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.

OBJECTIVE: An examination of 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/severe cancer pain. METHODS: Randomized, double-blind, active-controlled, double-dummy, parallel-group study in which 185 patients were randomized to receive up to 120 mg/day of OXN PR or OxyPR over 4 weeks. Efficacy assessments included Bowel Function Index (BFI), Brief Pain Inventory Short-Form (BPI-SF), laxative and rescue medication use. Quality of life (QoL) and safety assessments were conducted. RESULTS: After 4 weeks, mean BFI score was significantly lower with OXN PR; mean total laxative intake was 20% lower with OXN PR. Mean BPI-SF scores were similar for both treatments and the average rate of analgesic rescue medication use was low and comparable. QoL assessments were stable and comparable with greater improvements in constipation-specific QoL assessments with OXN PR. Overall, rates of adverse drug reactions were similar. CONCLUSIONS: OXN PR provides superior bowel function in cancer pain patients, compared with OxyPR, without compromising analgesic efficacy or safety. This study confirms that OXN PR is well tolerated and efficacious in cancer pain patients and results are in line with those seen in non-malignant pain patients.

Efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of moderate/severe chronic non-malignant pain: results of a prospectively designed pooled analysis of two randomised, double-blind clinical trials.

BACKGROUND: Two randomised 12-week, double-blind, parallel-group, multicenter studies comparing oxycodone PR/naloxone PR and oxycodone PR alone on symptoms of opioid-induced bowel dysfunction in patients with moderate/severe non-malignant pain have been conducted. METHODS: These studies were prospectively designed to be pooled and the primary outcome measure of the pooled data analysis was to demonstrate non-inferiority in 12-week analgesic efficacy of oxycodone PR/naloxone PR versus oxycodone PR alone. Patients with opioid-induced constipation were switched to oxycodone PR and then randomised to fixed doses of oxycodone PR/naloxone PR (n = 292) or oxycodone PR (n = 295) for 12 weeks (20-80 mg/day). RESULTS: No statistically significant differences in analgesic efficacy were observed for the two treatments (p = 0.3197; non-inferiority p < 0.0001; 95% CI -0.07, 0.23) and there was no statistically significant difference in frequency of analgesic rescue medication use. Improvements in Bowel Function Index score were observed for oxycodone PR/naloxone PR by Week 1 and at every subsequent time point (-15.1; p < 0.0001; 95% CI -17.3, -13.0). AE incidence was similar for both groups (61.0% and 57.3% of patients with oxycodone PR/naloxone PR and oxycodone PR alone, respectively). CONCLUSIONS: Results of this pooled analysis confirm that oxycodone PR/naloxone PR provides effective analgesia and suggest that oxycodone PR/naloxone PR improves bowel function without compromising analgesic efficacy. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov identifier: NCT00412100 and NCT00412152.

Meeting the challenges of opioid-induced constipation in chronic pain management - a novel approach.

Opioid analgesics are the cornerstone of pain management for moderate-to-severe cancer pain and, increasingly, chronic noncancer pain. Despite proven analgesic efficacy, the use of opioids is commonly associated with frequently dose-limiting constipation that seriously impacts on patients' quality of life. Agents currently used to manage opioid-induced constipation (OIC), such as laxatives, do not address the underlying opioid receptor-mediated cause of constipation and are often ineffective. A significant need therefore exists for more effective treatment options. A novel approach for selectively and locally antagonizing the gastrointestinal effects of opioids involves the coadministration of a mu-opioid receptor antagonist with negligible systemic availability, such as oral naloxone. Combination therapy with prolonged-release (PR) oxycodone plus PR naloxone has been shown to provide effective analgesia while preventing or reducing constipation. The current article highlights this novel strategy in its potential to significantly improve the quality of life of patients suffering from chronic pain, affording patients the benefit of full analgesia, without the burden of OIC.

Single- and multiple-dose pharmacokinetic evaluation of oxycodone and naloxone in an opioid agonist/antagonist prolonged-release combination in healthy adult volunteers.

BACKGROUND: There is an increasing body of evidence supporting the need for prophylactic management of the adverse events (AEs) associated with long-term opioid use in patients with chronic pain. Symptoms of bowel dysfunction, such as constipation, may have a significant impact on a patient's quality of life and willingness to continue opioid therapy, and therefore should be managed proactively to ensure that the patient can continue effective pain management. The fixed-dose combination (FDC) prolonged-release (PR) oxycodone/naloxone (OXN) may be an effective therapeutic approach to delivering analgesia, with a reduced risk for opioid-induced constipation. OBJECTIVE: The aim of this paper was to report the pharmacokinetic results from a single-dose study and a multiple-dose bioequivalence study of OXN versus separate formulations of oxycodone PR and naloxone PR administered concurrently in healthy subjects. METHODS: Both studies were open-label, randomized crossover studies in healthy adult male and female subjects. In the single-dose study, subjects were randomly assigned to 1 of 4 treatment groups: OXN FDC (44 x 10/55-mg, 2 x 20/110-mg, or 1 x 40/20-mg dose strength [each given at a total combined dose of 40/220 mg]) or oxycodone PR 40 mg + naloxone PR 20 mg given in separate formulations. In the multiple-dose study, 34 subjects were randomly assigned to 1 of 3 treatment groups: OXN FDC 40/20 mg, oxycodone PR 40 mg, or naloxone PR 20 mg. Treatments were considered bioequivalent if the 90% CIs for relative bioavailability calculations fell within a predetermined range of 80% to 125%. AEs were assessed by the investigator at each study visit. RESULTS: The single-dose study included 28 subjects (22 men, 6 women; mean [SD] age, 32.3 [5.44] years; weight, 75.5 [9.3] kg; and body mass index [BMI], 24.2 [2.5] kg/mm(2)). The mean plasma oxycodone concentration-time curves for OXN and oxycodone PR + naloxone PR were similar. With oxycodone, the mean (SD) AUC(t) values with OXN 10/5, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 473.49 (72.16), 491.22 (82.18), 488.89 (91.04), and 502.28 (84.13) ng . h/mL, respectively; mean C(max) values were 34.91 (4.36), 35.73 (4.93), 34.46 (5.03), and 40.45 (4.71) ng/mL. For naloxone-3-glucuronide (the primary analyte of naloxone), the mean (SD) AUC(t) values with OXN 10/5, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 539.93 (142.24), 522.45 (128.57), 520.10 (133.18), and 523.37 (119.75) ng . h/mL, respectively; mean C(max) values were 62.01 (15.96), 63.62 (19.51), 61.95 (18.37), and 63.55 (16.75) ng/mL. There were no statistically significant differences between the treatments, and each of the treatment comparisons resulted in 90% CIs within the range for bioequivalence. The multiple-dose steady-state bioequivalence study included 34 subjects (28 men, 6 women; mean [SD] age, 36 [9.4] years; weight,78.9 [11.7] kg; and BMI, 24.6 [1.9] kg/m(2)). No significant differences were observed between the treatments, with the exception of naloxone-3-glucuronide C(min,ss) values. Mean C(min,ss) values of 22.6 and 24.0 ng/mL were obtained for the OXN combination and naloxone PR tablet, respectively. In the multiple-dose study, the most frequently reported AEs with OXN,oxycodone PR, and naloxone PR were headache (7%, 26%, and 17%, respectively), anorexia (10%, 16%, and 13%), and nausea (10%, 13%, and 7%). CONCLUSIONS: The results from the single-dose study were consistent with the regulatory definition of bioequivalence of the FDCs and single components across the range of doses administered. The pharmacokinetic properties of the OXN FDC were similar to those of oxycodone PR + naloxone PR given as separate formulations, based on the regulatory definition. These findings were consistent with the results of the multiple-dose steady-state bioequivalence study. In this population of healthy volunteers, the pharmacokinetic properties of oxycodone apparently were not significantly influenced by administering oxycodone in a combination product, and the availability of naloxone-3-glucuronide from OXN was similar to that from the naloxone PR tablet. These findings suggest that the coadministration of oxycodone PR and naloxone PR in an FDC would not significantly affect the bioavailability of either of its constituents in these subjects.

A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation.

BACKGROUND: Opioid-induced constipation can have a major negative impact on patients' quality of life. This randomised, double-blinded study evaluated the analgesic efficacy of prolonged-release (PR) oral oxycodone when co-administered with PR oral naloxone, and its impact on opioid-induced constipation in patients with severe chronic pain. Another objective was to identify the optimal dose ratio of oxycodone and naloxone. METHODS: A total of 202 patients with chronic pain (mainly non-cancer related, 2.5% of patients had cancer-related pain) under stable oral oxycodone therapy (40, 60 or 80 mg/day) were randomised to receive 10, 20, 40 mg/day naloxone or placebo. After a 4-week maintenance phase, patients received oxycodone only for 2 weeks. Pain intensity was evaluated using a numerical analogue scale and bowel function was assessed using the bowel function index. RESULTS: No loss of analgesic efficacy with naloxone was observed. Mean pain intensity scores on randomisation were comparable for placebo, 10mg, 20mg and 40 mg naloxone dose, and remained unchanged during treatment. Bowel function improved with increasing naloxone dose. Naloxone 20mg and 40 mg significantly improved bowel function at the end of the maintenance phase compared with placebo (p<0.05). Overall, the combination was well tolerated, with no unexpected adverse events. There was a trend towards an increased incidence of diarrhoea with higher doses of naloxone. The 2:1 oxycodone/naloxone ratio was identified as the most suitable for further development. CONCLUSION: Co-administration of PR oral naloxone and PR oral oxycodone is associated with a significant improvement in bowel function compared with PR oral oxycodone alone, with no reduction in the analgesic efficacy of oxycodone.

Opioid-induced bowel dysfunction in cancer-related pain: causes, consequences, and a novel approach for its management.

Opioids are the mainstay of management for patients with cancer-related pain. Although the analgesic efficacy of opioid therapy is well documented, the recent European Pain in Cancer survey demonstrated that the management of moderate-to-severe pain in patients with cancer is far from optimal. Bowel dysfunction, and importantly constipation, is a common side effect and has a significant impact on the patient's morbidity and quality of life. Nonpharmacological strategies and laxatives are often not effective in the management of opioid-induced constipation (OIC), making it necessary to search for new strategies for the treatment of opioid-induced bowel dysfunction. One promising strategy is the prevention of OIC with peripherally acting opioid antagonists that specifically target the underlying cause of this condition, without affecting centrally mediated analgesia. In recent studies, the novel combination of prolonged-release oral oxycodone and prolonged-release oral naloxone provided effective analgesia with improved bowel function in patients suffering from severe cancer-related and noncancer-related pain. The combination has the potential to improve the quality of pain management significantly in these patients.

Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain.

UNLABELLED: This randomized, double-blind, placebo- and active-controlled, parallel-group study was designed to demonstrate the superiority of oxycodone in combination with naloxone in a prolonged release (PR) formulation over placebo with respect to analgesic efficacy. The active control group was included for sensitivity and safety analyses, and furthermore to compare the analgesic efficacy and bowel function of oxycodone PR/naloxone PR with oxycodone PR alone. The analgesic efficacy was measured as the time from the initial dose of study medication to multiple pain events (ie, inadequate analgesia) in patients with moderate to severe chronic low back pain. The full analysis population consisted of 463 patients. The times to recurrent pain events were significantly longer in the oxycodone PR/naloxone PR group compared with placebo (P < .0001-.0003); oxycodone PR/naloxone PR reduced the risk of pain events by 42% (P < .0001; full analysis population). The appearance of pain events was comparable for oxycodone PR/naloxone PR versus oxycodone PR, confirming that the addition of naloxone PR to oxycodone PR in a combination tablet did not negatively affect analgesic efficacy of the opioid. Furthermore, oxycodone PR/naloxone PR offers benefits in terms of an improvement in bowel function. In a therapeutic area of great unmet need, therefore, the combination tablet of oxycodone PR/naloxone PR offers patients effective analgesia while improving opioid-induced bowel dysfunction. Taken together with the observation that the safety profile of oxycodone PR/naloxone PR is consistent with that expected from other opioid analgesics except opioid-induced constipation, these findings indicate that the addition of naloxone to oxycodone in a PR combination tablet offers improved tolerability. Oxycodone PR/naloxone PR is therefore a promising new treatment approach for the management of chronic pain. PERSPECTIVE: This study evaluated the analgesic efficacy and safety of the combination of oxycodone PR/naloxone PR in chronic nonmalignant pain. Opioids are often reduced in dosage or even discontinued as a result of impaired bowel function, leading to insufficient pain treatment. Not only does oxycodone PR/naloxone PR demonstrate analgesic efficacy comparable with oxycodone PR, but it also improves opioid-induced bowel dysfunction, and may therefore improve the acceptability of long-term opioid treatment for chronic pain.