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The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome

      Abstract

      Restless legs syndrome (RLS) is a distinct disorder, differing from chronic pain in many ways. Refractory RLS is characterized by unresponsiveness to dopamine agonists or alpha-2-delta ligands due to inadequate efficacy, augmentation, or adverse effects. This may result in severely impaired quality of life, profound insomnia, and suicidal depression. Opioid therapy is a mainstay in the management of these patients. This article summarizes the basic science and clinical evidence in support of their use, including the positive result of a large controlled multicenter study of 306 subjects, and outlines an approach to their use in clinical practice. Treatable explanations for RLS refractoriness, such as low iron stores, and other therapeutic options, such as combination therapy, should be considered before prescribing opioids. The agents most commonly used are oxycodone and methadone, but tramadol, codeine, morphine, and hydrocodone can also be considered. Controlled-release medication should be used for evening dosage and short-acting drugs, if needed, during the day. Effective doses are considerably lower than used for chronic pain (oxycodone 10-30 mg daily; methadone 5-20 mg daily) and the risk of opioid use disorder is relatively low. However, sensible precautions should be undertaken, including assessing opioid risk with standard questionnaires, using an opioid contract, using urine drug screens, consulting state prescription drug monitoring programs, and frequent reevaluation of effectiveness and side effects. Opioid use in selected patients with refractory RLS may be life-transforming with favorable risk-benefit ratio.

      Abbreviations and Acronyms:

      RLS (restless legs syndrome)
      Restless legs syndrome (RLS) is a common disorder, with about 2% of the population afflicted with symptoms occurring at least twice a week and resulting in moderate or severe distress.
      • Allen R.P.
      • Bharmal M.
      • Calloway M.
      Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States.
      • Allen R.P.
      • Stillman P.
      • Myers A.J.
      Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: prevalence and characteristics.
      Most patients obtain at least initial relief with first-line agents, specified as dopamine agonists (pramipexole, ropinirole, rotigotine patch) and alpha-2-delta ligands (gabapentin, gabapentin enacarbil, pregabalin).
      • Silber M.H.
      • Becker P.M.
      • Earley C.
      • Garcia-Borreguero D.
      • Ondo W.G.
      Medical Advisory Board of the Willis-Ekbom Disease Foundation
      Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome.
      However, adverse effects prevent their use in some patients and the therapeutic effect can wear off with time. Importantly, as many as 50% to 70% of patients using dopamine agonists develop drug-induced augmentation over 10 years,
      • Lipford M.C.
      • Silber M.H.
      Long-term use of pramipexole in the management of restless legs syndrome.
      • Silver N.
      • Allen R.P.
      • Senerth J.
      • Earley C.J.
      A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome.
      characterized by earlier symptom onset, involvement of arms and trunk, and shorter duration of relief from treatment. When RLS becomes unresponsive to monotherapy with first-line agents of both classes due to inadequate efficacy, augmentation, or adverse effects, it is considered refractory to treatment.
      • Silber M.H.
      • Becker P.M.
      • Earley C.
      • Garcia-Borreguero D.
      • Ondo W.G.
      Medical Advisory Board of the Willis-Ekbom Disease Foundation
      Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome.
      The worsening epidemic of prescription and illicit opioid abuse has made many caregivers wary of prescribing opioids. Current consensus is that opioids have only a limited role in the management of chronic pain in the absence of malignancy or end-of-life care.
      • Dowell D.
      • Haegerich T.M.
      • Chou R.
      CDC guideline for prescribing opioids for chronic pain—United States, 2016.
      In contrast, published clinical trials and case series demonstrate the considerable effectiveness of opioids in treating refractory RLS, a distinct disorder with a different etiology, pathophysiology, and epidemiology from chronic pain syndromes.
      • Allen R.P.
      Restless legs syndrome/Willis-Ekbom disease pathophysiology.
      Differentiating features of the disorder include the identification of several risk alleles by genomewide association studies, brain iron deficiency, and abnormalities in the dopamine system. Despite this, patients with RLS frequently report difficulty obtaining opioid prescriptions from providers.
      The aim of this article is to summarize the basic science and clinical evidence supporting the use of opioids for the treatment of refractory RLS and to outline a responsible approach to their use. It is our opinion that the risk-benefit ratio of opioid use in patients with RLS who are selected according to our guidelines is positive and that risk can be minimized as long as reasonable precautions are followed.

