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Effects of cannabinoids on pain control, quality of life and opioid-sparing in cancer patients: systematic review

ABSTRACT

BACKGROUND AND OBJECTIVES:

Cannabinoids, such as delta-9-tetrahydrocannabinol and cannabidiol, have several therapeutic properties that may be useful in medicine. The objective of this study was to analyze the impact of cannabinoid use on pain control, quality of life and opioid-sparing in patients with advanced cancer.

CONTENTS:

A systematic review of the evidence for the use of cannabinoids in patients with advanced cancer was conducted on 1) Pain control; 2) Quality of life; and 3) Opioid-sparing effect. PubMed, Web of Science and Cochrane databases were searched for articles, written in English, published between January 1, 2011, and December 31, 2022, with the filters “randomized controlled trials” and “clinical trials”. Using oral formulations of cannabinoids was accepted as “intervention” and placebo as “control”. Risk of bias analysis was performed with Cochrane’s RoB 2 and ROBINS-I tools. This review followed the 2020 PRISMA- statement. Ten studies were included, with 1169 participants, most with moderate risk of bias. The studies were from Australia (n=4), Canada (n=1), Israel (n=1), Mexico (n=1), The United Kingdom (n=1); two were multinationals. Eight were randomized, placebo-controlled trials; two were non-randomized studies. The most used formulation was nabiximols oral spray. Cannabinoids provide a clinical improvement in pain control. Evidence of improved quality of life with cannabinoids is inconclusive. Cannabinoids do not affect the daily dose of opioids in refractory cancer pain. Cannabinoid use cannot be said to have an opioid-sparing effect.

CONCLUSION:

It is necessary to expand research on the prescription of cannabinoids in individuals with cancer and other progressive diseases, with several comorbidities and multiple medications, in different health contexts.

Keywords:
Analgesics; Cancer; Cancer pain; Cannabinoids; Opioid; Palliative care; Quality of life

RESUMO

JUSTIFICATIVA E OBJETIVOS:

Os canabinoides, como o delta-9-tetrahidrocanabinol e o canabidiol, possuem propriedades terapêuticas que podem ser úteis em pacientes oncológicos. O objetivo deste estudo foi avaliar o impacto do uso de canabinoides no controle da dor, na melhoria da qualidade de vida, e no efeito poupador de opioides em pacientes com câncer avançado.

CONTEÚDO:

Realizou-se uma revisão sistemática sobre a evidência da utilização de canabinoides em pacientes com câncer avançado, relativamente a: 1) Controle da dor; 2) Qualidade de vida; e 3) Efeito poupador de opioides. Foram buscados artigos na Pubmed, Web of Science e Cochrane, em inglês, publicados entre 2011 e 2022, com os filtros “randomized controlled trials” e “clinical trials”. Aceitaram-se como “intervenção” qualquer uso de formulações orais de canabinoides e como “controle” o uso de placebo. Fez-se análise de viés com as ferramentas da Cochrane RoB 2 e ROBINS-I. Seguiu-se a Declaração PRISMA 2020. Foram incluídos 10 estudos, com 1169 participantes, a maioria com risco moderado de viés. Os estudos provinham de Austrália (n=4), Canadá (n=1), Israel (n=1), México (n=1), Reino Unido (n=1); dois eram multinacionais. Oito eram ensaios randomizados controlados com placebo; dois eram não randomizados. A formulação mais usada foi spray bucal de nabiximóis. Os canabinoides proporcionam uma melhoria clínica do controle da dor. A evidência da melhoria da qualidade de vida com canabinoides é inconclusiva. Os canabinoides não afetam a dose diária de opioides na dor oncológica refratária. Não se pode afirmar que o uso de canabinoides tem um efeito poupador de opioides.

CONCLUSÃO:

É necessário incrementar a investigação sobre a prescrição de canabinoides em indivíduos com câncer e outras doenças progressivas, com comorbilidades e polimedicação, em diferentes contextos de saúde.

Descritores
Analgésicos; Canabinoides; Câncer; Cuidados paliativos na terminalidade da vida; Dor do câncer; Opioides; Qualidade de vida

HIGHLIGHTS

  • There is evidence of clinical improvement in pain control with cannabinoids.

  • The evidence for improved quality of life with cannabinoids is inconclusive; however, cannabinoids do not impair quality of life in cancer patients.

  • There is no evidence that cannabinoids have an opioid-sparing effect in patients with cancer pain.

HIGHLIGHTS

  • There is evidence of clinical improvement in pain control with cannabinoids.

  • The evidence for improved quality of life with cannabinoids is inconclusive; however, cannabinoids do not impair quality of life in cancer patients.

  • There is no evidence that cannabinoids have an opioid-sparing effect in patients with cancer pain.

INTRODUCTION

Chronic pain (CP) affects more than 30% of people worldwide11 Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021;397(10289):2082-97., representing a huge personal and economic burden, and is a common reason for seeking medical attention22 Kay C, Wozniak E, Bernstein J. Utilization of health care services and ambulatory resources associated with chronic noncancer pain. Pain Med. 2017;18(7):1236-46..

