Use of cannabis and its derivates in chronic pain management: systematic review

Lopes Júnior, Dorgival Nafs Pinto da Silva; Bonfim, Breno de Medeiros; Silva Neto, Ricardo Wagner Gomes da; Marinho, Alexandre Magno da Nóbrega

doi:10.5935/2595-0118.20230089-en

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REVIEW ARTICLE • BrJP 6 (4) • Oct-Dec 2023 • https://doi.org/10.5935/2595-0118.20230089-en copy

Use of cannabis and its derivates in chronic pain management: systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

BACKGROUND AND OBJECTIVES:

Chronic pain is a clinical condition that affects an important part of the Brazilian and world population, significantly affecting their lives. The medicinal properties of Cannabis have been explored for millennia, but recently its use for the relief of chronic pain symptoms has increased.

A systematic review was carried out with the objective of evaluating the use of cannabis and its derivatives in the management of chronic pain, analyzing its potential side effects and safety. For this, the following databases were used: Pubmed, Embase, Cochrane Library and BVS, searching for studies published in the last 5 years, in Portuguese, Spanish or English, using MeSH descriptors and relevant free terms. Randomized, double-blind clinical trials with at least 10 participants in each comparison arm and with at least 2 weeks of intervention were included. After screening the authors, a quantitative analysis of 4 clinical trials (586 patients) was performed, which were analyzed for the outcomes of: patients with 50% or 30% reduction in pain intensity compared to baseline, improvement in pain intensity average pain, discontinuation due to adverse effects, serious adverse effects, and any adverse effects.

CONCLUSION:

The analysis did not yield high-quality evidence pertaining to the evaluation of efficacy, safety, or adverse effects associated with the use of cannabis-derived treatments in the management of chronic pain. Consequently, the formulation of recommendations or restrictions in these regards is not feasible, leaving the utilization of these therapeutic modalities subject to individual assessment.

Keywords:
Cannabidiol; Cannabis; Chronic pain; Dronabinol; Systematic review

HIGHLIGHTS

The traditional treatment of chronic pain consists of the use of analgesic drugs and physiotherapeutic treatment modalities with a variable response and short-lived improvement results.

The variety of pain measurement scales, even greater in this review due to the variety of conditions included, makes it difficult to generalize the use of cannabis-derived treatments for the treatment of chronic pain in these conditions.

The use of cannabis-derived treatments for chronic pain requires a careful assessment of each individual situation.

Evaluation of certainty							Nº of patients		Effect		Certainty	Importance
Nº of studies	Study design	Risk of bias	Inconsistency	Indirect evidence	Imprecision	Other considerations	[Cannabis]	[placebo]	Relative (95% CI)	Absolute (95% CI)
Patients with 50% improvement in pain
2	RCT	Not severe	Not severe	Very severe^a a Two different populations, one of the articles21 deals with cancer patients and the other29 deals with patients with psoriasis or hand OA.	Very severe^b b CI crosses the center line.	None	32 / 269 (11.9%)	30 / 264 (11.4%)	OR 1.04 (0.60 to 1.79)	4 more per 1,000 (from 42 less to 73 more)	⊕◯◯◯ Very low	Critical
Patients with 30% improvement in pain
2	RCT	Not severe	Not severe	Very severe^a a Two different populations, one of the articles21 deals with cancer patients and the other29 deals with patients with psoriasis or hand OA.	Very severe^b b CI crosses the center line.	Highly suspicious publication bias^c c More than 70% of the data entered comes from studies funded by the pharmaceutical industry.	80 / 269 (29.7%)	71 / 264 (26.9%)	OR 1.15 (0.78 to 1.68)	28 more per 1,000 (from 46 less to 113 more)	⊕◯◯◯ Very low	Important
Average improvement on the pain scale
4	RCT	Not severe	Not severe	Severe^d d There is a wide variety of groups, but different drugs, dosages and even routes of drug administration are used.	Very severe^b3 GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-59.	Highly suspicious publication bias^c c More than 70% of the data entered comes from studies funded by the pharmaceutical industry.	296	290	-	SMD 0.14 SD higher (0.03 less to 0.3 more)	⊕◯◯◯ Very low	Important
Discontinuation due to adverse effects
4	RCT	Not severe	Not severe	Severe^d d There is a wide variety of groups, but different drugs, dosages and even routes of drug administration are used.	Very severe^b b CI crosses the center line.	Highly suspicious publication bias^c c More than 70% of the data entered comes from studies funded by the pharmaceutical industry.	40 / 296 (13.5%)	38 / 290 (13.1%)	OR 1.08 (0.66 to 1.77)	9 more per 1,000 (from 41 less to 80 more)	⊕◯◯◯ Very low	Critical
Severe adverse effects
4	RCT	Not severe	Not severe	Severe^d d There is a wide variety of groups, but different drugs, dosages and even routes of drug administration are used.	Very severe^b b CI crosses the center line.	Highly suspicious publication bias^c c More than 70% of the data entered comes from studies funded by the pharmaceutical industry.	49 / 296 (16.6%)	45 / 290 (15.5%)	OR 1.10 (0.70 to 1.75)	13 more per 1,000 (from 41 less to 88 more)	⊕◯◯◯ Very low	Critical
Any adverse effects
4	RCT	Not severe	Not severe	Severe^d d There is a wide variety of groups, but different drugs, dosages and even routes of drug administration are used.	Very severe^b b CI crosses the center line.	Highly suspicious publication bias^c c More than 70% of the data entered comes from studies funded by the pharmaceutical industry.	212 / 296 (71.6%)	198 / 290 (68.3%)	OR 1.09 (0.40 to 2.96)	18 more per 1,000 (from 220 less to 182 more)	⊕◯◯◯ Very low	Important