      Clinical Need

      Refractory RLS is a common clinical problem. The following case scenario illustrates a typical patient with RLS refractory to first-line therapies who is an excellent candidate for opioid therapy.
      A 59-year-old woman with a family history of RLS in her father and brother presented with worsening RLS symptoms over 25 years. Pramipexole had been prescribed 15 years previously at a time when her symptoms occurred only after going to bed, delaying sleep onset by an hour. Initially a dose of 0.25 mg taken 2 hours before going to bed gave full relief. As time passed, symptoms began earlier in the day and eventually started whenever she sat down after 1 pm, also occurring in her arms. The dose of pramipexole had been increased to 1 mg daily. Pramipexole was discontinued a year before presentation and a rotigotine patch was substituted at 3 mg daily. Initially this was effective but over several months the effect wore off with recurrence of symptoms during the day and night, persisting after withdrawal of the drug. Pregabalin 300 mg in the evening failed to control symptoms adequately and caused feelings of depression. She did not snore and was not obese. Serum ferritin level was 135 μg/mL and transferrin saturation was 27%. At the time of presentation, the patient was sleeping only 3 hours a night and could not sit down without symptoms after 1 pm.

      Preclinical Studies: Opioid Pathophysiology in RLS

      Opioid medications stimulate G-protein–linked mu, kappa, delta,
      • Law P.Y.
      • Wong Y.H.
      • Loh H.H.
      Molecular mechanisms and regulation of opioid receptor signaling.
      and opioid receptor like-1 receptors,
      • Meunier J.C.
      • Mollereau C.
      • Toll L.
      • et al.
      Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor.
      which are found throughout the nervous system, especially in the spinal cord, brainstem, and thalamus. These are preserved throughout evolution, and serve other purposes in addition to their overt human clinical role in analgesia. Pathophysiologic understanding of RLS is incomplete and likely multifactorial.
      • Allen R.P.
      Restless legs syndrome/Willis-Ekbom disease pathophysiology.
      Major clues include therapeutic responses, most specifically with dopaminergics, iron, and opioids. Other lines of research demonstrate abnormalities in iron, dopamine, hypocretin, opioid, and glutamatergic systems, and peripheral nerve sensory processing.
      In a postmortem study evaluating opioid pathology,
      • Walters A.S.
      • Ondo W.G.
      • Zhu W.
      • Le W.
      Does the endogenous opiate system play a role in the restless legs syndrome? A pilot post-mortem study.
      5 brains from patients with RLS and 6 brains from controls without other neurological disease were stained with antibodies for beta-endorphin, met-encephalin, and leu-encephalin, and cell numbers counted in a blinded fashion. In the thalamus, beta-endorphin–positive cells were reduced by 37.5% (P=.006; effect size, 2.16), and met-encephalin cells by 26.4% (P=.028; effect size, 1.58) in patients with RLS compared with controls but there was no difference in leu-encephalin cells. In the substantia nigra, there were no differences in beta-endorphin, met-encephalin, or leu-encephalin. Tyrosine hydroxylase staining for dopamine cells was normal. RLS pathology in the thalamus is also implicated by voxel-based magnetic resonance imaging studies, which inconsistently show increased pulvinar size,
      • Etgen T.
      • Draganski B.
      • Ilg C.
      • et al.
      Bilateral thalamic gray matter changes in patients with restless legs syndrome.
      • Unrath A.
      • Juengling F.D.
      • Schork M.
      • Kassubek J.
      Cortical grey matter alterations in idiopathic restless legs syndrome: an optimized voxel-based morphometry study.
      reduced single-photon emission computerized tomography scan N-acetylaspartate:creatine ratio and N-acetylaspartate concentrations in the medial thalamus,
      • Rizzo G.
      • Tonon C.
      • Testa C.
      • et al.
      Abnormal medial thalamic metabolism in patients with idiopathic restless legs syndrome.
      and functional magnetic resonance imaging studies, which show increased activity in the thalamus and cerebellum while RLS symptoms are present. Although these studies do not specifically implicate opioid systems, opioid receptors are very abundant in the thalamus.
      Daytime positron emission tomography imaging using the nonspecific opioid ligand [11C] diprenorphine did not differentiate between human RLS and controls. Correlations were, however, found between mu-receptor–binding potential in amygdala, medial thalamus, anterior cingulate, and orbitofrontal cortex and RLS subjects' reported severity as measured by the International RLS Study Group severity scale.
      • Von Spiczak S.
      • Whone A.L.
      • Hammers A.
      • et al.
      The role of opioids in restless legs syndrome: an [11C]diprenorphine PET study.
      These 4 regions have been shown to have varying degrees of interconnection and are associated not only with emotion and reward in decision making but also with addiction, impulsivity, and anxiety.
      • Ray J.P.
      • Price J.L.
      The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys.
      Decreased binding suggests either increased endogenous opioid receptor occupancy or downregulation/internalization of the receptors.
      There is evidence supporting opioid interactions with dopaminergic systems on the basis of in vitro and clinical data. Stimulation of opioid receptors, especially mu receptors, which are robustly associated with dopamine receptors, can facilitate dopamine release as demonstrated by microdialysis studies in mice and on functional imaging of dopamine receptor occupancy in humans.
      • Di Chiara G.
      • Imperato A.
      Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.
      • Hagelberg N.
      • Kajander J.K.
      • Nagren K.
      • Hinkka S.
      • Hietala J.
      • Scheinin H.
      Mu-receptor agonism with alfentanil increases striatal dopamine D2 receptor binding in man.
      Importantly, pretreatment of RLS with a dopamine antagonist will negate any benefit of opioids, also suggesting that opioids interact with or work via dopaminergic systems to treat RLS.
      • Montplaisir J.
      • Lorrain D.
      • Godbout R.
      Restless legs syndrome and periodic leg movements in sleep: the primary role of dopaminergic mechanism.
      If naloxone, an opioid antagonist, is given to untreated subjects with RLS, no overt effect is seen,
      • Walters A.S.
      Review of receptor agonist and antagonist studies relevant to the opiate system in restless legs syndrome.
      • Winkelmann J.
      • Schadrack J.
      • Wetter T.C.
      • Zieglgansberger W.
      • Trenkwalder C.
      Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients.
      but if given in a double-blind fashion to opioid-treated patients with RLS, the RLS signs and symptoms reappear, suggesting that naloxone blocks the beneficial effects of the opioid agonist.
      • Walters A.
      • Hening W.
      • Cote L.
      • Fahn S.
      Dominantly inherited restless legs with myoclonus and periodic movements of sleep: a syndrome related to the endogenous opiates?.
      • Hening W.A.
      • Walters A.
      • Kavey N.
      • Gidro-Frank S.
      • Côté L.
      • Fahn S.
      Dyskinesias while awake and periodic movements in sleep in restless legs syndrome: treatment with opioids.
      However, naloxone does not block the beneficial effects of a dopamine agonist, suggesting that the dopaminergic response is not mediated via an opioid mechanism.
      • Akpinar S.
      Restless legs syndrome treatment with dopaminergic drugs.

