NPC Archive Item: Prolonged release oxycodone/naloxone▼ in cancer pain

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22 December 2011

A 4 week clinical trial in patients with moderate to severe cancer pain found some limited benefit in constipation symptoms with prolonged release (PR) oxycodone/naloxone▼ compared with PR oxycodone alone. There was no difference in pain relief between the two groups. It is not known whether PR oxycodone/naloxone offers any advantage to the use of PR oxycodone, or other strong opioids (e.g. modified-release morphine), when given with prophylactic laxatives.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Healthcare professionals should continue to manage pain in patients with cancer according to WHO’s pain relief ladder, where strong opioids are recommended for relief of moderate to severe pain. Although oxycodone can be considered as an alternative, the SIGN guideline for control of pain in adults with cancer recommends that morphine should be used first-line for oral use in severe cancer pain. There is a lack of evidence from high quality comparative trials that other opioids have advantages over morphine in terms of either efficacy or side effects.

While most patients who are prescribed opioids for moderate to severe pain will develop constipation, there is uncertainty about the best management of constipation in these patients. The SIGN guideline suggests that the best prophylactic treatment for opioid-induced constipation is a combination of stimulant and softening laxatives. The present study provides no reason to change this practice. NICE is currently developing a guideline on the use of opioids in palliative care, which is due for publication in May 2012.

What is the background to this?
PR oxycodone/naloxone contains a combination of a strong opioid (oxycodone) and an opioid antagonist (naloxone). Naloxone (which has no significant central effect when given orally and it is rapidly metabolised on first pass through the liver) is included with the aim of reducing the likelihood of opioid-induced constipation, without reducing the analgesic effect of the oxycodone. PR oxycodone/naloxone needs to be given cautiously and monitored carefully in patients with mild hepatic or renal impairment (and is contraindicated in moderate to severe hepatic impairment) as plasma levels of naloxone may be raised, which can antagonise the analgesic effect of oxycodone.

Previous studies, mainly in people with chronic musculoskeletal pain, have demonstrated that PR oxycodone/naloxone has similar analgesic properties and a similar adverse event profile to PR oxycodone alone when used at the same oxycodone dose. The addition of naloxone reduced but did not eliminate the prevalence of constipation. The present double-blind, randomised controlled trial (RCT) compared the effects of PR oxycodone/naloxone with PR oxycodone alone over a four-week period in 185 patients with cancer and moderate to severe cancer pain.

What does this study claim?
After four weeks, the change in Bowel Function Index (BFI) scores (primary endpoint) from baseline were statistically significantly lower in the PR oxycodone/naloxone group compared with the PR oxycodone group (–11.14, 95% confidence interval [CI] –19.03 to –3.24). Although there was an average 20% reduction in laxative use (secondary endpoint) in the PR oxycodone/naloxone group relative to the PR oxycodone group, this difference was not significantly different (p=0.17).

There was no significant difference in the change in Brief Pain Inventory Short-Form scores (BPI-SF) between groups at 4 weeks (primary endpoint, –0.011, 90% confidence interval –0.47 to 0.45, p<0.01) and it was concluded that PR oxycodone/naloxone was not inferior to PR oxycodone alone with regard to pain relief.

Adverse event related to study treatment occurred at a similar frequency and overall quality of life scores were similar between groups during the study.

So what?
This short-term RCT (4-weeks) demonstrated that PR oxycodone/naloxone had similar analgesic properties to PR oxycodone in patients with cancer, and was accompanied by some reduction in constipation symptoms. The difference in the reduction in the primary outcome between groups used to assess the change in constipation symptoms (BFI) was statistically significant between groups. Although this difference was of borderline clinical significance (i.e. reported to be at least 12 points), the authors considered the difference clinically relevant after taking other analyses into account. Although other secondary outcome results and other analyses do support a reduction in constipation symptoms, the statement given by the authors that the difference is clinically relevant is not robust.

The results of this trial, although only short-term, are broadly consistent with previous studies in non-cancer patients. However, as with other studies, it does not address whether or not PR oxycodone/naloxone offers any benefits over standard treatment with a strong opioid (e.g. modified-release morphine) and conventional prophylactic laxative treatment. Oxycodone is one of the strong opioids that can be considered as an alternative to morphine, however, a recent systematic review of oxycodone in the management of cancer pain found no evidence of a significant difference in analgesia or adverse effects between oxycodone and morphine or hydromorphone.

Although this study allowed the use of bisacodyl as a rescue measure, preventative laxatives were not used (e.g. regular use of stool softeners). A Drug and Therapeutics Bulletin review of PR oxycodone/naloxone in 2010, recognised this limitation when seen in earlier studies and, when the greater cost compared to standard opioid plus regular laxative treatment was taken into account, could see “no reason why PR oxycodone/naloxone should be prescribed”. In 2009 the Scottish Medicines Consortium (SMC) did not recommend PR oxycodone/naloxone for use in NHS Scotland, stating that “the addition of naloxone to oxycodone did not impair analgesia and improved bowel function when patients were not receiving regular laxative therapy. However the clinical benefit in patients receiving regular laxative therapy is uncertain and the manufacturer did not present a sufficiently robust economic analysis to gain acceptance by SMC”.

Study details
Ahnedzai SH, et al. 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. Palliat Med published online 21 September 2011. DOI: 10.1177/0269216311418869

Randomised, double-blind, active-controlled, double-dummy, parallel-group study.

Patients (n=185) with cancer and moderate to severe chronic cancer pain requiring round-the-clock opioid therapy. Mean ages were 62 and 64 in the PR oxycodone/naloxone and PR oxycodone groups respectively.

Intervention and comparison:
Patients were randomised to PR Oxycodone/naloxone or PR Oxycodone up to 120 mg/day oxycodone for four weeks. PR oxycodone was available for rescue analgesia and bisacodyl was available as laxative rescue medication.

Outcomes and results
Based on a modified intention-to-treat population (excluding 28 patients who discontinued early after randomisation) the change in Bowel Function Index (BFI) scores (a primary endpoint) from baseline after four weeks were statistically significantly lower in the PR oxycodone/naloxone group compared with the PR oxycodone group (–11.14, 95% confidence interval [CI] –19.03 to –3.24).

There was no significant difference in the change in Brief Pain Inventory Short-Form scores (BPI-SF) between groups at four weeks (a primary endpoint, –0.011, 90% confidence interval –0.47 to 0.45, p<0.01); PR oxycodone/naloxone was non-inferior to PR oxycodone in this regard.

The proportion of patients with adverse events related to study medication was similar (PR oxycodone/naloxone 34.8%, PR oxycodone 38%: serious adverse events 3.3% and 5.4% respectively).

There was no significant difference in laxative (bisacodyl) use (PR oxycodone/naloxone 26 mg, PR oxycodone 33 mg) during the study (p=0.17). Patient assessment of constipation symptom scores were statistically significantly lower with PR oxycodone/naloxone after four weeks than with PR oxycodone (total symptom scores and frequency of symptoms, p<0.01). The use of rescue analgesia was low in both groups and was not significantly different. Quality of life scores using a range of instruments were similar for both treatment groups over time.

Sponsorship: Funded by Mundipharma Research GmbH & Co. KG

Further information can be found on NHS Evidence and in the pain overview e-learning materials on the NPC website

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