Authors	Type of Study	Population	Groups	Intervention	Outcomes	Notes
Lichtman et al.²⁷27 Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Kornyeyeva E, Fallon MT. Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain. J Pain Symptom Manage. 2018;55(2):179-88.e1.	RCT double-blind	Cancer patients with uncontrolled chronic pain.	Control group: Age 60.7; Gender (H): 52%; Ethnicity (White) 93.4%; Time since cancer diagnosis 3.3 years; Mean NRS 5.6; Time since onset of pain 1.7 years. Intervention group: Age 59.2; Gender (H): 55.8%; Ethnicity (White) 93% Time since cancer diagnosis 3.3 years; mean NRS 5.6; Time since onset of pain 1.7 years.	Nabiximols (spray - oral mucosa) (THC: 27mg/dL CBD: 25mg/dL) vs Placebo. Duration: 2 weeks of dose titration + 3 weeks of intervention.	Patients with 50% improvement in pain, patients with 30% improvement in pain, improvement in average pain intensity. Discontinuation due to adverse effects, serious adverse effects and patients with adverse effects.	-
van Amerongen et al.²⁸28 van Amerongen G, Kanhai K, Baakman AC, Heuberger J, Klaassen E, Beumer TL, Strijers RLM, Killestein J, van Gerven J, Cohen A, Groeneveld GJ. Effects on spasticity and neuropathic pain of an oral formulation of δ9-tetrahydrocannabinol in patients with progressive multiple sclerosis. Clin Ther. 2018;40(9):1467-82.	RCT Crossover	Patients with progressive multiple sclerosis.	Control group: Age 51.4 years; Gender (H): 33.3%; Time of illness: 12.6 years. Intervention group: Age 57.3 years; Gender (H): 33.3%; Time of illness: 10.3 years.	THC (Oral) 9-29mg/d vs Placebo. Duration: 4 weeks.	Improvement in average pain intensity. Discontinuation due to adverse effects, serious adverse effects and patients with adverse effects.	Form of recruitment not specified
Vela et al.²⁹29 Vela J, Dreyer L, Petersen KK, Arendt-Nielsen L, Duch KS, Kristensen S. Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind, placebo-controlled trial. Pain. 2022;163(6):1206-14.	RCT double-blind	Patients with psoriasis or osteoarthritis of the hands.	Control group: Age 61.5; Gender (H): 30%; Average VAS 6.1; Distribution: Psoriatic arthritis 42% (28), Hand osteo-arthritis 58% (38). Intervention group: Age 62; Gender (H): 40%; Mean VAS 5.2; Distribution: Psoriatic arthritis 44% (31), Hand osteo-arthritis 56% (39).	CBD (oral) 20-30mg/d vs Placebo. Duration: 12 weeks.	Patients with 50% improvement in pain, patients with 30% improvement in pain, improvement in average pain intensity. Discontinuation due to adverse effects, serious adverse effects and patients with adverse effects.	It doesn’t mention the recruitment method.
Xu et al.³⁰30 Xu DH, Cullen BD, Tang M, Fang Y. The effectiveness of topical cannabidiol oil in symptomatic relief of peripheral neuropathy of the lower extremities. Curr Pharm Biotechnol. 2020;21(5):390-402.	RCT Crossover	Patients with peripheral neuropathy in the lower limbs.	Control group: Age 66.6 years; Gender (H): 50%; Previous use of CBD (n): 5 participants: Etiology of neuropathic pain (n): 9 diabetes mellitus, 2 pharmacological, 2 idiopathic, 1 embolism. Intervention group: Age 69.5 years; Gender (H): 73.3%; Previous use of CBD (n): 2 participants: Etiology of neuropathic pain (n): 9 diabetes mellitus, 1 pharmacological 1 idiopathic, 1 sciatica.	CBD Oil (Topical) (250 mg CBD/3 fl. oz) vs Placebo. Duration: double-blind 4 weeks + open study 4 weeks.	Improvement in average pain intensity. Discontinuation due to adverse effects, serious adverse effects and patients with adverse effects.	Data used only from the frst 4 weeks (double-blind), excluding data from the open study phase.

