;18:999–1012. https://doi.org/10.1002/j.1532-2149.2013.00445.x.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet. 1999;353:1959–64. https://doi.org/10.1016/S0140-6736(99)01307-0.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Sommer C. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett. 2004;361:184–7. https://doi.org/10.1016/s0304-3940(03)01387-9.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Pitchford S, Levine JD. Prostaglandins sensitize nociceptors in cell culture. Neurosci Lett. 1991;132:105–8. https://doi.org/10.1016/0304-3940(91)90444-X.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Davies AL, Hayes KC, Dekaban GA. Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury. Arch Phys Med Rehabil. 2007;88:1384–93. https://doi.org/10.1016/j.apmr.2007.08.004.

    Article  PubMed  Google Scholar 

  35. 35.

    Hayes KC, Hull TCL, Delaney GA, Potter PJ, Sequeira KAJ, Campbell K, et al. Elevated serum titers of proinflammatory cytokines and CNS autoantibodies in patients with chronic spinal cord injury. J Neurotrauma. 2002;19:753–61. https://doi.org/10.1089/08977150260139129.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010;2:355–74. https://doi.org/10.3390/nu2030355.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Ware MA. Medical cannabis research: issues and priorities. Neuropsychopharmacology. 2018;43:214–5. https://doi.org/10.1038/npp.2017.222.

    Article  PubMed  Google Scholar 

  38. 38.

    Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A. Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2017;125:1638–52. https://doi.org/10.1213/ANE.0000000000002110.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Croxford JL, Yamamura T. Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J Neuroimmunol. 2005;166:3–18. https://doi.org/10.1016/j.jneuroim.2005.04.023.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Mackie K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharm Toxicol. 2006;46:101–22. https://doi.org/10.1146/annurev.pharmtox.46.120604.141254.

    CAS  Article  Google Scholar 

  41. 41.

    Karschner EL, Darwin WD, McMahon RP, Liu F, Wright S, Goodwin RS, et al. Subjective and physiological effects after controlled sativex and oral THC administration. Clin Pharm Ther. 2011;89:400–7. https://doi.org/10.1038/clpt.2010.318.

    CAS  Article  Google Scholar 

Download references

Funding

This study is funded by a grant from the Ontario Neurotrauma Foundation.

Author information

Affiliations

Authors

Contributions

DSD and EL were substantially involved in the conception and design of the study. ARA, DJA, DSD, and EL are participating in the coordination of the study and the acquisition of data. DJA drafted the paper with the assistance of DSD, EL, ARA, and BCFC. DSD, EL, BCFC, and AR critically revised the text. The present publication has been approved by all involved.

Corresponding author

Correspondence to David J. Allison.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The protocol, informed consent form, recruitment materials, and all participant materials will be submitted for ethical approval through the University of Western REB and the Brock University REB prior to participant recruitment. The study will be conducted in full conformity with the ICH E6, Health Canada Food and Drugs Act, and Good Clinical Practice.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Allison, D.J., Agudelo, A.R., Chan, B.C.F. et al. Cannabinoids and an anti-inflammatory diet for the treatment of neuropathic pain after spinal cord injury (The CATNP Study): study protocol for a randomized controlled trial. Spinal Cord (2020). https://doi.org/10.1038/s41393-020-0508-5

Download citation