Opioids are commonly prescribed for chronic pain33 International Narcotics Control Board. Narcotic drugs. Estimated world requirements for 2023. Vienna, Austria: United Nations; 2023. [Accessed 4 Aug 2023]. Available from: https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2022/Narcotic_Drugs_Technical_Publication_2022.pdf
https://www.incb.org/documents/Narcotic-...
; however, they only provide benefits for certain patients. A study44 Busse JW, Wang L, Kamaleldin M, Craigie S, Riva JJ, Montoya L, Mulla SM, Lopes LC, Vogel N, Chen E, Kirmayr K, De Oliveira K, Olivieri L, Kaushal A, Chaparro LE, Oyberman I, Agarwal A, Couban R, Tsoi L, Lam T, Vandvik PO, Hsu S, Bala MM, Schandelmaier S, Scheidecker A, Ebrahim S, Ashoorion V, Rehman Y, Hong PJ, Ross S, Johnston BC, Kunz R, Sun X, Buckley N, Sessler DI, Guyatt GH. Opioids for chronic noncancer pain: a systematic review and meta-analysis. JAMA. 2018;320(23):2448-60. containing 96 studies found high-certainty evidence that, compared to placebo, opioids provide significant pain relief for 12% of patients for whom opioids are prescribed. In addition, opioids are associated with adverse effects that depend on the dose55 Bedson J, Chen Y, Ashworth J, Hayward RA, Dunn KM, Jordan KP. Risk of adverse events in patients prescribed long-term opioids: A cohort study in the UK Clinical Practice Research Datalink. Eur J Pain. 2019;23(5):908-22.. There is considerable interest in therapies that can enable CP patients taking opioid therapy to reduce the doses needed to treat pain. One promising approach is to add cannabis therapy, which scientific evidence suggests may be equally effective to opioids in reducing pain and improving physical functioning among people living with chronic pain44 Busse JW, Wang L, Kamaleldin M, Craigie S, Riva JJ, Montoya L, Mulla SM, Lopes LC, Vogel N, Chen E, Kirmayr K, De Oliveira K, Olivieri L, Kaushal A, Chaparro LE, Oyberman I, Agarwal A, Couban R, Tsoi L, Lam T, Vandvik PO, Hsu S, Bala MM, Schandelmaier S, Scheidecker A, Ebrahim S, Ashoorion V, Rehman Y, Hong PJ, Ross S, Johnston BC, Kunz R, Sun X, Buckley N, Sessler DI, Guyatt GH. Opioids for chronic noncancer pain: a systematic review and meta-analysis. JAMA. 2018;320(23):2448-60.. Experimental studies have shown that opioids and cannabis have similar signal transduction systems66 Attal N, Mazaltarine G, Perrouin-Verbe B, Albert T, SOFMER French Society for Physical Medicine and Rehabilitation. Chronic neuropathic pain management in spinal cord injury patients. What is the efficacy of pharmacological treatments with a general mode of administration? (oral, transdermal, intravenous). Ann Phys Rehabil Med. 2009;52(2):124-41., and observational studies have shown that opioid-related mortality rates decreased after the legalization of cannabis77 Livingston MD, Barnett TE, Delcher C, Wagenaar AC. Recreational cannabis legalization and opioid-related deaths in Colorado, 2000-2015. Am J Public Health. 2017;107(11):1827-9.,88 Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668-73..

The cannabis sativa plant contains almost 500 bioactive compounds, with more than 140 different cannabinoids99 Arnold JC, Nation T, McGregor IS. Prescribing medicinal cannabis. Aust Prescr. 2020;43(5):152-9.. The most widely studied cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with THC being the most psychoactive and euphoric component1010 Herbert A, Hardy J. Medicinal cannabis use in palliative care. Aust J Gen Pract. 2021;50(6):363-8.. The benefits of these compounds include analgesia, anti-emesis, muscle relaxation, improved quality of life (QoL), among others 99 Arnold JC, Nation T, McGregor IS. Prescribing medicinal cannabis. Aust Prescr. 2020;43(5):152-9.. Adverse effects can be overcome clinically with a gradual titration of THC1111 Banister SD, Arnold JC, Connor M, Glass M, Mcgregor IS. Dark Classics in Chemical Neuroscience: ∆9-Tetrahydrocannabinol. ACS Chem Neurosci. 2019;10(5):2160-75.. CBD is less toxic, even at high doses, and has anxiolytic, antipsychotic, anti-inflammatory, antioxidant, anticonvulsant and neuroprotective effects1212 Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ, O’Sullivan SE. A systematic review of cannabidiol dosing in clinical populations. Br J Clin Pharmacol. 2019;85(9):1888-1900.. It is thought that CBD can reduce the adverse psychotropic effects of THC1313 Thiele E, Marsh E, Mazurkiewicz-Beldzinska M, Halford JJ, Gunning B, Devinsky O, Checketts D, Roberts C. Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. Epilepsia. 2019;60(3):419-28.. Cannabis sativa preparations with a standardized extract of THC and CBD are called nabiximols1414 Freeman AM, Petrilli K, Lees R, Hindocha C, Mokrysz C, Curran HV, Saunders R, Freeman TP. How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review. Neurosci Biobehav Rev. 2019;107:696-712..

