Prolonged release oxycodone–naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension

doi:10.1016/S1474-4422(13)70239-4

The Lancet Neurology

Volume 12, Issue 12, December 2013, Pages 1141-1150

https://doi.org/10.1016/S1474-4422(13)70239-4 Get rights and content

Summary

Background

Opioids are a potential new treatment for severe restless legs syndrome. We investigated the efficacy and safety of a fixed-dose combination of prolonged release oxycodone–naloxone for patients with severe restless legs syndrome inadequately controlled by previous, mainly dopaminergic, treatment.

Methods

This multicentre study consisted of a 12-week randomised, double-blind, placebo-controlled trial and 40-week open-label extension phase done at 55 sites in Austria, Germany, Spain, and Sweden. Patients had symptoms for at least 6 months and an International RLS Study Group severity rating scale sum score of at least 15; patients with severe chronic obstructive pulmonary disease or a history of sleep apnoea syndrome were excluded. Patients were randomly assigned (1:1) to either study drug or matched placebo with a validated interactive response technology system in block sizes of four. Study drug was oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated according to investigator's opinion to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day; in the extension, all patients started on oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day. The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at 12 weeks. This study is registered with ClinicalTrials.gov (number NCT01112644) and with EudraCT (number 2009-011107-23).

Findings

We screened 495 patients, of whom 306 were randomly assigned and 276 included in the primary analysis (132 to prolonged release oxycodone–naloxone vs 144 to placebo). 197 patients participated in the open-label extension. Mean International RLS Study Group rating scale sum score at randomisation was 31·6 (SD 4·5); mean change after 12 weeks was −16·5 (SD 11·3) in the prolonged release oxycodone–naloxone group and −9·4 (SD 10·9) in the placebo group (mean difference between groups at 12 weeks 8·15, 95% CI 5·46–10·85; p<0·0001). After the extension phase, mean sum score was 9·7 (SD 7·8). Treatment-related adverse events occurred in 109 of 150 (73%) patients in the prolonged release oxycodone–naloxone group and 66 of 154 (43%) in the placebo group during the double-blind phase; during the extension phase, 112 of 197 (57%) had treatment-related adverse events. Five of 306 (2%) patients had serious treatment-related adverse events when taking prolonged release oxycodone–naloxone (vomiting with concurrent duodenal ulcer, constipation, subileus, ileus, acute flank pain).

Interpretation

Prolonged release oxycodone–naloxone was efficacious for short-term treatment of patients with severe restless legs syndrome inadequately controlled with previous treatment and the safety profile was as expected. Our study also provides evidence of open-label long-term efficacy of this treatment. Opioids can be used to treat patients with severe restless legs syndrome who have had no benefit with first-line drugs.

Funding

Mundipharma Research.

Introduction

Dopaminergic drugs are the recommended first-line treatment for patients with restless legs syndrome.¹ Although initially effective, long-term dopaminergic treatment can result in loss of efficacy, difficulties with tolerability, or augmentation (worsening of symptoms after initial response to treatment),² necessitating a change of drug regimen. The treating physician faces the difficult question of whether to use off-label drugs such as gabapentin, pregabalin, benzodiazepines, or opioids—either alone or in combination—or to increase the dose of dopaminergic drug, which can lead to augmentation.

Opioids have long been used to treat patients with severe restless legs syndrome for whom other drugs have failed. They are recommended as off-label second-line treatment3, 4 although clinical evidence of their effectiveness is scarce—efficacy and safety of opioids for treatment of restless legs syndrome have been investigated in only one double-blind study and a few open-label or retrospective case series.5, 6, 7, 8, 9

Although opioids are usually well tolerated, bowel dysfunction can occur.¹⁰ However, a fixed-dose combination—prolonged release oxycodone–naloxone—improves bowel dysfunction compared with oxycodone, without compromise of analgesia in patients with pain.11, 12 We investigated the efficacy and safety of prolonged release oxycodone–naloxone for treatment of patients with inadequately controlled severe restless legs syndrome who had daytime symptoms.