      Clinical Studies

      Despite how long opioid drugs have been used for RLS, there are few high-quality, placebo-controlled studies to support their use. A parallel-group study randomized 306 patients with moderate to severe RLS and previous unsuccessful treatment to receive flexibly dosed prolonged-release oxycodone/naloxone or placebo.
      • Trenkwalder C.
      • Benes H.
      • Grote L.
      • et al.
      RELOXYN Study Group
      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.
      After 12 weeks, oxycodone/naloxone resulted in a greater symptom reduction than placebo as found using the International Restless Legs Syndrome Scale
      • Walters A.S.
      • LeBrocq C.
      • Dhar A.
      • et al.
      International Restless Legs Syndrome Study Group
      Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome.
      (−8.15; 95% CI, −10.85 to −5.46), with a mean dose of oxycodone of 21.9±15.0 mg and that of naloxone of 11.0±7.5 mg. The Clinical Global Impression responder rate was significantly higher in the oxycodone/naloxone group (67%) than in the placebo group (35%). Sleep adequacy and quantity improved more in the oxycodone/naloxone group than in the placebo group as measured by the Medical Outcome Studies sleep subscales. Daytime somnolence was not different between groups. During a subsequent 40-week open-label phase involving 197 subjects, oxycodone/naloxone was titrated from 5 mg oxycodone twice daily to a maximum of 40 mg twice daily. Forty subjects discontinued therapy, including 6 because of lack of therapeutic effect and 21 because of adverse events. At the end of the 40 weeks, the mean daily oxycodone dose was 18.1±10.5 mg. Efficacy was maintained with a reduction in the International Restless Legs Syndrome Scale score from onset of the open-label phase. Drug withdrawal symptoms were noted in only 3 of 176 subjects. Prolonged-release oxycodone/naloxone is approved for the treatment of RLS in more than 20 European countries, including the United Kingdom, France, and Germany.
      A small double-blind crossover study randomized 11 patients with moderate to severe RLS to receive oxycodone in divided doses (2 hours before and at bedtime) or placebo. On self-rated 0 to 4 scales, oxycodone (mean dose of 15.9 mg/d) improved RLS symptoms of motor restlessness and leg paresthesia better than placebo.
      • Walters A.S.
      • Wagner M.L.
      • Hening W.A.
      • et al.
      Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo.
      A retrospective long-term study of various opioids in refractory RLS showed that 20 of 36 continued on opioid monotherapy (mean, 5 years and 11 months) and only 1 patient discontinued because of the development of tolerance and addiction.
      • Walters A.S.
      • Winkelmann J.
      • Trenkwalder C.
      • et al.
      Long-term follow-up on restless legs syndrome patients treated with opioids.
      Two open-label studies support the effectiveness of the chronic use of methadone for refractory RLS. One study evaluated 27 subjects who failed on average 5 or more previous treatments for RLS.
      • Ondo W.G.
      Methadone for refractory restless legs syndrome.
      Seventeen remained on methadone for 23±12 months at a dose of 15.5±7.7 mg (range, 5-40 mg) and reported continued benefit and tolerability. Most patients who stopped methadone did so in the first month of therapy. Another longitudinal study reported on a consecutive series of 76 patients on methadone with primary RLS and complete data between 1997 and 2007.
      • Silver N.
      • Allen R.P.
      • Senerth J.
      • Earley C.J.
      A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome.
      Unlike dopamine agonist treatment, the long-term tolerability was excellent, without any evidence of augmentation. The median daily dose after 6 months of treatment was 10 mg. This did not increase in the first 3 years of use but did increase by a median of 5 mg and a maximum of 10 mg in those patients who had been followed for 4 to 7 years. No one who took methadone for at least a year subsequently discontinued it.
      Methadone is frequently used to treat narcotic addiction because it has less abuse potential than do other narcotics.
      • Sees K.L.
      • Delucchi K.L.
      • Masson C.
      • et al.
      Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial.
      In contrast to morphine and most other narcotics, its use does not cause intracellular forskolin-stimulated cyclic adenosine monophosphate accumulation, a mechanism thought to contribute to opioid tolerance.
      • Blake A.D.
      • Bot G.
      • Freeman J.C.
      • Reisine T.
      Differential opioid agonist regulation of the mouse mu opioid receptor.
      Methadone also uniquely antagonizes N-methyl-d-aspartate receptors in the spinal cord,
      • Callahan R.J.
      • Au J.D.
      • Paul M.
      • Liu C.
      • Yost C.S.
      Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in Xenopus oocytes: stereospecific and subunit effects.
      an area heavily implicated in RLS symptom genesis.
      • Bara-Jimenez W.
      • Aksu M.
      • Graham B.
      • Sato S.
      • Hallett M.
      Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex.
      • Ondo W.G.
      • He Y.
      • Rajasekaran S.
      • Le W.D.
      Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome.
      Therefore, although there is no human clinical comparison of different opioid medications, there is scientific rationale to specifically support the use of methadone, especially when long-term treatment is required.