Among cannabinoids, there is uncertainty about the best product/combination to control a specific symptom, route of administration and best dosage1515 Rabgay K, Waranuch N, Chaiyakunapruk N, Sawangjit R, Ingkaninan K, Dilokthornsakul P. The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: a systematic review and network meta-analysis. J Am Pharm Assoc. 2020;60(1):225-34.e6.. It is unknown whether the type/dose of cannabinoid suitable for one clinical situation can also be applied in another99 Arnold JC, Nation T, McGregor IS. Prescribing medicinal cannabis. Aust Prescr. 2020;43(5):152-9.. There are concerns about safety and interaction with other drugs, especially because of the synergism between cannabinoid and opioid receptors in the antinociceptive system1616 Brown D, Watson M, Schloss J. Pharmacological evidence of medicinal cannabis in oncology: a systematic review. Support Care Cancer. 2019;27(9):3195-207.. The opioid-sparing effect (OPE) provided using medical cannabis for CP remains uncertain. Between 64% and 77% of CP patients who responded to cross-sectional surveys reported a reduction in long-term opioid use after adding medical cannabis to their treatment1717 Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. J Pain. 2016;17(6):739-44.,1818 Piper BJ, DeKeuster RM, Beals ML, Cobb CM, Burchman CA, Perkinson L, Lynn ST, Nichols SD, Abess AT. Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep. J Psychopharmacol. 2017;31(5):569-75.. A systematic review concluded that preclinical studies provided robust evidence for the opioid-sparing effects of cannabis1919 Nielsen S, Sabioni P, Trigo JM, Ware MA, Betz-Stablein BD, Murnion B, Lintzeris N, Khor KE, Farrell M, Smith A, Le Foll B. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology. 2017;42(9):1752-65..

The aim of this study was to evalu”te t’e Impact of cannabinoid use on pain control, QoL improvement and the opioid-sparing effect in patients with advanced cancer.

CONTENTS

This study looked at the evidence for the use of cannabinoids in patients with advanced cancer, in relation to: 1) pain control; 2) QoL; and 3) OPE. Searches were carried out in Medline/Pubmed, Cochrane and Web of Science. The last search took place on January 3, 2023.

The following terms were used: “Cannabinoid*” AND (“Cancer” OR “Neoplasm* OR “Antineoplastic Agents”) AND (“palliative care” OR “refractory” OR “Advanced”), identified in the Titles and Abstracts. The following filters were used: “randomized controlled trials”, “clinical trials”. We searched for articles in English, published between January 1, 2011 and December 31, 2022. No manual search was carried out.

The inclusion criteria were: adult patients (≥18 years) with advanced cancer. Interventions - all medical prescriptions for cannabinoids, in various formulations (mouth sprays, oral capsules, oil solutions). Comparators - any, especially placebo. Outcomes - pain control; QoL; OPE. All the studies had more than 10 participants and used validated, internationally recognized scales/questionnaires.

From the articles found, the following were excluded: repeated articles; different types of study; different interventions; small sample size; pre-clinical trials; different population; and hidden cannabinoid dose. The titles of the articles were screened by the first author. Articles deemed eligible were selected for full analysis by two independent reviewers (SS, PRP). In the event of disagreement over inclusion/exclusion, a consensus was reached by dialog. The extracted data was compared, and any discrepancies were resolved by consensus. All the articles included explained the protocol applied, how the results were collected, and the methodologies involved.

The full text of the articles was assessed for eligibility criteria by two independent researchers (SS, PRP). The authors of the articles were not contacted for further information. No automation tools were used.

Data list

Data was sought for the three outcomes: pain control, QoL, OPE. The articles included had to address at least one of the outcomes.

Data was also searched for other variables: authors and country of origin; year of publication; study design; study objectives; site and sample; type of intervention; control group; main outcomes; observations.

Assessment of the risk of bias in studies

The randomized and non-randomized studies were assessed using the Cochrane RoB 2, 2020 Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. and ROBINS-I,2121 Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I, Carpenter JR, Chan AW, Churchill R, Deeks JJ, Hróbjartsson A, Kirkham J, Jüni P, Loke YK, Pigott TD, Ramsay CR, Regidor D, Rothstein HR, Sandhu L, Santaguida PL, Schünemann HJ, Shea B, Shrier I, Tugwell P, Turner L, Valentine JC, Waddington H, Waters E, Wells GA, Whiting PF, Higgins JP. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. tools, respectively.

Effect measures

In the studies that compared cannabinoids and placebo, the results were measured by comparing the start and end of the intervention in both groups, with p-value being used as the main measure of effect.

In the studies that presented results after treatment with cannabinoids, the measures of effect used were mainly differences in means or percentage differences.

Due to the small number of studies and their heterogeneity, it was decided not to carry out a meta-analysis. A qualitative analysis of the studies was carried out.

In order to better synthesize the information, it was decided to group the results according to the outcomes: 1) Pain control; 2) QoL; and 3) OPE.

RESULTS

Initially, 172 articles were found. After removing duplicates, 145 articles were examined based on title/abstract, eliminating 92. Of the remainder, articles were excluded due to: different types of study (n=16); different interventions (n=12); few participants (n=4); pre-clinical trials (n=4); different population (n=3); hidden cannabinoid dose (n=1). Ten articles were included.

The selection process was described in the flow diagram2222 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:71. shown in figure 1.

Figure 1
Flowchart of the search and selection process.

Study characteristics

Ten articles were included with a total of 1169 participants, with average ages between 55 and 67. The studies came from five continents, some of which were multinational: Oceania (n=4), Europe (n=3), America (North, n=3; South, n=2), Asia (n=1) and Africa (n=1).

The characteristics of the studies in this review are shown in table 1.

Table 1
Main characteristics of the included studies (n=10)

Randomized controlled trial (RCT) 2323 Hardy J, Greer R, Huggett G, Kearney A, Gurgenci T, Good P. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol. 2023;41(7):1444-52. with 144 patients with advanced cancer to evaluate the efficacy of CBD on symptom control, QoL, safety and OPE. The intervention group was prescribed an oral solution of CBD oil (100 mg/ml); the control group was prescribed placebo. There was dose titration for 14 days and maintenance until 28 days2323 Hardy J, Greer R, Huggett G, Kearney A, Gurgenci T, Good P. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol. 2023;41(7):1444-52..

Clinical trial with 25 patients with advanced cancer,2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543. to evaluate the analgesic efficacy of THC/CBD, QoL and safety. The intervention group was prescribed THC/CBD mouth spray (1.25mg/1.25mg in one spray); the control group was prescribed placebo. Doses were titrated for nine days, maintained for 10-15 days and followed up for the next 16-30 days2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543..

Another RCT with 81 patients2525 Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-60. with cancer at any stage, receiving intravenous chemotherapy. The aim was to evaluate the effect of THC/CBD on nausea and vomiting, QoL and safety. The design included three cycles: 1st cycle (1-4 capsules 8/8h of THC 2.5mg/CBD 2.5mg, orally); 2nd cycle (placebo), crossing participants; and 3rd cycle (the participant chose their favorite cannabinoid or placebo). Cycles 1+2 were completed by 72 participants2525 Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-60..

An open, two-arm, prospective trial2626 Good PD, Greer RM, Huggett GE, Hardy JR. An open-label pilot study testing the feasibility of assessing total symptom burden in trials of cannabinoid medications in palliative care. J Palliat Med. 2020;23(5):650-5. with 21 patients with metastatic or locally advanced cancer. The aim was to assess the effect of cannabinoids on symptom control, QoL, OPE and safety. One group was prescribed an oral solution of CBC oil (100mg/mL) and the other a solution of THC oil (10mg/mL). Doses were increased according to protocol, then maintained for 14, ideally 28 days2626 Good PD, Greer RM, Huggett GE, Hardy JR. An open-label pilot study testing the feasibility of assessing total symptom burden in trials of cannabinoid medications in palliative care. J Palliat Med. 2020;23(5):650-5..

Clinical trial with 24 cancer patients2727 Bar-Sela G, Zalman D, Semenysty V, Ballan E. The effects of dosage-controlled cannabis capsules on cancer-related cachexia and anorexia syndrome in advanced cancer patients: pilot study. Integr Cancer Ther. 2019;18:1534735419881498. (87.5% were undergoing chemotherapy) to assess the effect of THC/CBD on appetite, QoL and safety. THC/CBD oral capsules (9.5mg/0.5 mg) were prescribed 12/12h for six months2727 Bar-Sela G, Zalman D, Semenysty V, Ballan E. The effects of dosage-controlled cannabis capsules on cancer-related cachexia and anorexia syndrome in advanced cancer patients: pilot study. Integr Cancer Ther. 2019;18:1534735419881498..

Multicenter (phase III) RCT2828 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. with 380 patients with advanced cancer and CP refractory to opioids. The aim was to evaluate the effect of nabiximols on symptom control, QoL and OPE. The intervention group was prescribed nabiximols mouth spray (THC 27mg/ml + CBD 25mg/mL), the control group was prescribed placebo mouth spray. The doses were titrated up to 14 days and maintained for three weeks2828 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..

Another pilot RCT, 2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38. with 65 lung cancer patients, 47 of whom were randomized. The aim was to assess the effect of nabilone on weight, symptom control, QoL, anthropometric and biochemical variables. Oral capsules of nabilone (0.5mg) or placebo were prescribed. Doses were titrated up to 1mg for six weeks2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38..

