Key points from the evidence | Restless legs syndrome: Oxycodone/naloxone prolonged release | Advice

Summary

In a 12‑week randomised controlled trial (RCT) in people with severe restless legs syndrome (RLS), there was a moderate improvement in the score on the International RLS study group severity rating scale with oxycodone/naloxone prolonged release tablets compared with placebo. Adverse effects such as fatigue, constipation and nausea were very common. As with all opioids, there is a risk that people may develop opioid dependence. There are no published studies which compare oxycodone/naloxone with other possible treatments for restless legs syndrome and there is limited long‑term efficacy and safety data for its use in this indication.

Regulatory status: Oxycodone/naloxone prolonged release tablets (Targinact) were originally launched in the UK in 2009 for the treatment of severe pain which can be adequately managed only with opioid analgesics. The license extension for use in restless legs syndrome was granted in the UK in April 2015.

Effectiveness

There was a statistically significant reduction in the International RLS study group severity rating scale sum score with oxycodone/naloxone compared with placebo (treatment difference 8.15 [on a scale from 0 to 40]; 1 RCT; 12 weeks; n=306); described as a moderate effect in the European Medicines Agency (EMA) referral assessment report.
There were statistically significant improvements in sleep scores, pain scores, quality of life scores and daytime symptoms with oxycodone/naloxone compared with placebo; the clinical significance of these improvements is unclear.

Safety

People taking oxycodone/naloxone for restless legs syndrome should have their treatment evaluated at least every 3 months and it should only be continued if the benefit is considered to outweigh the risks.
The contraindications to the use of oxycodone/naloxone in the summary of product characteristics (SPC) are in‑line with the usual contraindications of opioids as a drug class.
The SPC lists the following very common adverse effects (1 in 10 or more) when oxycodone/naloxone is used for the treatment of restless legs syndrome: headache, somnolence, vertigo, hot flushes, blood pressure alterations, constipation, nausea, flatulence, hyperhidrosis and fatigue.
The National Patient Safety Agency (NPSA) issued a rapid response report in July 2008 on reducing dosing errors with opioid analgesics.

Patient factors

Oxycodone is a strong opioid and about 1.5 times the potency of oral morphine. As with all opioids, there is a risk that people may develop opioid dependence.
Oxycodone can impair cognitive function and affect a person's ability to drive safely. People taking oxycodone/naloxone must be informed that if their treatment causes somnolence they must not drive or take part in activities where impaired alertness may put themselves or others at risk.
Loss of efficacy commonly occurs for all drugs in the treatment of restless legs syndrome.

Resource implications

Costs for 28 days treatment with oxycodone/naloxone for restless legs syndrome ranges from £21.16 to £126.94 depending on the dose.
Costs for 28 days treatment of pregabalin, gabapentin, clonazepam and codeine phosphate (all off‑label use) depend on the drug choice and dosage used. For example, pregabalin capsules 75 mg twice daily cost £64.40 and codeine phosphate tablets 30 mg twice daily cost £2.80.

Introduction and current guidance

Restless legs syndrome is a neurological disorder characterised by an irresistible urge to move the limbs (usually the legs) accompanied by uncomfortable sensations. Symptoms are typically worse in the evenings, and are often associated with sleep disturbance. In most people with restless legs syndrome there is no apparent underlying cause. Frequency of symptoms vary considerably from less than once a month to daily, and severity of symptoms can vary from mildly annoying to disabling. For people with mild symptoms, explanation, reassurance and self‑help measures may be sufficient. First line drug treatment options for people with frequent or daily symptoms include non‑ergot dopamine agonists (for example, pramipexole, ropinirole or rotigotine) (NICE Clinical Knowledge Summary).

Full text of introduction and current guidance.

Product overview

Oxycodone/naloxone prolonged release tablets (Targinact) are licensed for the second line symptomatic treatment of adults with severe to very severe idiopathic restless legs syndrome after failure of dopaminergic therapy (SPC: Targinact). They are only licensed for use in adults who have had restless leg syndrome for at least 6 months and who have daily symptoms including daytime symptoms on at least 4 days a week. The SPC recommends that the usual starting dose for restless legs syndrome is oxycodone/naloxone 5 mg/2.5 mg at 12 hourly intervals and the maximum daily dose is oxycodone/naloxone 60 mg/30 mg (usually as 30 mg/15 mg at 12 hourly intervals). This is lower than the maximum daily dose for the pain indication. There is no clinical experience of using oxycodone/naloxone for longer than 12 months to treat restless legs syndrome; the SPC recommends that before continuing treatment beyond 12 months, a 'discharge regimen' should be considered, to establish if continued treatment with oxycodone/naloxone is indicated (SPC: Targinact).

