Portenoy, R.K., Ganae-Motan, E.D., Allende, S., Yanagihara, R., Shaiova, L., Weinstein, S., . . . Fallon, M.T. (2012). Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial. The Journal of Pain: Official Journal of the American Pain Society, 13(5), 438–449.

To obtain information about the dose response for analgesia and safety in a population with medical illness and pain that is inadequately controlled by an opioid

Patients were randomly assigned to different-dose groupings of nabiximol or placebo delivered as an oral spray. Study design included a 5- to 14–day baseline period, five weeks of treatment titration, and a poststudy follow-up after two weeks. Patients received a daily call, from a voice recording system, that asked them to grade average pain. Patients continued the use of scheduled opioids and usual analgesics for the treatment of breakthrough pain. Patients who received at least one dose of the study drug were included in intent-to-treat analysis.

• The sample was composed of 263 patients.
• Mean patient age was 58 years. Age range was 20–93 years.
• Of all patients, 51.7% were male and 48.3% were female.
• Patients had active cancer and moderate to severe chronic pain despite opioid titration. Of all patients, 15% had breast cancer, 17.8% had gastrointestinal cancer, 17.8% had lung cancer, 12.2% had prostate cancer, 33.9% had some other cancer, and 3.3% had an unknown type of cancer.
• Patients were excluded if they had a major psychiatric or cardiovascular disorder, epilepsy, or significant renal or hepatic impairment or if they were pregnant, lactating, or used inadequate contraception. Also excluded were those expecting to receive therapies that would change pain and patients who were currently using or had used marijuana, cannabinoid-based medications, or rimonabant within 30 days of study entry and were unwilling to abstain for the duration of the study.

• Multisite
• Eighty-four study centers across North America, Europe, Latin America, and South Africa
   

• Phases of care: multiple phases of care
• Clinical applications: end-of-life care and palliative care
   

Randomized placebo-controlled, graded-dose trial

• Data obtained in response to six daily questions delivered via interactive voice-recording system
• Brief Pain Inventory (Short Form) (BPI-SF)
• European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30) Version 3.0
• Patient Assessment of Constipation Quality of Life (PAC-QOL)
• Montgomery-Asberg Depression Rating Scale (MADRS)
   

• Analysis of continuous responder rate favored the nabiximols groups (P = 0.035). However, this analysis was significant in the lower-dose groups only.
• The adjusted mean change in pain score for the low-dose group favored nabiximols (P = 0.006).
• Post hoc analysis that combed the low- and medium-dose groups showed a treatment difference in favor of nabiximols (P = 0.019). When weekly mean scores of average pain were compared across the groups, the low-dose group showed the greatest reduction, favoring nabiximols (P = 0.024).
• Sleep disruption scores were comparable at baseline for all groups. When evaluated at the end of treatment, the significant treatment effect (P = 0.012) was attributed to the low-dose group (p = 0.003). 
• The EORTC QLQ-C30 showed that nabiximols negatively affected cognitive functioning. In addition, compared to patients using placebo, patients using nabiximols experienced a significant amount of nausea and vomiting (P = 0.019). Authors noted that most nausea and vomiting occurred in the high-dose group (P = 0.0090).
• Of nabiximol-treated patients, 29.5% experienced a serious adverse event. Of placebo-using patients, 24.2% experienced a serious adverse event.

Nabiximols can be beneficial in the treatment of the refractory pain of patients with cancer. This study represents a start in regard to discovering the optimum dose effect and safety of nabiximols. In this study, low to medium doses were associated with the greatest effect.

• The study lacked dose individualization; therefore, the study cannot provide the most accurate picture of analgesic efficacy or side effects.
• The opioid-sparing effect could not be evaluated.
• Investigators might have avoided adverse events by lowering the dose of opioid.
• Reporting regarding sleep disruption could have been stronger if the study had used a validated tool.
• Authors provided no analysis of differences regarding breakthrough pain or total opioid doses between groups.
• According to the authors' power calculations, the study was underpowered and intention-to-treat analysis using last result forward could have had over- or underestimated effects.

This study affects nursing by providing a potential treatment option for patients with opioid-refractory pain. Nurses should be able to recognize opioid-refractory patients. Nurses should be educated regarding this novel cannabinoid treatment, its administration, and its side effects. Nurses should be able to teach patients how to use nabiximols.