Palliative Care

DGS PraxisLeitlinie v2.0 (2024) on cannabis in pain medicine; includes palliative care indications with recommendations on dosing, forms of administration and clinical management for tumor pain, cachexia and refractory symptoms.

Cannabis-based medicines (nabiximols, THC, nabilone, CBD) show no clinically relevant advantages over placebo in pain relief in cancer patients with opioid-refractory or chemotherapy-associated pain.

Cochrane SR on cannabis-based medicines for tumour pain (adults). Evaluates benefits and harms vs. placebo or established analgesics; primary outcomes: ≤mild pain, PGIC much/very much improved, withdrawals due to AE. Search up to 26.01.2023, inclusion criteria: double-blind RCTs, ≥10 participants per arm.

Moderate evidence for chronic pain and spasticity, low evidence for nausea/vomiting, weight gain and sleep disorders; increased risk of side effects.

Comprehensive SR across 79 RCTs (n=6.462) on medical cannabis; moderate evidence for chronic pain (incl. cancer-associated pain) and MS spasticity, weak evidence for chemotherapy-induced nausea/vomiting, appetite stimulation in HIV/AIDS and palliative symptom control.

Positive treatment effects reported for some cannabis products for pain, nausea, appetite and sleep in cancer patients as well as appetite and agitation in dementia patients, however very low to low evidence quality across all included studies.

Systematic review on cannabis in palliative medicine; k=52 studies (20 RCTs, 32 non-randomised), n=4.786 participants (cancer n=4.491, dementia n=43, AIDS n=235, spasticity n=16). Positive treatment effects (p<0.05) for some cannabis products for pain, nausea/vomiting, appetite, sleep, fatigue in cancer patients; appetite/agitation in dementia; appetite/nausea in AIDS. Evidence quality consistently 'very low' or 'low'. Meta-analysis not feasible due to heterogeneity of products and outcomes.

Cannabinoids reduced pain and anxiety, showed trends toward improvement in appetite and nausea/vomiting, but had no effect on constipation, depression, fatigue, mobility or quality of life; THC-dominant formulations increased the risk of psychiatric, neurological and gastrointestinal adverse events.

Systematic review + meta-analysis across k=98 studies on cannabinoids for cancer-associated symptoms (PROSPERO CRD42023479375). Significant pain reduction (MD=-1.22, 95% CI: -1.92; -0.52) and anxiety reduction (MD=-1.30, 95% CI: -2.22; -0.39) vs. baseline. THC-dominant formulations increase the risk of psychiatric adverse events (OR=10.62, 95% CI: 1.35; 83.57), neurological (OR=2.24, 95% CI: 1.15; 4.35) and gastrointestinal events (OR=2.69, 95% CI: 0.73; 9.90). Trend toward improvement in appetite, chemotherapy-induced nausea and insomnia without statistical significance.

Cannabinoids showed superiority over placebo for weight gain and appetite in HIV wasting syndrome, but not for cancer pain, caloric intake or sleep problems; megestrol acetate was superior to dronabinol.

Systematic review + meta-analysis on cannabinoids in palliative medicine; k=9 RCTs (n=1.561) in advanced/end-stage illnesses (cancer, HIV, Alzheimer's). Cancer outcomes not significant: 30% pain reduction RD=0.07 (95% CI: -0.01 to 0.16, p=0.07), caloric intake SMD=0.2 (p=0.65), sleep problems SMD=-0.09 (p=0.72). HIV: significant weight gain SMD=0.57 (95% CI: 0.22-0.92, p=0.001) and appetite SMD=0.57 (95% CI: 0.11-1.03, p=0.02).

Nabilone was not superior to placebo with regard to quality of life and treatment-related symptoms during head and neck radiotherapy.

Randomised double-blind placebo-controlled study (n=56) of nabilone for improving quality of life and alleviating side effects during radiotherapy in head and neck carcinomas. Nabilone was not superior to placebo: no significant benefit in quality of life (P=,43), pain (P=,60), nausea (P=,71), loss of appetite (P=,33), weight (P=,15), mood (P=,32) or sleep (P=,44). No benefit demonstrable at the dosage used (negative result). Limitation: small sample size, possibly too low a dose.