      Using Opioids for the Treatment of RLS

       Indications

      Restless leg syndrome is considered refractory to treatment when it is unresponsive to monotherapy with tolerable doses of first-line agents of both classes (dopamine agonists and alpha-2-delta ligands) due to inadequate efficacy, augmentation, or adverse effects.
      • Silber M.H.
      • Becker P.M.
      • Earley C.
      • Garcia-Borreguero D.
      • Ondo W.G.
      Medical Advisory Board of the Willis-Ekbom Disease Foundation
      Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome.
      Doses of dopamine agonists should generally not exceed those recommended to prevent the development of augmentation.
      • Garcia-Borreguero D.
      • Silber M.H.
      • Winkelman J.W.
      • et al.
      Guidelines for the first-line treatment of restless legs syndrome/Willis–Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.
      Before considering opioid therapy, physicians should consider other alternative approaches.
      • Garcia-Borreguero D.
      • Silber M.H.
      • Winkelman J.W.
      • et al.
      Guidelines for the first-line treatment of restless legs syndrome/Willis–Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.
      • 1.
        Is there evidence for low systemic iron stores (serum ferritin concentration of <75 μg/mL)? Oral or intravenous iron therapy may relieve symptoms without the need for additional medications.
        • Silber M.H.
        • Becker P.M.
        • Earley C.
        • Garcia-Borreguero D.
        • Ondo W.G.
        Medical Advisory Board of the Willis-Ekbom Disease Foundation
        Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome.
        • Connor J.R.
        • Patton S.M.
        • Oexle K.
        • Allen R.P.
        Iron and restless legs syndrome: treatment, genetics and pathophysiology.
      • 2.
        Have other factors that might exacerbate RLS been considered, such as the use of drugs that can worsen symptoms, including antihistamines, serotonergic antidepressants, and dopamine antagonists, or the presence of other sleep disorders such as obstructive sleep apnea?
      • 3.
        Has combination therapy been considered, using lower doses of agents of different classes? In patients with severe symptoms this may not be appropriate and in some patients with profound RLS associated with dopamine agonist augmentation, opioids may be indicated even if alpha-2-delta agents have not had an adequate trial.
      • 4.
        In the case of dopamine agonist augmentation, has a 10-day washout period, without immediate substitution of an opioid, been considered? Although this may allow determination of the severity of baseline symptoms off all drugs, an exacerbation of RLS with profound insomnia very frequently develops during the washout period and this approach is appropriate only for some carefully selected patients.
      Not all these options may be relevant or appropriate in every patient. The time of initiation of opioid therapy depends on many factors, including the severity of the symptoms and their effect on sleep and quality of life. Although the benefits and risks should be carefully weighed, appropriate patients should not be deprived of opioids simply because of fear of opioid use disorder.