Studies	Reason for exclusion
Abrams et al.⁴⁵45 Abrams DI, Couey P, Dixit N, Sagi V, Hagar W, Vichinsky E, Kelly ME, Connett JE, Gupta K. Effect of inhaled cannabis for pain in adults with sickle cell disease: a randomized clinical trial. JAMA Netw Open. 2020;3(7):e2010874.	The method of data analysis was not by intention to treat.
Alessandria et al.³⁴34 Alessandria G, Meli R, Infante MT, Vestito L, Capello E, Bandini F. Long-term assessment of the cognitive effects of nabiximols in patients with multiple sclerosis: A pilot study. Clin Neurol Neurosurg. 2020;196:105990.	Object of the different study of the efficacy of cannabis-derived treatments for chronic pain.
Almog et al.³⁵35 Almog S. Metered-Dose Cannabis Inhaler Provides Consistent, Dose-Related THC Blood Concentration and Analgesic Effects, in Patients with Chronic Neuropathic Pain. The 2nd International Annual Congress on Controversies on Cannabis-Based Medicines, Barcelona, Spain, May 23-24, 2019. Med Cannabis Cannabinoids 19 December 2019;2(2):69–83.	Object of the different study of the efficacy of cannabis-derived treatments for chronic pain.
Almog et al.³⁸38 Almog S, Aharon-Peretz J, Vulfsons S, Ogintz M, Abalia H, Lupo T, Hayon Y, Eisenberg E. The pharmacokinetics, efficacy, and safety of a novel selective-dose cannabis inhaler in patients with chronic pain: A randomized, double-blinded, placebo-controlled trial. Eur J Pain. 2020;24(8):1505-16.	Intervention time less than two weeks.
Chaves, Bittencourt and Pelegrini⁴³43 Chaves C, Bittencourt PCT, Pelegrini A. Ingestion of a THC-rich cannabis oil in people with fibromyalgia: a randomized, double-blind, placebo-controlled clinical trial. Pain Med. 2020;21(10):2212-8.	Number of participants per treatment group less than 10 participants.
Gao et al.⁴⁴44 Gao Y, Li Y, Tan Y, Liu W, Ouaddi S, McCoy J, Kovacevic M, Situm M, Stanimirovic A, Li M, Wambier C, Goren A, Zou Y. Novel cannabidiol aspartame combination treatment (JW-100) significantly reduces ISGA score in atopic dermatitis: results from a randomized double-blinded placebo-controlled interventional study. J Cosmet Dermatol. 2022;21(4):1647-50.	It has no outcome measures for pain in the treatment phase.
NCT03984565⁴⁰40 NCT03984565. Sublingual Cannabidiol for Chronic Pain. In: ClinicalTrials.gov. 2019. Disponível em: https://clinicaltrials.gov/show/NCT03984565. Acesso em: 19 mar. 2023. https://clinicaltrials.gov/show/NCT03984...	Results not yet published.
Poli et al.⁴²42 Poli P, Crestani F, Salvadori C, Valenti I, Sannino C. Medical cannabis in patients with chronic pain: effect on pain relief, pain disability, and psychological aspects. a prospective non randomized single arm clinical trial. Clin Ter. 2018;169(3):e102-e107.	It is not a randomized double-blind clinical trial.
Sharon et al. ³⁶36 Sharon H. Cannabis induces changes in functional brain connectivity that correlate with increased vagal tone and clinical analgesia in chronic neuropathic pain. 30th International Symposium on the Autonomic Nervous System. Clin Auton Res. 2019;29:479-546.	Object of the different study of the efficacy of cannabis-derived treatments for chronic pain.
Van Dam et al.⁴¹41 van Dam CJ, van Velzen M, Kramers C, Schellekens A, Olofsen E, Niesters M, Dahan A. Cannabis-opioid interaction in the treatment of fibromyalgia pain: an open-label, proof of concept study with randomization between treatment groups: cannabis, oxycodone or cannabis/oxycodone combination-the SPIRAL study. Trials. 2023;24(1):64.	Results not yet published.
Van de Donk et al.³⁹39 van de Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A, van Velzen M. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain. 2019;160(4):860-9.	Intervention time less than two weeks.
Weizman et al.³⁷37 Weizman L, Dayan L, Brill S, Nahman-Averbuch H, Hendler T, Jacob G, Sharon H. Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity. Neurology. 2018;91(14):e1285-e1294.	Object of the different study of the efficacy of cannabis-derived treatments for chronic pain.

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[1] Correspondence to: Dorgival Nafs Pinto da Silva Lopes-Júnior E-mail: dorgivalnafs@gmail.com

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Use of cannabis and its derivates in chronic pain management: systematic review

ABSTRACT

BACKGROUND AND OBJECTIVES:

CONTENTS:

CONCLUSION:

HIGHLIGHTS