In the UK, they carried out an open,3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18. follow-up, multicenter trial with 43 patients with advanced cancer, with refractory pain under opioids, to evaluate the effect of cannabinoids on pain, QoL and safety. One group was medicated with a nabiximol mouth spray (THC 27mg/mL and CBD 25mg/mL), the other with a THC 27mg/mL mouth spray. The average duration of treatment for THC/CBD was 25 days, for THC it was 151.5 days3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18..

An international collaboration3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49. carried out an RCT with 360 patients with advanced cancer and opioid-refractory pain to evaluate the effect of nabiximols on symptom control, QoL and safety. Patients were medicated with nabiximols mouth spray (THC 27mg/ml and CBD 25mg/ml) or placebo spray. There was a baseline period of 5-14 days, followed by five weeks with titration and treatment (in four groups, with three doses). Maximum study duration was nine weeks3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49..

A pilot RCT (phase II)32 with 21 patients with advanced cancer (33% receiving chemotherapy) to assess the effect of THC on taste and odor perceptions, appetite, caloric intake, QoL and safety. The intervention group was prescribed oral capsules of THC 2.5mg; the control group was prescribed placebo. The duration was 18 days, with doses titrated up to 20mg a day3232 Brisbois TD, de Kock IH, Watanabe SM, Mirhosseini M, Lamoureux DC, Chasen M, MacDonald N, Baracos VE, Wismer WV. Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial. Ann Oncol. 2011;22(9):2086-93..

Risk of bias in studies

The risk of bias of randomized and non-randomized studies is shown in figures 2 and 3, respectively. Most of the studies had a moderate risk of bias. Three studies had domains with a high risk of bias.

Figure 2
Risk of bias of randomized studies (n=6)

Figure 3
Risk of bias of non-randomized studies (n=4)

One particular study took place over three cycles, which were not differentiated when the results were presented. In the last cycle, most of the participants opted for the same treatment arm, which may have had an impact on the results; therefore, domain 4 was considered to be a high risk of bias2525 Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-60..

In the study by authors2727 Bar-Sela G, Zalman D, Semenysty V, Ballan E. The effects of dosage-controlled cannabis capsules on cancer-related cachexia and anorexia syndrome in advanced cancer patients: pilot study. Integr Cancer Ther. 2019;18:1534735419881498., domain 5 was classified as high risk of bias, as many participants were lost: there were 24 participants at the start in both groups, with only six completing the treatment. This study had a high risk of bias overall.

In Johnson et al. domain 5 was considered to have a high risk of bias because, of the 43 participants followed, only one remained until the end. Dropouts were for various reasons, mostly (n=24) due to adverse effects. Overall, the risk of bias was high3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18..

Results of individual studies

A summary table was drawn up with the main findings and differences between the studies (Table 2). Next, the findings are presented according to the proposed outcomes.

Table 2
Analysis of differences between individual studies (n=10)

Pain control

Pain was one of the symptoms most addressed in seven of the 10 articles included in this review, five of which were RCTs.

In the study2828 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. there were differences in terms of improvement in the percentage of average pain from the start of the intervention to the end in the “intention-to-treat” population (p=0.09). There was no difference between nabiximols and placebo in terms of “average pain” and “worst pain” (p=0.25 and p=0.68, respectively)2828 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.. However, considering the percentage improvement in mean pain from the start of treatment to the end in the “per-protocol” population, there was an improvement in pain in favor of nabiximols (p<0.05). In this multicenter study, it was also found that the population of the United States of America showed all the most favorable results, compared to the population of European countries2828 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..

Another study evaluated: 1) different doses of nabiximols: low, medium, and high, compared to placebo; and 2) all doses combined, compared to placebo3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49.. Regarding the proportion of participants with 30% pain relief, there was no significance (p=0.59). The results were found to be clinically in favor of nabiximols, but only considering the low and medium doses, versus placebo, although without statistical significance. Looking at the whole spectrum of responses (from 0 to 100%), there was already an improvement (p<0.05); however, when the different dosages were analyzed, it was clear that the results were only due to the low and medium doses (p=0.01 and p<0.05, respectively) and, in terms of the response of improvement in average daily pain, only the group given low doses benefited (p<0.01). At the end of treatment, in terms of average daily “worst pain”, a difference was evident for low-dose nabiximols (p<0.05), with medium and high doses showing a greater reduction than placebo, but not a significant one3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49.. There was a clinical improvement in the pain severity indices for the low, medium, and high doses, but this was not significant (p=0.24, p=0.12 and p=0.86, respectively). Regarding pain interference indices, there was clinical improvement at the low and medium doses, while at the high dose the treatment was not in favor of nabiximols (p=0.87, p=0.09, p=0.9, respectively)3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49..

In another research using CBD, pain was measured numerically from zero to 1023. There were no differences at day 14 (p=0.25) or day 28 (p=0.54). When pain was assessed as a QoL parameter, despite the clinical improvement, there was no relevant difference (p=0.26).2323 Hardy J, Greer R, Huggett G, Kearney A, Gurgenci T, Good P. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol. 2023;41(7):1444-52. In another multicenter RCT2525 Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-60., the association THC/CBD versus placebo improved pain in cancer patients, with relevance (p<0.01). In the study.2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38., between the start and end of treatment with nabilone (synthetic THC), there were differences in terms of pain as an element of QoL (p<0.05), which was not the case with placebo (p=0.36).