Full text of product overview.

Evidence review

This evidence summary is based on a 12‑week double-blind RCT which compared oxycodone/naloxone with placebo in 306 adults with restless legs syndrome that had not responded to previous treatment (Trenkwalder et al. 2013). This study also had a 40‑week open label extension phase which included 197 participants, 157 of whom completed 40 weeks of treatment. During the double‑blind RCT phase of the study the mean daily dose in the active treatment group was oxycodone/naloxone 22/11 mg. In the open‑label phase the mean daily dose was oxycodone/naloxone 18/9 mg.
For the primary outcome of change from baseline to week 12 in the International restless legs syndrome (RLS) study group severity rating scale sum score there was a statistically significant improvement with oxycodone/naloxone compared with placebo. This scale ranges from 0 (no symptoms) to 40 (very severe symptoms). In the oxycodone/naloxone group the mean score reduced from 31.7 at baseline to 15.1 at week 12; in the placebo group it reduced from 31.6 to 22.1. The estimated mean treatment difference between the 2 groups at week 12 was 8.15 (95% CI 5.46 to 10.85; p<0.0001), described as a moderate effect in the European Medicines Agency (EMA) referral assessment report for oxycodone/naloxone prolonged‑release tablets.
There was an approximately 43 minute increase in time asleep in the oxycodone/naloxone group compared with the placebo group. At baseline, sleep quantity was 5.15 and 4.97 hours in the oxycodone/naloxone and placebo groups respectively. After 12 weeks treatment, this increased to 6.25 and 5.36 hours in the oxycodone/naloxone and placebo groups respectively (p<0.0001). However, there was no statistically significant difference between the 2 groups at week 12 for feeling drowsy or sleepy during the day.
There were statistically significant improvements in pain scores and daytime symptoms with oxycodone/naloxone compared with placebo. On a scale from 0 (no pain) to 10 (worst imaginable pain) there was a reduction in the oxycodone/naloxone and placebo groups respectively from 6.57 and 6.54 at baseline to 2.65 and 4.63 at 12 weeks (p<0.0001 for comparison at 12 weeks). On a scale from 0 (not present) to 10 (very severe) for daytime symptoms at rest there was a reduction in the oxycodone/naloxone and placebo groups respectively from 6.70 and 6.69 to 2.50 and 4.44 (p<0.0001 for comparison at 12 weeks).
The EMA referral assessment report for oxycodone/naloxone prolonged release tablets states that a review of the safety data from the double‑blind RCT phase and open‑label extension phase of Trenkwalder et al. (2013) showed that the safety profile when used for restless legs syndrome was in‑line with the known safety profile when used for pain. See the SPC for further information on contraindications, potential interactions and adverse effects of oxycodone/naloxone.
Oxycodone/naloxone has only been compared with placebo. There are no published studies which compare it with other possible treatments for restless legs syndrome. Efficacy and safety data from a double‑blind RCT are only available for relatively short‑term use in restless legs syndrome (12 weeks). Trenkwalder et al. (2013) did include a 40‑week open‑label extension phase, however only 85 participants had active treatment for 52 weeks.

Full text of evidence review.

Context

Oxycodone/naloxone should only be considered after failure of dopaminergic therapy. Other non‑dopaminergic drug treatment options for restless legs syndrome include off‑label use of pregabalin, gabapentin, clonazepam or weak opioids such as codeine. Apart from oxycodone/naloxone prolonged‑release tablets, no other opioid preparations are specifically licensed for the treatment of restless legs syndrome.

Full text of context.

Estimated impact for the NHS

Oxycodone/naloxone is a potential second‑line treatment option for people with severe to very severe restless legs syndrome. However, the risk of opioid dependence will need to be considered and people prescribed this treatment will need to be reviewed on a regular basis in‑line with the SPC to assess if the benefits of treatment are continuing to outweigh the risks. Oxycodone is a strong opioid and about 1.5 times the potency of oral morphine (British National Formulary [BNF]). As recommended in the NPSA rapid response report on reducing dosing errors with opioid analgesics, health professionals should check that the intended opioid dose is safe for the individual patient whenever opioids including oxycodone are prescribed, dispensed or administered.

Based on market research conducted in 2013 amongst neurologists, the manufacturer estimates that approximately 1133 patients with restless legs syndrome or 2.1% of those treated with first line dopamine agonists would be considered for treatment with oxycodone/naloxone (Personal communication: Napp Pharmaceuticals August 2015).

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.