Section snippets

Study design and participants

We did this 12-week randomised, double-blind, placebo-controlled study with a subsequent 40-week open-label extension at 55 sites (hospitals and specialised private neurology practices) in Austria, Germany, Spain, and Sweden from April, 2010, to March, 2012. For the double-blind phase, we enrolled adult patients with a diagnosis of restless legs syndrome according to essential and supportive diagnostic criteria¹³ as assessed by the RLS diagnostic index¹⁴ (score ≥11; appendix). Patients had to

Results

We screened 495 patients, of whom 306 were enrolled and randomly assigned (figure 1). The double-blind safety population consisted of 304 patients (mean age 62·4 years, SD 11·2); 150 assigned to prolonged release oxycodone–naloxone, 154 assigned to placebo. 204 (67%) of these patients completed 12 weeks of treatment, with discontinuation more common in the placebo group than in the prolonged release oxycodone–naloxone group (57/154 [37%] vs 43/150 [29%]). The efficacy analysis included 132

Discussion

Our findings show a significant and sustained treatment effect of prolonged release oxycodone–naloxone for patients with severe restless legs syndrome insufficiently treated with first-line drugs. The 16·6 point reduction on the International RLS Study Group severity rating scale during the double-blind phase translates into a significant clinical improvement from “very severe” at start of treatment to on average “mild” or “moderate” at the end of the double-blind phase. At the end of the

References (55)

N Silver et al.
A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome
Sleep Med
(2011)
RP Allen et al.
Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health
Sleep Med
(2003)
H Beneš et al.
Validation of an algorithm for the diagnosis of restless legs syndrome: The Restless Legs Syndrome-Diagnostic Index (RLS-DI)
Sleep Med
(2009)
D García-Borreguero et al.
Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine—International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute
Sleep Med
(2007)
RH Dworkin et al.
Core outcome measures for chronic pain clinical trials: IMMPACT recommendations
Pain
(2005)
RD Hays et al.
Psychometric properties of the Medical Outcomes Study Sleep measure
Sleep Med
(2005)
D García-Borreguero et al.
Validation of the Augmentation Severity Rating Scale (ASRS): a multicentric, prospective study with levodopa on restless legs syndrome
Sleep Med
(2007)
GR Wunderlich et al.
An item response analysis of the international restless legs syndrome study group rating scale for restless legs syndrome
Sleep Med
(2005)
E Kalso et al.
Opioids in chronic non-cancer pain: systematic review of efficacy and safety
Pain
(2004)
D García-Borreguero et al.
The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group
Sleep Med
(2013)

H Lauerma et al.

Treatment of restless legs syndrome with tramadol: an open study

J Clin Psychiatry

(1999)

WG Ondo

Methadone for refractory restless legs syndrome

Mov Disord

(2005)

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SRMD are common. Treatments are well established for RLS, PLMD, and perhaps bruxism, but the same cannot be said for leg cramps or rhythmic movement disorder. Treatment algorithms for restless legs syndrome in adults are reviewed. It must be recognized that placebo response in RLS is high to many therapeutic interventions, whether pharmacological or non-pharmacologic. Double-blind, placebo-controlled RLS trials should be the standard for determining efficacy. Iron status should be assessed by measurement of serum ferritin and values <50 ng mL⁻¹ should be replaced. Practice guidelines consider α2δ and DA agents to be the first-line therapy for patients with moderate-to-severe RLS symptoms. Avoidance of and management of dopamine-related augmentation is discussed. Alpha-2-delta and dopamine agonists also appear to reduce PLMS and improve PLMD. High quality therapeutic studies on best practices are not available for other SRMD. Referral for dental services is recommended for sleep bruxism.
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ArticlesProlonged release oxycodone–naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

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Prolonged release oxycodone–naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension