Abstract
Background
Restless legs syndrome (RLS) is a distressing and common neurological disorder that may have a huge impact in the quality of life of those with frequent and intense symptoms. Patients complain of unpleasant sensations in the legs, at or before bedtime, and feel an urge to move the legs, which improves with movement, such as walking. Symptoms start with the patient at rest (e.g. sitting or lying down), and follow a circadian pattern, increasing during the evening or at night. Many pharmacological intervention are available for RLS, including drugs used to treat Parkinson’s disease (L-Dopa and dopaminergic agonists), epilepsy (anticonvulsants), anxiety (benzodiazepines), and pain (opioids). Dopaminergic drugs are those most frequently used for treatment of RLS, but some patients do not respond effectively and require other medication. Opioids, a class of medications used to treat severe pain, seem to be effective in treating RLS symptoms, and are recommended for patients with severe symptoms, because RLS and pain appear to share the same mechanism in the central nervous system. All available drugs are associated to some degree with side effects, which can impede treatment. Opioids are associated with adverse events such as constipation, tolerance, and dependence. This justifies the conduct of a systematic review to ascertain whether opioids are safe and effective for treatment of RLS.
Objectives
To asses the effects of opioids compared to placebo treatment for restless legs syndrome in adults.
Search methods
We searched the Cochrane Central Register of Controlled trials, CENTRAL 2016, issue 4 and MEDLINE, EMBASE, and LILACS up to April 2016, using a search strategy adapted by Cochraneto identify randomised clinical trials. We checked the references of each study and established personal communication with other authors to identify any additional studies. We considered publications in all languages.
Selection criteria
Randomised controlled clinical trials of opioid treatment in adults with idiopathic RLS.
Data collection and analysis
Two review authors independently screened articles, independently extracted data into a standard form, and assessed for risk of bias. If necessary, they discussed discrepancies with a third researcher to resolve any doubts.
Main results
We included one randomised clinical trial (N = 304 randomised; 204 completed; 276 analysed) that evaluated opioids (prolonged release oxycodone/naloxone) versus placebo. After 12 weeks, RSL symptoms had improved more in the drug group than in the placebo group (using the IRLSSS: MD -7.0; 95% CI -9.69 to -4.31 and the CGI: MD -1.11; 95% CI -1.49 to -0.73). More patients in the drug group than in the placebo group were drug responders (using the IRLSSS: RR 1.82; 95% CI 1.37 to 2.42 and the CGI: RR1.92; 95% ICI 1.49 to 2.48). The proportion of remitters was greater in the drug group than in the placebo group (using the IRLSSS: RR 2.14; 95% CI 1.45 to 3.16). Quality of life scores also improved more in the drug group than in the placebo group (MD -0.73; 95% CI -1.1 to -0.36). Quality of sleep was improved more in the drug group measured by sleep adequacy (MD -0.74; 95% CI -1.15 to -0.33), and sleep quantity (MD 0.89; 95% CI 0.52 to 1.26).
There was no difference between groups for daytime somnolence, trouble staying awake during the day, or naps during the day. More adverse events were reported in the drug group (RR 1.22; 95% CI 1.07 to 1.39). The major adverse events were gastrointestinal problems, fatigue, and headache.
Authors’ conclusions
Opioids seem to be effective for treating RLS symptoms, but there are no definitive data regarding the important problem of safety. This conclusion is based on only one study with a high dropout rate (low quality evidence).
Plain language summary
Opiods for restless legs syndrome
Background
Restless legs syndrome (RLS) is a very common neurological disorder in which patients complain of an intense need to move their legs, and unpleasant sensations felt deep in their legs, all occurring while at rest, mostly at bedtime. The number of patients complaining of RLS varies according to race, gender, age, country, and health status. About 5% to 10% of people are affected; , and, among these, 2% to 5% need continual pharmacological treatment (medication). When RLS does not respond to medications generally used for Parkinsons Disease and epilepsy, their doctors often prescribe opioids.
Question
Are opioids effective and safe for people with RLS?
Methods
We searched the literature for studies in any language, published or not, that considered opioids for the treatment of RLS
Results
We included one randomised controlled clinical trial with moderate risk of bias that tested a combination of oxycodone and naloxone against placebo capsules, taken twice daily in participants whodid not respond to more usual medications. Researchers used the International RLS severity scale to find out if patients were improved after 12 weeks of treatment. Particpants receiving the combined oxycodone and naloxone reported improvement in RLS symptoms, Quality of life, and sleep quality; 42% of the drug group were symptom-free.
Discussion
The study was well designed overall, but was at a high risk of bias due to the high percentage of participants who withdrew from treatment (attrition bias). Eighty-four percent of the drug group developed adverse events, which were mostly related to the gastrointestinal system, headache, fatigue, and sleepiness (somnolence); 9.8% left the study because of the adverse events.
Conclusion
The use of opioids for the treatment of RLS in patients resistant to conventional treatment is supported by low-quality evidence. Prescription of these medications should be based on clinical experience, and caution used due to the potential for abuse, dependency, and adverse events. No patient on opioids complained that their symptoms worsened.