CBD oil provided no additional benefit over placebo for symptom burden in palliative care patients with advanced cancer.

n=144 advanced cancer patients under palliative care, CBD oil (100 mg/mL titrated up to 600 mg/day) vs. placebo over 28 days. Primary endpoint ESAS Total Symptom Distress Score (TSDS) day 14: CBD -3.0 vs. placebo -6.2, no significant difference (p=0.24). Response rate (TSDS reduction ≥6): CBD 44.8% vs. placebo 58.7% (p=0.13). CBD showed no additional benefit over specialised palliative care; dyspnoea more frequent under CBD.

THC:CBD combination oil showed no significant benefit over placebo for overall symptom burden, with only a small pain benefit that was offset by greater psychomimetic toxicity.

RCT (n=144) on 1:1 THC:CBD oil (10 mg/ml) vs. placebo in advanced cancer over 28 days; primary endpoint Total Symptom Distress Score (TSDS) day 14: no difference between arms (MC -6.30±12.3, placebo -6.98±12.56, p=0.76). ESAS pain score significant for MC (MC -1.42±2.15, placebo -0.46±2.83, p=0.04), but higher psychomimetic toxicity. Global Impression of Change and pain-QoL favoured MC.

THC reduced nausea/vomiting versus placebo, but offered no advantage over prochlorperazine and was associated with considerably more CNS side effects.

n=116 cancer patients undergoing chemotherapy, THC 15 mg 3x daily vs. prochlorperazine vs. placebo; THC showed superior antiemesis vs. placebo, no advantage over prochlorperazine; CNS side effects significantly more frequent/severe with THC; overall experience more burdensome for older patients (median age 61 years) with THC.

Levonantradol 0,5 mg showed better antiemetic effect than chlorpromazine, but is not recommended due to unacceptable CNS side effects.

n=108 cancer patients; levonantradol 0,5 mg as palliative antiemetic therapy during chemotherapy; antiemetically superior to chlorpromazine 25 mg (active standard); however dysphoric reactions in 22–50% depending on dose and insufficient protection against cisplatin-induced emesis. The authors do not recommend routine use due to the high rate of unacceptable CNS side effects.

The 1:1 ratio of medical cannabis significantly improved sleep, physical and functional capacity without serious adverse effects.

Phase 2 RCT n=88 terminally ill glioma patients; 1:1 THC:CBD ratio improved FACT-Br (physical p=0,025, functional p=0,014) and sleep (p=0,009) after 12 weeks; no serious adverse events; well tolerated as palliative adjunct therapy.

THC significantly improved chemosensory perception, taste of food, pre-meal appetite, and protein intake compared to placebo in cancer patients with chemosensory alterations.

Pilot RCT in n=21 cancer patients with chemosensory alterations; THC 2,5 mg 2× daily vs. placebo over 18 days. THC group showed improved taste/smell perception (p=0.026), better tasting (p=0.04), increased pre-meal appetite (p=0.05), and increased protein intake (p=0.008) vs. placebo. Improvement in sleep quality (p=0.025) and relaxation (p=0.045).

All levonantradol doses significantly reduced chemotherapy-induced emesis compared to placebo (p<0,01) without a demonstrable dose-response effect.

n=20 cancer patients in advanced disease stage; levonantradol i.m. as antiemetic supportive therapy during chemotherapy; significant symptom control (p<0,01) versus placebo for all dosages 0,5–2,0 mg. Relevant for palliative supportive therapy for control of chemotherapy-induced emesis.

Oral THC (15-20 mg) reduces tumor pain significantly better than placebo, but is accompanied by pronounced sedation and mental clouding.

Pilot study (n=10, cancer patients with tumor pain), oral THC (5/10/15/20 mg) vs. placebo double-blind: significant pain relief at high doses (15 mg and 20 mg); side effects (sedation, mental clouding) at analgesically effective doses relevant for palliative risk-benefit assessment.

Cannabinoids (CBD/THC) were predominantly well tolerated and led to a relevant symptom reduction in 43% of palliative patients, however without a control group and with a high dropout rate by day 28.

Pilot trial n=21 palliative patients with advanced cancer (CBD arm n=16, THC arm n=5); 9/21 (43%) achieved clinical response (≥6-point reduction TSDS); median maximum tolerated dose CBD 300 mg/day (range 100–600 mg), THC 10 mg/day (range 5–30 mg); 86% completed primary endpoint on day 14; drowsiness most common adverse event — feasibility study with limited informative value.