Two non-comparative studies evaluated the use of cannabinoids in pain. One of them, with THC/CBD, showed significant pain relief (as an element of QoL) (p<0.001 for breast and prostate cancers, and p<0.01 for other cancers) 2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543.. However, with another evaluation method, they measured: 12% improvement in pain initially, 30% in the post-treatment phase, with a subsequent worsening of 13% compared to baseline after the follow-up phase (in which the cannabinoid was discontinued)2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543.. The study3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18. analyzed pain scores, recording a decrease compared to baseline in scores at all observation times for average pain (~5.5 to ~4.5 on the scale used), pain severity (~5.5 to ~4.0) and worst pain (~7.5 to ~6.0), with improvements of 24% (as a QoL parameter). There was an improvement in terms of pain, although the researchers felt that the participants’ pain control was suboptimal. Regarding the interference of pain in daily life, pain worsened in the first week and improved again in the fifth week, but still worsened compared to the start of treatment (~6.5 to ~5.5)3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18..

Quality of life

In all the studies, QoL was assessed in some way.

In the study2828 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., which used nabiximols, results were measured on the basis of: 1) global perception of change questionnaires by the clinician, 2) by the participant, and 3) a global patient satisfaction questionnaire, measured at the third week of follow-up (p<0.05, p=0.10, p=0.0001, respectively), at the fifth week (p<0.01, p<0.05, p<0.05) and at the last visit (p<0.01 p=0.09, p=0.08, respectively). The results tended towards clinical and individual improvement with nabiximols at the last visit2828 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..

In the study3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49., also using nabiximols, there was similarly no relevance in the overall impression of change felt by the participant (regardless of the low, medium or high dose used) at the end of treatment (p=0.27; p=0.66; p=0.54 respectively). However, a small effect in terms of treatment improvement was observed in most of the QoL subscales. In the study3232 Brisbois TD, de Kock IH, Watanabe SM, Mirhosseini M, Lamoureux DC, Chasen M, MacDonald N, Baracos VE, Wismer WV. Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial. Ann Oncol. 2011;22(9):2086-93. with THC, overall QoL was assessed, and there was an improvement, but no significant difference compared to placebo (p=0.70). In the study2323 Hardy J, Greer R, Huggett G, Kearney A, Gurgenci T, Good P. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol. 2023;41(7):1444-52. using CBD, there were no differences in symptom burden, either at 14 days (p=0.98) or 28 days (p=0.36). In fact, in both arms the participants reported feeling better, but in a higher percentage in the placebo group (65%) than in the CBD group (53%).

Also, in the study2525 Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-60. there were no differences in QoL between the groups, specifically in relation to happiness, coping and relationships (p=0.50, p=0.67, p=0.61, respectively). However, THC/CBD capsules improved QoL based on “usefulness” (p<0.05) and the “super” physical dimension (which included items such as pain; “seeing, hearing, communicating”; and “independent living”) (p<0.001). In lung cancer patients, in the study2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38., when QoL was analyzed, there were better results in the placebo group than in the nabilone group, but no differences (p=0.31 and p=0.76, respectively). Despite this, the use of nabilone was associated with significant benefits in terms of social, emotional and role functioning (p<0.05 in all), which was not the case with placebo2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38..

As far as non-comparative studies are concerned, there is one prospective study2626 Good PD, Greer RM, Huggett GE, Hardy JR. An open-label pilot study testing the feasibility of assessing total symptom burden in trials of cannabinoid medications in palliative care. J Palliat Med. 2020;23(5):650-5. that used one arm with CBC and the other with THC in increasing doses27. The authors2626 Good PD, Greer RM, Huggett GE, Hardy JR. An open-label pilot study testing the feasibility of assessing total symptom burden in trials of cannabinoid medications in palliative care. J Palliat Med. 2020;23(5):650-5. found a “global impression of change” reported by patients of around 44% and by doctors of 50%. However, the general assessment of QoL did not register any changes (p=0.11), nor improvements in the physical (p=0.23) or well-being (p=0.65) subscales.

The authors2727 Bar-Sela G, Zalman D, Semenysty V, Ballan E. The effects of dosage-controlled cannabis capsules on cancer-related cachexia and anorexia syndrome in advanced cancer patients: pilot study. Integr Cancer Ther. 2019;18:1534735419881498. showed that with THC/CBD there was no significant difference in QoL, but almost all their participants reported improvements in pain, fatigue, sleep quality and appetite. Also, with THC/CBD, the study2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543., despite showing a clinical benefit, revealed that there was no statistical significance in overall QoL. However, there were significant differences in terms of individual QoL parameters such as role functioning, emotional functioning, fatigue, pain, insomnia and dyspnea2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543.. Finally, in the open label study3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18., which used THC and THC/CBD, patients’ overall health status went from scores of ~31 to ~40. There were beneficial clinical differences in emotional and social functioning, a worsening in physical functioning and no changes in role functioning3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18..

Opioid-sparing effect

Five of the studies examined the effect of cannabinoids on patients medicated with opioids.

In the study2828 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. with nabiximols, there was no significant impact on regular, rescue or total daily opioid doses (p=0.64, p=0.42, p=0.93, respectively). Nor was there any difference in the number of responders between the treatment groups (p=0.11). The authors3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49. observed that patients in the nabiximols group, versus placebo, showed a better response profile to opioids (p=0.08), and only at the lowest dose of nabiximols was statistical significance obtained (p<0.05). The authors used an “opioid composite measure” which was calculated using both the change in the patient’s mean pain score and the change in opioid consumption (morphine milligram equivalents). A positive response was defined as a reduction in pain with a stable or decreasing use of opioids3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49.. They found this type of response only in the low and low/medium combined doses of cannabinoids (p=0.038 and p=0.05).

The study2323 Hardy J, Greer R, Huggett G, Kearney A, Gurgenci T, Good P. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol. 2023;41(7):1444-52. found no differences in the “oral morphine equivalent” dose between CBD and placebo at 14 and 28 days (p=0.10 and p=0.39, respectively), although there was an initial drop in the opioid dose on day 14, which was not maintained on day 28 in both groups. This was the only study to analyze survival between the groups, and there were no relevant differences (p=0.22).

Two non-comparative studies also evaluated the use of opioids. The authors2626 Good PD, Greer RM, Huggett GE, Hardy JR. An open-label pilot study testing the feasibility of assessing total symptom burden in trials of cannabinoid medications in palliative care. J Palliat Med. 2020;23(5):650-5. found that at the start of treatment (with either CBD or THC) the average number of morphine equivalents was 140mg/day, decreasing to 95mg/day on day 14. Analyzing the patients who completed the 14th day of treatment, they found significant changes (p=0.09). The authors2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543. confirmed that the use of THC/CBD did not lead to a sustained reduction in opioids, since on day 1 participants took a median of 60mg (45 to 170) morphine equivalents, on day 16 (end of treatment) they maintained 60mg (40 to 113) and on day 30 (end of follow-up) they rose to 63mg (32 to 128) morphine equivalents.

DISCUSSION

In this study, which aimed to evaluate the impact of cannabinoid use on pain control, QoL improvement and OPE in patients with advanced cancer, most of the studies showed that prescribing cannabinoids has the potential for benefits, with a tendency for a beneficial effect at low doses, influencing some QoL characteristics and little evidence for the issue of cannabinoids versus opioids.

In general, there is evidence of clinical improvement in pain control with cannabinoids. Sometimes in general, versus placebo2525 Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-60.. In some studies, improvement in pain was an integral part of QoL2323 Hardy J, Greer R, Huggett G, Kearney A, Gurgenci T, Good P. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol. 2023;41(7):1444-52.,2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543.,2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38.,3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18.. In one RCT, there was no 30% improvement in pain with cannabinoids, but there was an improvement in the average “worst pain”, versus placebo, in low doses of cannabinoids3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49.. Only one RCT found no improvement in any of the variables used to measure pain with cannabinoids2828 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.. There is evidence in animal models supporting cannabinoid-induced analgesia3333 Kehl LJ, Kehl LJ, Hamamoto DT, Wacnik PW, Croft DL, Norsted BD, Wilcox GL, Simone DA. A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain. Pain. 2003;103(1-2):175-86.. In one RSL, most of the included studies demonstrated the analgesic effects of cannabinoids, although not all associations achieved statistical differences3434 Tateo S. State of the evidence: Cannabinoids and cancer pain--a systematic review. J Am Assoc Nurse Pract. 2017;29(2):94-103.. However, another RSL, which considered that it had included studies with a low risk of bias, showed that cannabinoids associated with opioids do not reduce pain in the context of cancer3535 Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ Support Palliat Care. 2020;10(1):14-24..

Three studies showed an improvement in QoL, with statistical relevance, especially in functionality2525 Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-60., emotional and “role” functioning2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543.,2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38. and social functioning2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38.. Three studies showed clinical improvement in QoL, but without significant differences3030 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18.

31 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49.
-3232 Brisbois TD, de Kock IH, Watanabe SM, Mirhosseini M, Lamoureux DC, Chasen M, MacDonald N, Baracos VE, Wismer WV. Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial. Ann Oncol. 2011;22(9):2086-93.. Six studies showed no statistically significant differences in other dimensions of 2323 Hardy J, Greer R, Huggett G, Kearney A, Gurgenci T, Good P. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol. 2023;41(7):1444-52.

24 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543.

25 Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-60.

