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

Sá, Sílvia Silva; Melo-Alvim, Cecília; Reis-Pina, Paulo

doi:10.5935/2595-0118.20230061-en

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REVIEW ARTICLE • BrJP 6 (3) • Jul-Sep 2023 • https://doi.org/10.5935/2595-0118.20230061-en copy

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

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.

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

Authors and Country	Type of study	Objective	Population	Formulation of Cannabinoids	Intervention	Control	Observations
Hardy et al.²²22 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. Australia	RCT (dose-escalated placebo, phase IIb).	Determine whether CBD oil can improve symptomatic distress in patients with advanced cancer receiving palliative care.	n=144 (52.8% men, age 64.6±12.8 years); advanced cancer (prostate 21.1%, breast 15.5%, colorectal 14.8%, gynecological 12.7%, pulmonary 9.2% and hematological 4.9%); patients received palliative care.	CBD oil solution (100 mg/mL) oral.	Dose titration 3/3 days: from 0.5mL 1x/day to 2mL 3x/day for 14 days, according to tolerability. Participants remained on the titrated dose until 28 days.	Placebo	Scales: ESAS; SGIC. Under treatment with opioids.
Clarke et al.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. Australia	Clinical trial	Assess the safety, tolerability, pharmacokinetics and analgesic effect of a new medicinal cannabis spray in patients with incurable cancer and pain uncontrolled with opioids.	n=5 in Stage I (which does not fulfil the eligibility criteria for this study). n=25 in Stage II (which is considered in this study); patients (60% women; age 55.9±11.9 years); advanced cancer (28% breast, 16% lung and gastrointestinal, 12% hematological, 8% pancreas and ovaries, 4% melanoma, prostate and central nervous system).	THC/CBD mouth spray (1.25mg/ 1.25mg per spray).	Stage I: 1 day with 2 sprays, next day with 6 sprays. Stage II: 1-9 days of dose escalation (1 spray 3 days; 2 sprays 3 days; and 3 sprays 3 days); 10-15 days of treatment with the dose tolerated in the previous stage; 16-30 days of follow-up.	-	Scale: EORTC-QLQ-C30-v3 Single-arm study, unblinded for researchers and participants.
Grimison et al.²⁵25 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. Australia	RCT (multicentre, double-blinded, placebo, phase II/III).	Assess an oral cannabis extract (THC:CBD) for the prevention of refractory nausea and vomiting induced by chemotherapy.	n=81 (78% women; ages: 18-49 years -30%, 50-69 - 63%, ≥70 years - 6%); cancer at any stage (breast 33%, colorectal 13%, lung 12%, esophageal/gastric 9%, gynecological 9%, pancreatic 9%, hematological 4%, testicular 4%).	THC/CBD oral capsules (2.5mg/ 2.5mg).	1st cycle: 1-4 self-titrated capsules 3 times a day, starting 1 day before intravenous chemotherapy, ending on day 5; 2nd cycle: placebo (cross-over between participants); 3rd cycle: treatment preferred by the participants.	Placebo	Various centers: New South Wales. 72 participants completed cycles 1 and 2. Scale: AQOL-8D.
Good et al.²⁶26 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. Australia;	Prospective two-arm open label trial of escalating doses.	Assess the response to medicinal cannabis, determine tolerated median doses of CBD and THC and document adverse events.	n=21 (66.7% women, age 57.5±12.4 years); metastatic or locally advanced cancer (breast 33%, prostate 19%, colorectal 14%, gynecological 10%, pancreas 10%, bone and soft tissue 5%, hematological 5%).	Oral solution of CBC oil (100mg/mL) and THC (10mg/mL).	1 dose with CBC (50-600mg/day), the other with THC (2.5-30mg/day). Increases every 2/2 days, until symptomatic control or unacceptable side effects. Then the dose was maintained for 14, ideally 28 days.	-	Scales: CGIC, DASS-21, EORTC-QLQ-C15-PAL, ESAS, PGIC. Participants were taking opioid therapy.
Bar-Sela et al.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. Israel	Clinical Trial	Asses the effect of dose-controlled cannabis capsules on anorexia-caquexia syndrome in patients with advanced cancer.	n=24 (62.5% men, average age 66 years); Most common cancers: pancreatic, colon, prostate and lung carcinoma.	THC/CBD oral capsules (9.5mg/ 0.5mg).	1 capsule 12/12h for 6 months. If adverse effects occur, reduce the dose by half.	-	Scale: EORTC-QLQ-C30. -87.5% of the participants were undergoing chemotherapy.