Intramuscular levonantradol achieved an antiemetic effect in 89 % of patients at low doses starting from 0,5 mg.

n=28 cancer patients undergoing chemotherapy, refractory to standard antiemetics, IM levonantradol 0,5–1,5 mg; response rate 89% (25/28) complete or partial; dysphoria as dose-limiting toxicity in 16% (5/31 evaluable patients); somnolence 48%, dry mouth 32%.

THC increased appetite in 13 of 18 evaluable cancer patients with anorexia and showed good tolerability.

Phase II study (n=18) on THC in palliative tumor-associated anorexia (life expectancy >4 weeks); 13/18 (72%) improved appetite; 10/18 completed full 28-day intake; 4 patients grade I toxicity; 3 discontinuations at patient's request; tolerability at 2,5 mg t.i.d. good.

THC/CBD spray showed improvement in pain intensity and worst pain as well as improvement in insomnia, pain and fatigue with good tolerability over longer-term use.

Open-label extension study (n=43) following a preceding 2-week RCT on THC/CBD oromucosal spray in refractory cancer pain. Brief Pain Inventory-Short Form: improvement in 'pain severity' and 'worst pain' at every follow-up visit. EORTC QLQ-C30: improvement in the domains insomnia, pain, fatigue. No dose increase over time (no indication of tolerance development), good long-term tolerability.

Levonantradol produced a substantial antiemetic effect in 15 of 20 refractory patients.

n=20 cancer patients with treatment-refractory chemotherapy-induced nausea/vomiting in a palliative context; levonantradol (THC analogue): 15/20 (75%) marked symptom relief, 10/20 preferred continuation — suggestion of benefit in conventionally exhausted patients.

In a subset of patients a clinically relevant weight gain and reduced appetite loss were observed, however with considerable study attrition and without a control group.

n=17 patients with advanced cancer disease (palliative situation), THC/CBD capsules (5–10 mg THC 2×daily); self-reported improvements in appetite, mood, pain and fatigue; appetite loss symptoms significantly improved (p=0,05); 3/17 with weight gain ≥10%; no serious side effects.

95,9% of evaluable patients reported an improvement in their cancer-associated symptoms after 6 months of medical cannabis treatment.

Prospective real-world data on n=2970 cancer patients with medical cannabis (Israel 2015–2017); main symptoms: sleep disorders (78,4%), pain (77,7%, median 8/10), weakness (72,7%), nausea (64,6%), loss of appetite (48,9%). After 6 months follow-up, 95,9% of the remaining responders (n=1211/2056, 60,6%) reported an improvement in their condition, 3,7% no change, 0,3% worsening. Cannabis as palliative treatment well tolerated, effective and safe for symptom control in cancer patients.

52,5% of patients achieved pain relief of more than 30%, 10% of more than 50%; approximately four symptoms or side effects from previous treatment were positively affected.

Retrospective analysis on dronabinol in geriatric pain and palliative care patients; description of tolerability, dosing strategies, and clinical outcomes in a vulnerable population with multimorbidity.

Cannabis group showed longer median survival time (5,66 vs. 0,83 months) and lower mortality rate, but authors warn of unmeasured confounding and call for prospective studies to confirm.

Retrospective cohort on medical cannabis in advanced cholangiocellular carcinoma (CCA), n=491 (87 cannabis therapy CT, 404 standard palliative care ST). Median survival CT=5.66 months (95% CI: 1.94–9.38) vs. ST=0.83 months (95% CI: 0.71–0.95). Multivariate analysis: CT associated with prolonged survival (HRadj=0.28; 95% CI: 0.20–0.37; p<0.001). Mortality rate CT=10.9/100 person-months vs. ST=48.35/100 person-months. Authors emphasize possible residual confounding.

Patients reported improvements in pain (70%), general condition (70%), appetite (60%) and nausea (50%), but only 46% of patients still alive after 6 months renewed their permit; side effects were mild (fatigue, dizziness).

Retrospective study on medical cannabis in n=279 Israeli cancer patients (84% metastatic); of n=113 users after 1 month, 70% reported improvement in pain, 70% in general wellbeing, 60% in appetite, 50% in nausea. Side effects mild (fatigue, dizziness). Of n=151 patients alive after 6 months, 46% renewed the cannabis permit.

MMJ use improved symptom scores and stabilized opioid consumption, while non-users showed a significant increase in opioid consumption.

n=232 oncological palliative care patients; MMJ(+) maintained stable opioid dose (45 mg/day MME) while MMJ(−) increased by 23% (p=0,004); ESAS total score and emotional symptoms significantly better in MMJ(+); medical cannabis as a viable adjuvant therapeutic in the palliative care context.

Cannabis use had no significant main effect on pain, but reduced the race-related pain disparity between African American and white cancer patients.

Observational study (n=136 cancer patients with tumor pain) on cannabis use and pain relief in the palliative setting: no significant main effect of cannabis on BPI pain scores (p=0.28), but significant moderation effect on racial pain disparity (p=0.03) — under cannabis use the difference between African American and white patients disappeared. Indication of potential as an adjuvant in palliative pain therapy.

All cancer- and treatment-associated symptoms showed significant improvement (P < 0.001), with the exception of memory deterioration with prolonged use.

Prospective observational study in n=131 cancer patients with cannabis license (of initially 211); all cancer- or therapy-associated symptoms showed significant improvement (p<0.001). Only significant side effect: memory impairment with prolonged use (p=0.002). No control group.

Dronabinol reduced or eliminated refractory spasticity in 12 of 16 pediatric palliative patients.

Pediatric palliative care, n=16 children/adolescents with complex neurological diseases and refractory spasticity; dronabinol (2,5% THC oil), median 0,33 mg/kg/d; 12/16 patients benefited (resolution of spasticity or marked improvement); severe or persistent adverse effects did not occur even in young children and long-term treatment (181 days median).

MC users predominantly reported symptom improvement in pain, appetite and anxiety; the most frequent side effect reported was cloudy thinking.

Survey (n=188 oncology patients); 24,5% used medical cannabis palliatively. Symptom improvement: pain 81% (34/42), appetite 77,3% (34/44), anxiety 73% (32/44); improved treatment tolerance 54,5% (24/44). Baseline symptom burden significantly higher in MC users (score 17,5 vs. 14,4, p<0.001). Low toxicity profile; most frequent adverse drug reaction: impaired thinking 16,7%.

Delta-8-THC completely prevented chemotherapy-induced vomiting in all treated children.

n=8 pediatric oncology patients (3–13 years) undergoing antineoplastic therapy, Delta-8-THC as antiemetic supportive measure (480 treatments, up to 8 months); complete prevention of chemotherapy-induced emesis in 100% of administrations; side effects negligible — relevant for palliative symptom control in children with hematological malignancies.

Nabilone led to worsening of nausea and vomiting (cannabinoid hyperemesis syndrome) instead of the expected relief; after discontinuation no return of symptoms.

Single case report (n=1): 70-year-old patient with small cell lung carcinoma in palliative care; nabilone (incrementally increased from 0.5 to 2 mg over 5 years) led to refractory vomiting (cannabinoid hyperemesis syndrome suspected). After discontinuation of nabilone complete remission of nausea/emesis, pain control successful with opioids.

Limited evidence for efficacy in cancer pain and gastrointestinal symptoms; mixed results for insomnia and mood disorders; side effects documented.

Review (2024) on medical cannabis products in palliative medicine; evidence synthesis on tumor pain, appetite, nausea and quality of life in oncological palliative patients, discussion of THC/CBD preparations and clinical practicability.

There is no high-quality evidence for the use of cannabis and cannabinoids in palliative care; they could be considered as a therapeutic trial for cancer pain, HIV-associated weight gain, and other symptoms, if established treatments fail.

Narrative review on cannabis/cannabinoids in palliative care, focused on the Mücke et al. SR. Conclusion: overall no high-quality evidence; cannabinoids may be considered as a therapeutic trial for tumor pain, weight gain (HIV), as well as nausea/loss of appetite, if established therapies fail. Further studies with larger patient numbers required; special conditions of palliative medicine make high-quality studies difficult.

Study shows information deficits among physicians in dealing with cannabis medicines and high rejection rates (36,1%) for cost coverage applications by health insurers.

Narrative review on the use of cannabis medicines in pain and palliative medicine; discussion of indications, forms of administration, dosage and practical aspects without systematic data extraction.