Oral Prolonged Release Oxycodone / Naloxone Combination Reduces Opioid-Induced Constipation In Severe Chronic Pain Patients, With No Loss Of Analgesia

Main Category: Back Pain
Also Included In: GastroIntestinal / Gastroenterology;  Clinical Trials / Drug Trials
Article Date: 17 Apr 2008 - 1:00 PDT

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The addition of oral prolonged release (PR) naloxone, an opioid antagonist, to the opioid PR oxycodone significantly reduces opioid-induced constipation (OIC) in severe chronic pain patients without affecting analgesia, according to three new studies presented at this year's British Pain Society Annual Scientific Meeting in Liverpool.

The data were welcomed by Dr Beverly Collett, Consultant in Pain Management at Leicester Royal Infirmary, who commented "These findings are very encouraging. OIC is a well known side effect of all opioids and can be distressing and debilitating enough to cause patients to reduce their doses, which often means less than optimal pain relief. This combination treatment offers a promising new approach to pain management through delivering full efficacy while minimising OIC".

Improvement in Bowel Function Index with increasing PR naloxone dose

In this controlled, double-blind study1, 202 patients with chronic pain under stable oxycodone therapy (40, 60, 80 mg/day) were randomised to 10, 20, or 40 mg/day naloxone or placebo leading to the following oxycodone / naloxone ratios: 1/1, 1.5/1, 2/1, 3/1, 4/1, 6/1, 8/1 and 40 mg/placebo, 60 mg/placebo, 80 mg/placebo. OIC was evaluated from the mean of the three components of the Bowel Function Index (BFI) - ease of defaecation, feeling of incomplete bowel evacuation and patient judgment of constipation - each assessed subjectively using a 0-100 numerical analogue scale (NAS; the greater the score, the worse the OIC).

Bowel function improved with increasing PR naloxone dose. Average BFI scores at pre-randomisation and after four weeks of combination therapy are shown below (p<0.05 for 20 mg and 40 mg PR naloxone vs. placebo). Importantly no loss of analgesic efficacy with naloxone was observed.

Average BFI scores

Placebo

-- Pre-randomisation - 48.0
-- After four weeks of therapy - 45.4

10 mg naloxone

-- Pre-randomisation - 52.8
-- After four weeks of therapy - 40.3

20 mg naloxone

-- Pre-randomisation - 49.4
-- After four weeks of therapy - 31.3



-- Pre-randomisation - 46.2
-- After four weeks of therapy - 26.1

While it's highly effective for treating severe chronic pain, oxycodone, like all other opioids, may cause OIC through its action on opioid receptors in the gastrointestinal tract which slow down gastric motility. The opioid receptor antagonist naloxone acts by blocking the action of oxycodone in the gut but since naloxone is broken down in the liver it has negligible systemic bioavailability, thus reducing or preventing OIC without hindering analgesia.

2:1 ratio most promising

A second study focused on the combination of PR oxycodone and PR naloxone in a 2:1 ratio as best suited for further development. The 2:1 ratio was rated as good or very good (using a rating scale of 1=very good to 7=very poor) regarding efficacy by 59.4% of investigators and patients alike2. Similar results were obtained for tolerability of this combination, with 68.7% of investigators and 68.8% of patients rating the tolerability of the 2:1 ratio as good or very good.

Long-term analgesic efficacy and tolerability preserved

In a third study3, 463 patients with moderate to severe, chronic non-malignant low back pain were randomised to one of three treatment groups: 20/10 or 40/20 mg/day oxycodone PR/naloxone PR (2:1 ratio), or oxycodone PR/placebo (20 or 40 mg/day oxycodone). After a 12-week double-blind maintenance phase, 380 patients entered a 12 month open-label treatment extension phase to assess the long-term efficacy and tolerability of oxycodone PR/naloxone PR. During both phases, oxycodone PR/naloxone PR's efficacy and tolerability profiles were comparable to that of oxycodone PR alone and consistent with that expected from other opioids.

The oxycodone / naloxone combination in a 2:1 ratio is currently under investigation by Napp Pharmaceuticals Limited as a fixed dose tablet.

About Napp Pharmaceuticals Limited

Napp Pharmaceuticals Limited is part of the Purdue/Mundipharma/Napp independent associated companies that have been developing vital new drugs for more than half a century. Napp pioneered the creation of prolonged release analgesics for the relief of severe pain. Napp also produces a number of other medicines for the treatment of cardiovascular disease, respiratory disease and gastrointestinal problems. For more information: http://www.napp.co.uk

References

1. Mueller-Lissner S, Leyendecker P, Hopp M et al. Oral prolonged release (PR) oxycodone/naloxone combination reduces opioid-induced constipation (OIC) in patients with severe chronic pain. Poster at BPS

2. Nadstawek J, Leyendecker P, Hopp M et al. Patient assessment of the efficacy and tolerability of coadministered prolonged release oral oxycodone and naloxone in severe chronic pain. Poster at BPS

3. Meissner W, Hopp M, Leyendecker P et al. Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release (PR) tablets in patients with moderate to severe chronic pain. Poster at BPS

What are Opioids?

For more information on what opioids are, and opioid-induced constipation (OIC), please see:
All About Opioids and Opioid-Induced Constipation (OIC)

Napp Pharmaceuticals Limited

View drug information on Oxycodone and Aspirin.