Lichtman et al.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. Several countries	RCT (multi-center, double-blind, placebo, phase III).	Asses the efficacy of nabiximols as adjuvants in advanced cancer patients with chronic pain unrelieved by optimized opioid therapy.	n=380 (men/age: experimental group 55.8%/59.2±12.0 years; control group 52%/ 60.7±11.1 years); advanced cancer (lung 16.9%, breast 15.6%, colon 10.8%, prostate 9.8%, hematological 6.0%, pancreas 5.8%, head and neck 5.5%); Patients with chronic pain refractory to optimized opioid treatment.	THC\|CBD mouth spray (27mg/mL\|25mg/mL).	On the 1st day, 1 spray, gradually increasing until: acceptable pain relief, unacceptable adverse effects, or maximum of 10 sprays/day. Complete titration at 14 days; then maintain for 3 weeks.	Placebo	114 centers from Belgium, Bulgaria, the Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Romania, the United Kingdom and the United States of America took part. Scales: PGIC, PSQ, SGIC.
Turcott et al.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. México	RCT (pilot, double-blind, placebo).	Asses the effect of nabilone vs. placebo on appetite, nutritional status and QoL in patients with advanced lung cancer.	n=65; 47 were randomized (women/age: experimental group 78.9%/61.1±10.6 years; control group 78.6%/52.6±11.8 years); advanced non-small cell lung cancer.	Oral capsules of synthetic THC (nabilone 0.5mg).	1 capsule/day for 2 weeks, then 2 capsules/day for 6 weeks.	Placebo	Scales: EORTC-QLQ-C30, EORTC-QLQ-LC13, FAACT, PG-SGA. Participants with a good performance status and with anorexia.
Johnson et al.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. United Kingdom	Long-term, open-label, follow-up study.	Investigate the long-term safety and tolerability of THC/CBD spray and THC spray for pain relief in patients with advanced cancer.	n=43 (men/age: THC/CBD group 59%/ 57.5±13.5 years; THC group 25%/ 58.6±6.3 years); advanced cancer (breast 21%, prostate 16%, rectum 16%, lung 7%, bone 5%); Patients with pain refractory to optimized opioid treatment.	Spray bucal de THC\|CBD (27mg/mL\|25mg/mL) (n=39); e Spray bucal de THC 27mg/mL (n=4).	Patients who had previously participated in the 2-week RCT. Self-titration. Visits: at the end of the RCT/screening; after 7-10 days; after 4/4 weeks; at study completion/dropout.	-	Centers: 21 in the UK and 1 in Belgium. Scales: BPI-SF, EORTC-QLQ-C30. Average duration of treatment: for THC/CBD - 25 days, for THC - 151.5 days. Participants taking opioid treatment.
Portenoy et al.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. Several Countries	RCT (double-blind, placebo graded dose).	Obtain information on the dose response to analgesia and the safety of nabiximols in a population with cancer and pain not controlled with opioids.	n=360 (51.7% men, age 58±12.2 years); advanced cancer (gastrointestinal 17.8%, lung 17.8%, breast 15%, prostate 12.2%); patients with pain refractory to optimized opioid treatment.	Spray bucal de THC\|CBD (27mg/mL\|25mg/mL); número de pulverizações: dor ligeira: 1-4; dor moderada: 6-10; dor intensa: 11-16.	A baseline period of 5-14 days, followed by 5 weeks, with titration and treatment (in 4 groups, with 3 doses). After 2 weeks, a post-study was carried out. Maximum duration of 9 weeks.	Placebo	A total of 84 centers in North and South America, Europe and South Africa participated. Scales: BPI-SF, EORTC-QLQ-C30-v3, MADRS, PGIC.
Brisbois et al.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. Canadá	RCT (pilot, double-blind, placebo, phase II).	Determine whether THC can improve the taste and perception of smell, appetite, calorie intake and QoL of cancer patients with chemosensory alterations.	n=21 (men/age: experimental group 64%/ 67.0±10.9 years; placebo group 50%/ 65.5+8.0 years); advanced cancer (THC/placebo: lung 45%/50%, genitourinary 27%/20%, gastrointestinal 18%/10%); patients with anorexia and chemosensory alterations.	Cápsulas orais de THC 2,5mg.	Treatment: Days 1-3, 1xday; Days 4-18, 3xday; with the option of increasing the dose up to 20mg/day.	Placebo	Scales: ESAS, FAACT. Around 33% of patients received chemotherapy.

Authors	With differences either 1) between the start and end of the study in the cannabinoid group; or 2) between the cannabinoid and control groups	No differences either 1) between the start and end of the study in the cannabinoid group or 2) between the cannabinoid and control groups.
Hardy et al.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.	Patients reported feeling better at 28 days (70% CBD, 64% placebo).	Proportion of responders (p=0.13). Effect of CBD on change in pain (p=0.26), physical functioning (p=0.77), and QoL (p=0.70). Patient global impression of change at 7, 14, 21 and 28 days (p=0.54; p=0.19; p=0.38; p=0.50; respectively). There was no correlation between the dose of CBD selected by the participant and the dose of opioid. The “oral morphine equivalent” dose had no differences at 14 days (p=0.10) and 28 days (p=0.39). Change between arms at 14 and 28 days in the individual pain component (p=0.25 and p=0.54, respectively)
Clarke et al.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.	Individual parameters of the EORTC-QLQ-C30: Pain (p<0.001 breast and prostate cancer, and p=0.009 in the remaining cancers); Emotional functioning (p=0.004) only in breast and prostate cancer patients.	Overall improvement in QoL, but not statistically significant (p=0.13 for breast and prostate cancer, p=0.44 for other cancers, respectively). In the other parameters of the EORTC-QLQ-C30, there were no statistically significant differences when comparing breast/prostate cancer and other cancers.
Grimison et al.²⁵25 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.	EORTC-QLQ-C30 parameters: Global QoL (p=0.019); Pain (p=0.003); Physical overdimension (p<0.001).	Complete response and no significant nausea (p=0.12). EORTC-QLQ-C30 parameters: independent living, happiness, coping, relationships, self-esteem, senses and mental overdimension (p=0.13; p=0.50; p=0.67; p=0.1; p=0.07; p=0.18 and p=0.27, respectively).
Good et al.²⁶26 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.	Reduction in the daily dose of morphine equivalents from the start of the study (median 100mg, range 0-420) to the end (95mg, range 0-370) (p=0.09). Median scores for depression (p=0.04) and stress (p=0.046) on day 14.	There were no significant changes in pain; in overall symptom burden (9 symptoms, including pain); and in the set of physical symptoms (including pain), between the beginning and the 14th day of treatment (p>0.05; p=0.11; and p=0.65; respectively).
Bar-Sela et al.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.	-50% of patients with pain reduction at six months.	No change in QoL (EORTC). No reduction in pain: at 2 weeks; between 2 weeks and 4.5 months.
Lichtman et al.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.	Percentage improvement in “average pain” in the “per-protocol” population (p=0.0378); Subjective impression of global change and patient satisfaction at week 3 (p=0.0024 and p=0.0001, respectively);	Mean pain and worst pain (p=0.253 and p=0.678, respectively). Regular opioid dose, opioid rescue dose and total daily opioid dose (p=0.6410, p=0.4217, p=0.9328). Percentage improvement in “average pain” in the “intention-to-treat” population (p=0.0854) Percentage improvement in average pain in the “per-protocol” population in Europe (p=0.3902). Subjective global impression, patient global impression of change and patient satisfaction at last visit (p=0.0521, p=0.0861, p=0.0836).
Turcott et al.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.	QoL between the start and after eight weeks of treatment: role functioning (p=0.030), emotional functioning (p=0.018), social functioning (p= 0.036) and insomnia (p=0.020).	No change in pain after eight weeks (p=0.06)
Johnson et al.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.	Sustained improvement in the “worst pain” and “pain severity” averages from the beginning to the end of the study. 24% reduction in pain (on the EORTC) from start to week 5.	No differences in the EORTC, except for the worsening of “physical functioning” with cannabinoids.
Portenoy et al.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.	Overall analgesic response (p=0.035), with more favorable results in the low and medium doses of cannabinoids (p=0.008 and p=0.038). Change in “average pain” in the lowest dose subgroup (p=0.006) and, combining the low+medium dose subgroups (p=0.019). Mean change in “worst pain” (p=0.047), with better results at the low dose (p=0.011). Reduction in weekly “average pain”, which was better at week 5 at the low dose (p=0.024). “Composite measure of opioids” at the low and low/medium doses of cannabinoids combined (p=0.038 and p=0.05).	>30% reduction in mean pain score (p=0.059). Continued response to high dose cannabinoids (p=0.68). Change in “moderate pain” in the subgroups with medium and high doses of cannabinoids (p=0.187 and p=0.750). Mean change in “worst pain” in the medium and high doses of cannabinoids (p=0.397, p=0.829). Regular opioid dose and rescue opioid dose (p>0.05). “Opioid composite measure” (pain reduction with opioid reduction or vice versa) considering all cannabinoid doses (p>0.05).
Brisbois et al.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.	-Improved QoL between the beginning and end of the study in the THC group (p=0.026). Improved relaxation (p=0.046), sleep (p=0.043) and appetite (p=0.05).	Global QoL scores improved in both groups (p=0.704).

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

HIGHLIGHTS

ABSTRACT

BACKGROUND AND OBJECTIVES:

CONTENTS:

CONCLUSION: