Portenoy et al. (2012): Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial

Reference ↗
Title	Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial
Topic	Cannabinoids
Author	Portenoy, K, Ganae-Motan, ED, Allende, S, Yanagihara, R, Shaiova, L, Weinstein, S, McQuade, R, Wright, S, Fallon, MT
Year	2012
Journal	The Journal of Pain
DOI	https://doi.org/10.1016/j.jpain.2012.01.003

Brief summary

In this study, the effect of nabiximol, a cannabis-containing oral spray, on the personal perception of pain in patients with various advanced cancers and moderate to severe tumor pain was investigated as a function of dose. The study compared four different arms, namely three different nabiximols arms (low dose, medium dose, high dose) and a placebo arm. With regard to the primary endpoint, namely the number of patients in whom treatment with nabiximols led to a significant improvement in pain perception (≥30%), there were no significant differences between the arms. However, it was found that patients with the low dose in particular, but in some cases also with the medium dose, responded better overall to the treatment compared to the placebo arm and reported a significantly greater improvement in pain and sleep disturbances on average over the course of the study. In addition, patients with the low dose of nabiximols required less opioids depending on the pain compared to the placebo arm.The large international sample was a positive aspect of this study, but there are also some points of criticism. In particular, the differences in treatment adherence between the arms, the lack of clarity as to whether the arms were comparable at the start of the study and the high drop-out rate during the course of the study should be mentioned. For this reason, the results of this study can only be interpreted with caution.

In dieser Studie wurde in Abhängigkeit der Dosis die Wirkung von Nabiximol, einem cannabishaltigen Mundspray, hinsichtlich der persönlichen Wahrnehmung von Schmerzen bei Patienten mit verschiedenen, vorangeschrittenen Krebserkrankungen und mittleren bis schweren Tumorschmerzen untersucht. In der Studie wurden vier verschiedene Gruppen verglichen, nämlich drei verschiedene Nabiximol-Arme (niedrige Dosis, mittlere Dosis, hohe Dosis) und eine Placebogruppe. Hinsichtlich des primären Endpunkts, nämlich der Anzahl an Patienten, bei denen die Behandlung mit Nabiximol zu einer deutlichen Verbesserung der Schmerzwahrnehmung (≥30%) geführt hat, zeigten sich keine bedeutsamen Unterschiede zwischen den Gruppen. Es wurde jedoch gefunden, dass vor allem Patienten mit der niedrigen Dosis, teilweise aber auch mit der mittleren Dosis im Vergleich zur Placebogruppe insgesamt besser auf die Behandlung ansprachen und im Mittel eine bedeutsam stärkere Verbesserung der Schmerzen und der Schlafstörungen im Verlauf der Studie berichteten. Zudem benötigen Patienten mit der niedrigen Nabiximoldosis weniger Opiode in Abhängigkeit der Schmerzen im Vergleich zur Placebogruppe. Positiv an dieser Studie war die große internationale Stichprobe, es lassen sich jedoch auch einige Kritikpunkte nennen. Dabei sind vor allem die Unterschiede in der Therapietreue zwischen den Armen, die Unklarkeit, ob die Gruppen zum Beginn der Studie vergleichbar waren zu nennen und die hohe Ausfallrate im Verlauf der Studie zu nennen. Deswegen lassen sich die Ergebnisse dieser Studie nur mit Vorsicht interpretieren.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	4

Study characteristics

Inclusion criteria	Adult patients with active cancer and chronic pain (moderate or severe despite a stable opioid regimen that could not be made more effective by further opioid dose titration); stable, average pain: NRS: ≥4≤ 8 (no change in 3 days > 2 points)
Exclusion criteria	Patients receiving long-term methadone therapy for pain; major psychiatric or cardiovascular disorder; epilepsy; significant renal or hepatic impairment; pregnant, lactating or not using adequate contraception; patients, who had received or who were due to receive therapies expected to change the pain (such as radiotherapy, or chemotherapy or hormonal therapy); marijuana use, cannabinoid-based medications or rimonabant within 30 days of study entry, and unwilling to abstain for the duration of the study
N randomized	360
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	ITT Analysis
Specifications on analyses	Missing data for the efficacy endpoints were imputed using the last observation carry forward (LOCF) method. The proportions of responders were compared between the treatments using logistic regression, with region (North America/Rest of the World) and treatment used as factors. The cumulative response to treatment was shown by plotting cumulative response rates against increasing thresholds for response, ie, percentage changes from baseline in the mean 11-point NRS pain score that defined a response. The cumulative response curves for each of the active treatment groups were compared with placebo using pairwise Wilcoxon rank-sum tests. The Hodges-Lehmann estimates and 95% CI for the median also were performed. The analysis of all the secondary efficacy assessments was considered supportive and no formal adjustments for multiple comparisons were made. The change in mean pain NRS scores, BPI-SF, sleep disruption NRS, PAC-QoL questionnaire, and MADRS were all analyzed using analysis of covariance (ANCOVA), with the baseline value as a covariate and region and treatment group as factors. An analysis also was performed on the mean pain NRS scores to assess the time course of the treatment effect using repeated measure analysis. Additionally, the difference in time required to establish baseline was investigated as a possible moderator of treatment effect by using the number of days until the patient became eligible for randomization and total number of days in the baseline period as covariates in the analysis of change in the mean daily NRS score for average pain.
Countries of data collection	Europe, South Africa, North America, Latin America
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T1: baseline (3 days) T2: day 21 T3: day 35 (end of intervention) T4: 14 days after treatment

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Palliative, NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Gastrointestinal Cancers, Lung Cancer, Prostate Cancer, Other Cancers
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Advanced Stage
Specifications on cancer stages	Mean (SD) duration = 3.6 (4.8) years
Comorbidities	Chronic, therapy-resistant tumor pain (treated with opioids)
Current cancer therapies	No therapy
Specifications on cancer therapies	NA
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Female n (%): 174 (48.3) Male n (%): 186 (51.7)
Age groups	Adults (18+)
Age groups specification	Mean (SD) age = 58 (12.2) years Range = 20-93 years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	91
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	20
Drop-out reasons	Side effects (n=5); consent withdrawn (n=1); progression of the disease (n=7); other reasons (n=3)
Intervention	Nabiximol
Dosage and regime	Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD) Week 1: dose finding; week 2-5: stable dose Maximal number of sprays: 1-4 (low dose)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	35
Side effects / Interactions	Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis; weight loss

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	88
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	21
Drop-out reasons	Side effects (n=6); consent withdrawn (n=5); progression of the disease (n=7); other reasons (n=3)
Intervention	Nabiximol
Dosage and regime	Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD) Week 1: dose finding; week 2-5: stable dose Maximal number of sprays: 6-10 (medium dose)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	35
Side effects / Interactions	Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis; weight loss

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	90
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	31
Drop-out reasons	Side effects (n=20); consent withdrawn (n=4); progression of the disease (n=7)
Intervention	Nabiximol
Dosage and regime	Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD) Week 1: dose finding; week 2-5: stable dose Maximal number of sprays: 11-16 (high dose)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	35
Side effects / Interactions	Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis weight loss

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	91
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	25
Drop-out reasons	Side effects (n=9); consent withdrawn (n=6); progression of the disease (n=7): no effect (n=1); other reasons (n=1); no follow-up (n=1)
Intervention	Placebo
Dosage and regime	Placebo via oral spray (self-applied by patient) Week 1: dose finding; week 2-5: stable dose Maximal number of sprays: variable (1-4, 6-10, 11-16)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	35
Side effects / Interactions	NI

Outcomes

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	Number of responders (≥ 30% pain reduction Numeric Rating Scale for average pain during the last 3 days of week 5 compared with the mean during the 3-day baseline period)
Type of measurement	NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to 5 weeks: no group differences; OR in each case Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.59 Nabiximol (1-4 sprays) vs. placebo: 1.37; p=0.33 Nabiximol (6-10 sprays) vs. placebo: 1.19, p=0.61 Nabiximol (11-16 sprays) vs. placebo: 0.9, p=0.76
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	Number per improvement level (10%, 20% etc.-100%)
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Over the course of the sudy significant difference between intervention combined arms and placebo: full spectrum 0-100% responders (OR in each case): Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.035 Nabiximol (1-4 sprays) vs. placebo: p=0.008 Nabiximol (6-10 sprays) vs. placebo: p=0.038 Nabiximol (11-16 sprays) vs. placebo: p=0.68
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	Change in NRS value for moderate pain
Type of measurement	NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to 5 weeks: No significant group differences between intervention groups combined and placebo: Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.072 Mean: Nabiximol (1-4 sprays): baseline = 5.8, day 35 = 4.3 Nabiximol (6-10 sprays): baseline = 5.8, day 35 = 4.7 Nabiximol (11-16 sprays): NI Placebo: baseline = 5.7, day 35 = 4.9 Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI) Nabiximol (1-4 sprays) vs. placebo = -0.75 (-1.28, 0.22), p=0.006 Otherwise no differences: Nabiximol (6-10 sprays) vs. placebo = -0.36 (-0.89, 0.18), p=0.19 Nabiximol (11-16 sprays) vs. placebo = -0.09 (-0.62, 0.44), p=0.75
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	Change in NRS value for the worst pain
Type of measurement	NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline to 5 weeks: Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI) Nabiximol (1-4 sprays) vs. placebo =- 0.73 (-1.30, -0.17), p=0.011 Otherwise no significant differences: Nabiximol (6-10 sprays) vs. placebo = -0.24 (-0.8, 0.3), p=0.4 Nabiximol (11-16 sprays) vs. placebo = -0.6 (-0.6, 0.5), p=0.83
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Sleep

Outcome type As specificed by the authors	Others
Outcome specification	Extent of sleep disturbance
Type of measurement	NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI) Nabiximol (1-4 sprays) vs. placebo = -0.88 (-1.45, -0.31), p = 0.003 Otherwise no differences: Nabiximol (6-10 sprays)/nabiximol (11-16 sprays) alone vs. placebo: not significant Combining low and high dose group: Significant difference vs. placebo in favor of nabiximols (p = .016)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Pain

Outcome type As specificed by the authors	NI
Outcome specification	Opiod consumption: score from change in self-assessed pain in relation to opiod consumption in morphine-equivalent milligrams)
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant group differences between intervention groups combined and placebo: OR (95% CI) Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo =1.54 (0.95, 2.50), p = 0.077 Significant difference for nabiximol (1-4 sprays) vs. placebo = 1.87, p=0.038 Otherwise no differences: Nabiximol (6-10 sprays)/nabiximol (11-16 sprays) vs. placebo: not significant
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Pain

Outcome type As specificed by the authors	Others
Outcome specification	NA
Type of measurement	BPI-SF (Brief Pain Inventory - Short Form)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 5 weeks: No significant differences.
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Quality of life

Outcome type As specificed by the authors	Others
Outcome specification	NA
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire), MADRS (Montgomery-Asberg Depression Rating Scale), PAC-QoL (Patient Assessment of Constipation - Quality of Life)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 5 weeks: Small effect of nabiximol on EORTC-QCQ-C30 (no values given), otherwise no significant differences for questionnaires.
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	high risk
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	high risk

Funding and Conflicts of Interest

Funding	Supported in part by the Huntsman Cancer Foundation (S.W.). GW Pharmaceuticals produces nabiximols, which is licensed in Canada as an adjunctive analgesic treatment in adult patients with advanced cancer. This study was funded by GW Pharmaceuticals and Otsuka.
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	Yes
- Reasons for insufficient sample size based on power analysis	NA
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	NA
Ethnicity mentioned	Yes

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	Compliance different in arms 94.5%, 85.1%, 62.2%, placebo NI Post-hoc analyses show confounding variables that lead to increased deaths in intervention arms: High level of white blood cells, low level of calcium, hemoglobin and lymphocytes --> doubts about comparability of the arms In the analyses of subjective perception of pain, no control of changes in opiod consumption

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	NI
Correction for multiple testing	Yes
Measurement of compliance	Yes
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	No
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	No
Side effects considered in result interpretation	NI
Ethics votum	Yes

Additional Notes

PRO:

• Ethical approval
• Intent-to-treat analysis
• Power analysis

CONTRA:

• Differences in treatment adherence
• Some descriptive differences at baseline without p-values provided (e.g., pain duration)
• Post-hoc analyses reveal confounding variables associated with higher mortality rates in intervention arms: high white blood cell count, low calcium, hemoglobin, and lymphocyte levels, raising doubts about group comparability.
• In analyses of subjective pain perception, changes in opioid consumption were not controlled for.
• Mostly one-dimensional pain parameters were considered.
• Results in the text are reported unclearly, with some values missing or not precisely specified.
• No information on cancer stage.
• Poor reporting quality.
• Correction for multiple comparison only for primary endpoints