26 Good PD, Greer RM, Huggett GE, Hardy JR. An open-label pilot study testing the feasibility of assessing total symptom burden in trials of cannabinoid medications in palliative care. J Palliat Med. 2020;23(5):650-5.
-2727 Bar-Sela G, Zalman D, Semenysty V, Ballan E. The effects of dosage-controlled cannabis capsules on cancer-related cachexia and anorexia syndrome in advanced cancer patients: pilot study. Integr Cancer Ther. 2019;18:1534735419881498.,2929 Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón F, Arrieta O. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer. 2018;26(9):3029-38.. A recent RSL with meta-analysis concluded that the evidence for the use of cannabinoids in QoL is inconclusive3636 Goldenberg M, Reid MW, IsHak WW, Danovitch I. The impact of cannabis and cannabinoids for medical conditions on health-related quality of life: a systematic review and meta-analysis. Drug Alcohol Depend. 2017;174(1):80-90..

Five articles focused on the impact of cannabinoid use on opioid therapy. In two trials, there was no significant difference in the dose of opioids with the prescription of cannabinoids (CBD in the study2323 Hardy J, Greer R, Huggett G, Kearney A, Gurgenci T, Good P. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol. 2023;41(7):1444-52. and nabiximols in the study2828 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.). In the trial2626 Good PD, Greer RM, Huggett GE, Hardy JR. An open-label pilot study testing the feasibility of assessing total symptom burden in trials of cannabinoid medications in palliative care. J Palliat Med. 2020;23(5):650-5. with both CBD and THC, there was a significant reduction in the daily dose of morphine equivalents from the beginning to the end of the study (p=0.09). In the RCT3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49. there was a significant reduction in the dose of opioids, but only at the low dose of nabiximols.

In the trial2424 Clarke S, Butcher BE, McLachlan AJ, Henson JD, Rutolo D, Hall S, Vitetta L. Pilot clinical and pharmacokinetic study of ∆9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One. 2022;17(10):e0270543. with nabiximols, opioid doses remained unchanged during the investigation. As a result, in three studies there was no OPE, in two there was (in one of them only with low doses of cannabinoids). However, it is important to consider that most of the studies assume that they were not designed to allow this evaluation to be carried out in a fair way, since the reduction in the dose of opioids was not protocolized, or else was not recommended2828 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.,3131 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-49..

There is some evidence of OPE from cannabinoids in medication-naive mice3737 Khasabova IA, Gielissen J, Chandiramani A, Harding-Rose C, Odeh DA, Simone DA, Seybold VS. CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. Behav Pharmacol. 2011;22(5-6):607-16.. In 2022, an RSL concluded that pre-clinical and observational studies support OPE by cannabinoids; however, it admitted that the findings of clinical trials are uncertain3838 Nielsen S, Picco L, Murnion B, Winters B, Matheson J, Graham M, Campbell G, Parvaresh L, Khor KE, Betz-Stablein B, Farrell M, Lintzeris N, Le Foll B. Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies. Neuropsychopharmacology. 2022;47(7):1315-30.. More research is undoubtedly needed.

This study has several limitations. Most of the studies included took place over a short period of time and with small samples. There was little inclusion of the elderly, a vulnerable population exposed to an increased incidence of cancer.

Studies with patients with “advanced cancer” were included, and the authors didn’t always define whether it was local or distant, which makes a difference. In most of the studies, the outcomes were assessed in different neoplasms, and therefore with different pathophysiological mechanisms. This contributes to the heterogeneity of the results and compromises comparison.

Another limitation is that the studies included did not break down the results according to the pathophysiological component of pain. On the other hand, subjective experiences were analyzed, both in terms of pain and QoL, which are always difficult to interpret and evaluate. The studies had heterogeneous interventions, even when evaluating the same outcome.

In addition, although the same assessment scales were sometimes used, they were applied in different ways. In some studies, there was no evaluation of the effects of cannabinoids when applied in different doses; thus, there is a risk of not knowing the dosage that maximizes the beneficial effect.

In the studies that allowed concomitant analgesic therapy, this was not well defined or controlled, nor were the doses considered for a possibly fairer randomization.

CONCLUSION

This study revealed that there is a benefit in prescribing cannabinoids to control pain in patients with advanced cancer. Cannabinoids do not seem to significantly increase the overall QoL of cancer patients; however, possible positive effects are not ruled out, and there was never a worsening of QoL in the studies analyzed.

Cannabinoids, especially nabiximols, are beneficial as adjuvants to analgesia in patients with cancer pain refractory to opioids. This benefit seems to exist in clinical practice but has not always been statistically significant. Although the association is possible and beneficial, it cannot be said that the use of cannabinoids has an opioid-sparing effect.

In the future, there should be greater investment in research in this area, considering the growing increase in chronic diseases, especially cancer, whose populations have so many care needs, not always easily met by conventional treatments.

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Publication Dates

  • Publication in this collection
    23 Oct 2023
  • Date of issue
    Jul-Sep 2023

History

  • Received
    08 June 2023
  • Accepted
    10 Aug 2023
Sociedade Brasileira para o Estudo da Dor Av. Conselheiro Rodrigues Alves, 937 Cj2 - Vila Mariana, CEP: 04014-012, São Paulo, SP - Brasil, Telefones: , (55) 11 5904-2881/3959 - São Paulo - SP - Brazil
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