       Precautions

      Physicians are increasingly reluctant to prescribe long-term opioids because of recent heightened scrutiny by regulatory agencies and increased concerns of high rates of addiction and overdose recently publicized by organizations such as the Centers for Disease Control and Prevention.
      • Dowell D.
      • Haegerich T.M.
      • Chou R.
      CDC guideline for prescribing opioids for chronic pain—United States, 2016.
      However, as long as reasonable precautions are taken, this should not deter physicians from prescribing medications necessary for the health of their patients. Refractory RLS can be a devastating condition, resulting in profound insomnia, suicidal depression, and severely compromised quality of life.
      • Earley C.J.
      • Silber M.H.
      Restless legs syndrome: understanding its consequences and the need for better treatment.
      Nevertheless, prescribers should act responsibly with an understanding of the opioid epidemic afflicting the United States and the legal requirements of individual states. Following simple standardized safety practices reduces risk to patients, allowing for effective use of the drugs (Table 1). Several guidelines for chronic opioid use for pain with evidence in support of the recommendations have been published, including examples of patient questionnaires and contracts.
      • Dowell D.
      • Haegerich T.M.
      • Chou R.
      CDC guideline for prescribing opioids for chronic pain—United States, 2016.
      • Chou R.
      • Fanciullo G.J.
      • Fine P.G.
      • et al.
      Opioid treatment guidelines: clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.
      • Chou R.
      • Fanciullo G.J.
      • Fine P.G.
      • Miaskowski C.
      • Passik S.D.
      • Portenoy R.K.
      Opioids for chronic noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline.
      • Brown Jr., E.G.
      • Sewell D.S.
      • Kirchmeyer K.
      Medical Board of California
      Guidelines for prescribing controlled substances for pain.
      Table 1Summary of Considerations in the Use of Opioids for Refractory RLS
      1. Opioids should be considered for the treatment of RLS that is not adequately controlled with first-line agents due to poor response, adverse effects, or, in the case of dopamine agonists, augmentation.
      2. Factors that may be responsible for an inadequate response, especially low iron stores, the use of medications that can exacerbate RLS, or obstructive sleep apnea, should be considered.
      3. Alternative approaches should be considered when relevant, including using combination therapy of nonopioid agents or, in the case of dopamine augmentation, a 10-day washout period before substituting an opioid. These approaches are not appropriate for all patients.
      4. Before initiating opioid therapy, patients should be assessed for risk of opioid use disorder, state prescription drug monitoring programs should be queried, and a urine drug screen performed.
      5. Patients should be informed about expectations of treatment and the risks of opioids.
      6. Patients should be asked to sign an opioid contract, including at a minimum the following:
      • An understanding of the side effects of opioids and the risk of opioid use disorder;
      • That medications should be obtained from only a single provider and a single pharmacy;
      • That early refill prescriptions will generally not be issued even if the medication is reported lost;
      • That the dose should not be altered by the patients without discussion with the prescribing physician;
      • That medication should not be shared with anyone else.
      7. Regular follow-up is needed, assessing effectiveness of therapy, side effects, and evidence for development of opioid use disorder. State prescription drug monitoring programs should be assessed regularly and a urine drug screen considered at least once annually, especially in high-risk patients.
      8. Testing initial response with a short-acting drug is reasonable, but long-acting or extended-release agents are preferred at night, with either short- or long-acting agents added during the day as needed.
      9. Treatment should commence with low doses, increasing as needed and tolerated, but the individual risk-benefit ratio should be carefully considered if doses above those listed in Table 2 are used, because such doses have been associated with increased overdose-related mortality.
      10. The choice of drug to be used depends on physician preference, patient factors, and cost, but the prescriber should be very familiar with dosing schedules and the individual differences between agents.
      11. Care should be taken with dosages when transitioning a patient between different opioids due to varying drug potencies and cross-tolerance.
      RLS = restless leg syndrome.
      Before initiating opioid therapy, patients should be questioned about a personal or family history of alcohol or drug abuse (including prescribed medications), and present and past psychiatric disease. These factors increase the risk of opioid dependence, which is also higher in men and younger patients. Screening questionnaires for depression and anxiety may be helpful, and validated tools are available to stratify risk, such as the Opioid Risk Tool
      • Webster L.R.
      • Webster R.M.
      Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool.
      and the revised Screener and Opioid Assessment for Patients with Pain.
      • Butler S.F.
      • Fernandez K.
      • Benoit C.
      • Budman S.H.
      • Jamison R.N.
      Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R).
      Opioids should not necessarily be withheld in patients at higher risk but more intensive monitoring may be needed.
      Alternative therapies should be discussed with the patient, and the reasons for an opioid prescription should be documented in the medical record. Treatment aims should be specified and tailored to the patient's primary complaint related to RLS, such as inability to initiate sleep at night. It should be emphasized that complete relief of symptoms is not a realistic long-term goal in most patients. The goal should be to reduce symptoms to a level that provides sustainable improvement in sleep and overall quality of life. Potential adverse reactions should be described, including nausea, constipation, pruritus, myoclonus, drowsiness, and cognitive impairment. The possibility of precipitating or exacerbating obstructive or central sleep apnea, or the conversion of treated obstructive sleep apnea to central sleep apnea, should be considered. Opioids should not be taken together with alcohol and preferably not together with benzodiazepines. An electrocardiogram to assess the QT interval should be obtained before prescribing methadone and should be repeated after initiation of the drug, particularly when it is combined with other agents that may cause QT prolongation.
      An opioid contract should be signed by each patient.
      • Dowell D.
      • Haegerich T.M.
      • Chou R.
      CDC guideline for prescribing opioids for chronic pain—United States, 2016.
      This should include an understanding of the risk of opioid use disorder, that medications should be obtained from only a single provider and a single pharmacy, that early refill prescriptions will generally not be issued even if the medication is reported lost, that the dose should not be altered by the patients without discussion with the prescribing physician, and that medication should not be shared with anyone. The patient should be informed that state prescription drug monitoring programs will be interrogated. A urine drug screen can be performed before initiation of therapy, especially if there is suspicion of existing opiate use. Patients should be reassessed at regular intervals, usually every 3 to 6 months, to determine efficacy, side effects, and any evidence for opioid use disorder or misuse. In particular, practitioners should consider whether patients with multiple comorbid conditions may have supplies of opioids prescribed in the past for other disorders.
      • Hogl B.
      • Lohner H.
      • Mikus G.
      • Huff H.
      Acute and painful exacerbation of RLS and PLM induced by opioid interaction - withdrawal syndrome.
      The prescription drug monitoring program data should be checked at each visit and random urine drug screens considered at least once yearly, especially in higher risk patients. The goals of urine drug screens are to determine whether the patients are taking any other unsuspected narcotic substance and to show that the patient is taking the prescribed opioid and not diverting it. Screens differ in the list of drugs tested, and physicians should familiarize themselves regarding which drugs are included in the specific screen ordered. In particular, assessment for tramadol or methadone may need to be specially requested. The interpretation of drug screens is complex and unexpected results should be discussed with the toxicologist or the laboratory performing the test before conclusions are reached. At follow-up visits, patients should be reassessed for the development of depression and anxiety and appropriately treated or referred.

       Drugs and Doses

      Most published studies of opioids in RLS have used oxycodone or methadone.
      • Trenkwalder C.
      • Benes H.
      • Grote L.
      • et al.
      RELOXYN Study Group
      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.
      • Walters A.S.
      • Wagner M.L.
      • Hening W.A.
      • et al.
      Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo.
      • Walters A.S.
      • Winkelmann J.
      • Trenkwalder C.
      • et al.
      Long-term follow-up on restless legs syndrome patients treated with opioids.
      • Ondo W.G.
      Methadone for refractory restless legs syndrome.
      There has been experience with other agents
      • Walters A.S.
      • Winkelmann J.
      • Trenkwalder C.
      • et al.
      Long-term follow-up on restless legs syndrome patients treated with opioids.
      but no comparative studies have been reported. Although lower potency drugs such as codeine or tramadol can be tried,
      • Walters A.S.
      • Winkelmann J.
      • Trenkwalder C.
      • et al.
      Long-term follow-up on restless legs syndrome patients treated with opioids.
      • Lauerma H.
      • Markkula J.
      Treatment of restless legs syndrome with tramadol: an open study.
      most patients with refractory symptoms will require the use of high-potency medications. Testing initial response with a short-acting opioid may be a reasonable initial option but in general, longer-acting and controlled-release drugs are preferred. This may be especially important at night, because short-acting opioids may not give adequate length of coverage and may be associated with end-of-dose rebound of RLS symptoms. However, shorter-acting drugs may be appropriate during the day when symptoms may be less severe, because lower doses can be used. Choice of a specific drug depends on individual prescriber and patient factors, including cost of medication.
      • De Biase S.
      • Merlino G.
      • Valente M.
      • Gigli G.L.
      Opioids in the treatment of restless legs syndrome: pharmacological and clinical aspects.
      Low doses should be given initially with titration to usual effective doses on the basis of efficacy and side effects. The timing of doses depends on symptoms: the first objective should be to give relief at night but some patients will require additional daytime doses. The goal should be to improve patient's quality of life but not to necessarily eliminate all RLS symptoms. Total daily doses above those listed in Table 2 may sometimes be needed, but the risk-benefit ratio should be carefully assessed because such doses have a significantly increased risk of overdose-related deaths in studies of patients with chronic noncancer pain.
      • Dunn K.M.
      • Saunders K.W.
      • Rutter C.M.
      • et al.
      Overdose and prescribed opioids: associations among chronic non-cancer pain patients.
      • Bohnert A.S.
      • Valenstein M.
      • Bair M.J.
      • et al.
      Association between opioid prescribing patterns and opioid overdose-related deaths.
      • Gomes T.
      • Mamdani M.M.
      • Dhalla I.A.
      • Paterson J.M.
      • Juurlink D.N.
      Opioid dose and drug-related mortality in patients with nonmalignant pain.
      Table 2Suggested Doses for Using Opioids in RLS
      DrugStarting total daily doseUsual effective total daily dose
      Tramadol (immediate or extended release)50 mg (100 mg ER)100-200 mg
      Codeine30 mg60-180 mg
      Morphine CR7.5-15 mg15-45 mg
      Oxycodone (immediate or extended release)5-10 mg10-30 mg
      Hydrocodone (immediate or extended release)10-15 mg20-45 mg
      Methadone2.5-5 mg5-20 mg
      CR = controlled release; ER = extended release; RLS = restless leg syndrome.
      In an attempt to simplify the available choices, this article will restrict discussion to only a few of the more commonly used agents. Methadone is anecdotally considered to be the most effective opioid for RLS, but has variable pharmacokinetics and pharmacodynamics, is long acting, may cause prolongation of the electrocardiogram QT interval at high doses,
      • Chou R.
      • Cruciani R.A.
      • Fiellin D.A.
      • et al.
      American Pain Society; Heart Rhythm Society
      Methadone safety: a clinical practice guideline from the American Pain Society and College on problems of drug dependence, in collaboration with the Heart Rhythm Society.
      and reduce testosterone levels. Practitioners prescribing methadone should be knowledgeable about these unique features. Extended-release oxycodone is frequently used but similar medications include controlled-release morphine. Tramadol carries a risk of seizures particularly when the patient is also taking antidepressants. There is anecdotal evidence that tramadol may cause augmentation.
      • Earley C.J.
      • Allen R.P.
      Restless legs syndrome augmentation associated with tramadol.
      • Vertrugno R.
      • La Morgia C.
      • D'Angelo R.
      • et al.
      Augmentation of restless legs syndrome with long-term tramadol treatment.
      • Chokroverty S.
      Opioid-induced hyperalgesia and dopamine-induced augmentation in an intractable and refractory case of RLS.
      Table 2 lists the recommended initial and usually effective dose ranges but it should be noted that a minority of patients may require higher doses than those listed to obtain relief from symptoms. These doses are derived from limited published studies, anecdotal experience, and the approximate equivalence in strength of different agents.
      It is important to emphasize that the doses of opioids used for refractory RLS are far lower than those used for the treatment of chronic pain syndromes. These lower doses markedly reduce the risk of opioid use disorder. In a study of nationwide US medical and pharmacy claims to Blue Cross and Blue Shield insurance companies in 2015, the rate of opioid use disorder in patients taking low-dose opioids for more than 90 days was 6/1000 patients, compared with 40/1000 patients using high-dose opioids, an almost 7 times lower frequency. Low-dose opioids were defined as less than 100 mg morphine or equivalent per day, an upper limit far higher than that recommended for RLS, suggesting that the rate of opioid use disorder in patients with RLS may be even lower.
      Blue Cross Blue Shield Blue Health Intelligence
      America's opioid epidemic and its effect on the nation's commercially-insured population.

