Ahmedzai, S.H., Nauck, F., Bar-Sela, G., Bosse, B., Leyendecker, P., & Hopp, M. (2012). A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliative Medicine, 26, 50–60.

To determine whether oxycodone/naloxone prolonged-release tablets (OXN PR) can improve constipation and maintain analgesia, compared with oxycodone prolonged-release tablets (OxyPR) in patients with moderate to severe cancer pain

This was a randomized, double-blind, active-controlled, double-dummy, parallel-group study in which 185 patients were randomized to receive up to 120 mg per day of OXN PR or OxyPR over four weeks. Efficacy assessments included Bowel Function Index (BFI), Brief Pain Inventory Short-Form (BPI-SF), and laxative and rescue medication use. Quality-of-life and safety assessments also were conducted.

• N = 184
• AGE = In the OXN PR group, 65.2% of the patients were aged 65 years or younger and 34.8% were older than 65 years. In the OxyPR group, 48.9% of the patients were aged 65 years or younger and 51.1% were older than 65 years.
• MALES: 51%, FEMALES: 49%
• KEY DISEASE CHARACTERISTICS: Eligible patients aged 18 years or older with a diagnosis of cancer and a documented history of moderate to severe, chronic cancer pain requiring around-the-clock opioid therapy equivalent to OxyPR 20–80 mg per day at the initiation of the trial
• OTHER KEY SAMPLE CHARACTERISTICS: Willing and able to participate in the use of medication, complete subjective evaluations, attend scheduled clinic visits, complete telephone contacts, and comply with protocol requirements as evidenced by providing written, informed consent

• SITE: International
• SETTING TYPE: Multi-center
• LOCATION: Australia, Czech Republic, France, Germany, Hungary, Israel, Netherlands, Poland, and United Kingdom

• PHASE OF CARE: Active treatment
• CLINICAL APPLICABILITY: Palliative care

• Randomized, double-blind, active-controlled, double-dummy, parallel-group study

• Evaluations of BFI, pain control (BPI-SF), use of rescue medication, and use of laxative medication during the last seven days were performed at each clinic visit.
• Quality-of-life assessments, including the European Quality of life (EuroQo) EQ-5D instrument and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) were conducted at screening and at study end.
• Patient Assessment of Constipation Symptoms (PAC-SYM) was conducted at screening, randomization, and four weeks.
• Adverse events were noted at each assessment post-randomization.
• Patients were followed up regarding adverse events and adverse drug reactions after study completion.

Overall, 133 of 184 patients (72.3%) completed the study. Rates of discontinuation were similar for OXN PR (28.3%) and OxyPR (27.2%). In both groups, the primary reason for discontinuation was adverse events. At randomization, mean BFI values were high and comparable in the OXN PR and OxyPR groups (63.97 [SD = 17.42] versus 62.40 [SD = 23.56], respectively), and similar to baseline assessments in previous phase III trials. The difference in change from baseline in BFI score between groups was statistically significant. A statistically significant difference between treatments in favor of OXN PR was observed at week 1.

At randomization, mean BPI-SF scores were comparable for OXN PR and OxyPR treatment groups (4.16 [SD = 1.87] versus 4.18 [SD = 1.87]). After four weeks of treatment, mean BPI-SF scores remained comparable between the two groups (3.50 [SD = 1.88] and 3.52 [SD = 1.80]). Results of the primary analysis confirmed non-inferiority of OXN PR to OxyPR.

Patients who were switched directly from other opioids to OXN PR experienced a similar analgesic effect as well as a statistically significant and clinically relevant improvement in bowel function, compared with those switched to OxyPR.

Opioid-induced bowel dysfunction is common and adds to the burden of living with chronic pain. Current oral and rectal laxatives often are ineffective and do not have a good evidence base. The new targeted approach of administering peripherally acting opioid antagonists is effective and supported by extensive clinical trial data. The present trial demonstrates that oral OXN PR tablets are well tolerated and can effectively and conveniently provide targeted treatment of opioid-induced constipation.