       Unresolved Clinical Questions

      Further well-designed research studies are needed to resolve a number of clinical questions. The comparative effectiveness and side effects of different opioids in patients with refractory RLS need to be determined. Studies are needed to confirm the clinical impression that maintaining a low dose of a dopamine agonist or alpha-2-delta ligand may allow a lower dose of opioid to be used. Further long-term studies of safety and efficacy are needed. In particular, larger studies are needed to assess the risk of dose escalation and abuse of opioids prescribed for RLS.
      There is no consensus on how to convert patients with refractory RLS from a dopamine agonist or alpha-2-delta ligand to an opioid.
      • Garcia-Borreguero D.
      • Silber M.H.
      • Winkelman J.W.
      • et al.
      Guidelines for the first-line treatment of restless legs syndrome/Willis–Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.
      One choice is to titrate the opioid to a therapeutic level and then slowly wean and discontinue the preexisting medication. However, in patients with severe augmentation, an alternative approach is to first taper down the previous drug before introducing an opioid. This allows evaluation of baseline symptoms off medication but often leads to transitory extremely severe RLS symptoms during the washout period. These varying approaches need to be systematically compared.

      Conclusion

      In summary, a number of opioid medications in low dose appear effective in refractory RLS.
      • Silver N.
      • Allen R.P.
      • Senerth J.
      • Earley C.J.
      A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome.
      The risks of opioid use are relatively low, taking into account the much lower doses used for RLS compared with those in patients with pain syndromes. As long as reasonable precautions are taken, the risk-benefit ratio is acceptable and opioids should not be unreasonably withheld from such patients.

      Acknowledgments

      This article was approved by the Scientific and Medical Advisory Board (SMAB) of the RLS Foundation. Members of the SMAB are as follows: Christopher J. Earley, MB, BCh, PhD, Johns Hopkins University, Baltimore, MA (Chair); Michael Aschner, PhD, Albert Einstein College of Medicine, Bronx, NY; Philip Becker, MD, Sleep Medicine Associates of Texas and University of Texas Southwestern, Dallas, TX; Marie-Françoise Chesselet, MD, PhD, University of California Los Angeles, CA; Stefan Clemens, PhD, East Carolina University, Greenville, NC; James R. Connor, PhD, Pennsylvania State College of Medicine, Hershey, PA; Jeffery S. Durmer, MD, PhD, Fusion Health, Suwanee, GA; Sergi Ferré, MD, PhD, National Institute on Drug Abuse, Baltimore, MD; Jennifer G. Hensley, EdD, CNM, WHNP, Vanderbilt University, Nashville, TN; Byron C. Jones, PhD, University of Tennessee, Memphis, TN; Brian B. Koo, MD, Yale University, New Haven, CT; Mauro Manconi, MD, PhD, Neurocenter of Southern Switzerland, Lugano, Switzerland; Mark P. Mattson, PhD, National Institute on Aging, Baltimore, MD; Emmanuel Mignot, MD, PhD, Stanford University, Palo Alto, CA; William Ondo, MD, Weill Cornell Medical School, Houston, TX; John W. Winkelman, MD, PhD, Harvard University, Boston, MA; Michael H. Silber, MB, ChB, Mayo Clinic College of Medicine and Science, Rochester, MN; Lynn Marie Trotti, MD, MSc, Emory University, Atlanta, GA; George Uhl, MD, PhD, VA Health Care System, Albuquerque, NM; Arthur S. Walters, MD, Vanderbilt University, Nashville, TN.

      Supplemental Online Material

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