Mark Buchfuhrer, MD

All Publications

• The Management of Restless Legs Syndrome: An Updated Algorithm. Mayo Clinic proceedings Silber, M. H., Buchfuhrer, M. J., Earley, C. J., Koo, B. B., Manconi, M., Winkelman, J. W., Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation, Earley, C. J., Becker, P., Berkowski, J. A., Buchfuhrer, M. J., Clemens, S., Connor, J. R., Ferre, S., Hensley, J. G., Jones, B. C., Karroum, E. G., Koo, B., Manconi, M., Ondo, W., Richards, K., Sharon, D., Silber, M. H., Trotti, L. M., Uhl, G., Walters, A. S., Winkelman, J. W. 2021; 96 (7): 1921-1937

  Abstract

  Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.

  View details for DOI 10.1016/j.mayocp.2020.12.026

  View details for PubMedID 34218864

• Noninvasive neuromodulation reduces symptoms of restless legs syndrome. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Buchfuhrer, M. J., Baker, F. C., Singh, H., Kolotovska, V., Adlou, B., Anand, H., de Zambotti, M., Ismail, M., Raghunathan, S., Charlesworth, J. D. 2021

  Abstract

  STUDY OBJECTIVES: Restless legs syndrome (RLS) is a common neurological disorder characterized by an uncontrollable nocturnal urge to move the legs and often associated with chronic sleep disturbances. The most common treatments for RLS are medications that can have debilitating side-effects. Here, we evaluated a novel alternative modality of RLS treatment, noninvasive bilateral electrical stimulation of the common peroneal nerve.METHODS: To assess the impact of this noninvasive peripheral nerve stimulation (NPNS) approach on RLS symptomatology, we conducted a multi-site randomized crossover study comparing NPNS to sham. RLS patients with moderate to severe RLS (n=37) self-administered NPNS and sham nightly for 14 days per treatment in randomized order.RESULTS: NPNS resulted in a reduction in RLS severity of 6.81 points on the International RLS Rating Scale (IRLS) relative to 3.38 for sham (p<0.01) and a 66% clinically significant responder rate on the Clinical Global Impressions-Improvement (CGI-I) scale compared to 17% for sham (p<0.01). Subgroup analysis indicated that medication-resistant and medication-naive participants both exhibited similarly robust responses. There were no moderate or serious device-related adverse events.CONCLUSIONS: These results suggest that NPNS could be a promising alternative to pharmacological therapies for RLS and could provide a solution for medication-resistant RLS patients and for medication-naive RLS patients who are unwilling or unable to take medication.CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome; Identifier: NCT04700683; URL: https://clinicaltrials.gov/ct2/show/NCT04700683.

  View details for DOI 10.5664/jcsm.9404

  View details for PubMedID 33949942

• VALIDATION OF THE SELF-ADMINISTERED VERSION OF THE INTERNATIONAL RESTLESS LEGS SYNDROME STUDY GROUP SEVERITY RATING SCALE - THE SIRLS Sharon, D., Allen, R. P., Martinez-Martin, P., Walters, A. S., Ferini-Strambi, L., Hoegl, B., Trotti, L., Buchfuhrer, M. J., Swieca, J., Bogan, R. K., Zak, R., Becker, P. M. OXFORD UNIV PRESS INC. 2019

  View details for Web of Science ID 000471071002224

• Validation of the self-administered version of the international Restless Legs Syndrome study group severity rating scale - The sIRLS SLEEP MEDICINE Sharon, D., Allen, R. P., Martinez-Martin, P., Walters, A. S., Strambi, L., Hoegl, B., Trotti, L., Buchfuhrer, M., Swieca, J., Bogan, R. K., Zak, R., Hensley, J. G., Schaefer, L. A., Marelli, S., Zucconi, M., Stefani, A., Holzknecht, E., Olvera, V., Meaklim, H., Laska, I., Becker, P. M., Int RLS Study Grp 2019; 54: 94-100

  View details for DOI 10.1016/j.sleep.2018.10.014

  View details for Web of Science ID 000458800800014

• Validation of the self-administered version of the international Restless Legs Syndrome study group severity rating scale - The sIRLS. Sleep medicine Sharon, D., Allen, R. P., Martinez-Martin, P., Walters, A. S., Ferini Strambi, L., Hogl, B., Trotti, L. M., Buchfuhrer, M., Swieca, J., Bogan, R. K., Zak, R., Hensley, J. G., Schaefer, L. A., Marelli, S., Zucconi, M., Stefani, A., Holzknecht, E., Olvera, V., Meaklim, H., Laska, I., Becker, P. M., International RLS Study Group 2018; 54: 94–100

  Abstract

  INTRODUCTION: The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically in clinical practice and in large population-based studies. In this study the validity and the reliability of the IRLS as a self-administered scale (sIRLS) is assessed.METHODS: Established RLS patients were recruited by eight centers in four countries and consented to participate in this study. The validity of the sIRLS was assessed by patients completing the sIRLS before a clinician administered the IRLS. The reliability of the sIRLS was assessed by patients completing the sIRLS again, two weeks after the first one, provided no change had occurred.RESULTS: Overall, 173 patients were recruited and 164 of them were included in the analyses. The sIRLS showed satisfactory scaling assumptions and no relevant floor or ceiling effect. One factor explained 61.3% of the variance. Cronbach's alpha was 0.93 and the item homogeneity index was 0.59. Intraclass correlation coefficient between the sIRLS and the IRLS was 0.94. The sIRLS standard error of measurement was 3.61 ( SD at baseline=4.11). The results mostly overlapped those of the IRLS analyzed in parallel.DISCUSSION: The sIRLS is a reliable, valid and precise instrument that showed tight association with the IRLS. These findings support the use of the sIRLS for self-evaluation of RLS severity. The responses obtained on the sIRLS and the IRLS scale varied slightly. Therefore, we recommend that either the sIRLS or the IRLS scale be used as the only scale for serial measures over time.

  View details for PubMedID 30529783

• In Reply-Additional Safety Considerations Before Prescribing Opioids to Manage Restless Legs Syndrome MAYO CLINIC PROCEEDINGS Silber, M. H., Becker, P. M., Buchfuhrer, M. J., Earley, C. J., Ondo, W. G., Walters, A. S., Winkelman, J. W. 2018; 93 (7): 955–56

  View details for PubMedID 29976378

• The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome MAYO CLINIC PROCEEDINGS Silber, M. H., Becker, P. M., Buchfuhrer, M. J., Earley, C. J., Ondo, W. G., Walters, A. S., Winkelman, J. W., Sci & Med Advisory Board Restless 2018; 93 (1): 59–67

  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.

  View details for PubMedID 29304922

• 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. Sleep medicine Garcia-Borreguero, D., Silber, M. H., Winkelman, J. W., Högl, B., Bainbridge, J., Buchfuhrer, M., Hadjigeorgiou, G., Inoue, Y., Manconi, M., Oertel, W., Ondo, W., Winkelmann, J., Allen, R. P. 2016; 21: 1-11

  Abstract

  A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine.

  View details for DOI 10.1016/j.sleep.2016.01.017

  View details for PubMedID 27448465

• The Effect of Gabapentin Enacarbil on Pain Associated with Moderate-to-Severe Primary Restless Legs Syndrome in Adults: Pooled Analyses from Three Randomized Controlled Trials CNS DRUGS Hermanowicz, N., Ellenbogen, A., Irving, G., Buchfuhrer, M., Jaros, M. J., Shang, G., Kim, R. 2016; 30 (5): 443-454

  Abstract

  Adults with moderate-to-severe primary restless legs syndrome (RLS) often experience painful dysesthesias, which may lead to impaired quality of life.The aim of this study was to assess the effects of gabapentin enacarbil (GEn) on pain associated with moderate-to-severe primary RLS in adults.Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials (NCT00298623, NCT00365352, NCT01332305) for adults receiving GEn or placebo once daily. Change in average daily RLS pain score and a combined International Restless Legs Scale (IRLS)-pain response were examined.The modified intention-to-treat population included 671 adults (placebo, n = 244; GEn 600 mg, n = 161; GEn 1200 mg, n = 266). Both GEn doses significantly improved average daily RLS pain score at week 12 (p < 0.001 for GEn 600 mg vs. placebo and GEn 1200 mg vs. placebo). The combined IRLS-pain response subanalysis included 366 patients with a baseline IRLS total score ≥15 and pain score ≥4 (placebo, n = 133; GEn 600 mg, n = 86; GEn 1200 mg, n = 147). Most patients were both IRLS and pain responders (placebo, 40 %; GEn 600 mg, 70 %; GEn 1200 mg, 67 %). Spearman rank correlations between IRLS total and pain score (change from baseline to week 12) were moderate or strong. The most frequent treatment-emergent adverse events were somnolence (placebo, 5 %; GEn 600 mg, 20 %; GEn 1200 mg, 23 %) and dizziness (placebo, 4 %; GEn 600 mg, 13 %; GEn 1200 mg, 22 %).This post hoc pooled analysis suggests that GEn (600 and 1200 mg) once daily significantly improved pain associated with moderate-to-severe primary RLS in adults; however, the analysis was not powered to detect statistical differences between the two GEn doses. Numerically, more GEn-treated patients had a combined IRLS-pain response than placebo-treated patients.

  View details for DOI 10.1007/s40263-016-0333-8

  View details for Web of Science ID 000376414100006

  View details for PubMedID 27095237

• Efficacy of gabapentin enacarbil in adult patients with severe primary restless legs syndrome SLEEP MEDICINE Lee, D. O., Buchfuhrer, M. J., Garcia-Borreguero, D., Avidan, A. Y., Ahmed, M., Hays, R., Ondo, W. G., Jaros, M. J., Kim, R., Shang, G. 2016; 19: 50-56

  Abstract

  Assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with severe primary restless legs syndrome (RLS).We pooled data from three 12-week, double-blind, placebo-controlled, randomized trials (NCT00298623, NCT00365352, NCT01332305) across GEn 600-mg, GEn 1200-mg, and placebo treatment groups for severe primary RLS (baseline International Restless Legs Scale (IRLS) total score ≥24). Co-primary end points at week 12 were mean change from baseline in IRLS total score and proportion of responders ("much"/very much" improved) on the investigator-rated Clinical Global Impression - Improvement (CGI-I) Scale. Outcomes for individual IRLS items (eg, sleep, mood, quality of life, pain, safety) were assessed.A total of 309 patients had severe primary RLS (placebo, n = 110; GEn 600 mg, n = 80; GEn 1200 mg, n = 119). GEn 600 mg and 1200 mg significantly improved least-squares mean IRLS total scores versus placebo at week 12 (placebo, -12.3; GEn 600 mg, -16.3; GEn 1200 mg, -18.0; treatment difference vs. placebo, both p <0.01). Significantly more patients with severe primary RLS treated with GEn 600 mg (64%) and 1200 mg (74%) were CGI-I responders at week 12 versus placebo (42%; p <0.01 for both GEn doses). Both GEn doses led to significant improvements in the other outcomes explored versus placebo at week 12. The most frequent treatment-emergent adverse events (TEAEs) were somnolence (GEn, 21-24%; placebo, 3%) and dizziness (GEn, 14-19%; placebo, 3%).GEn (600 mg or 1200 mg) once daily significantly improved RLS symptoms and consequences of these symptoms in severe primary RLS. The most frequent TEAEs were somnolence and dizziness.

  View details for DOI 10.1016/j.sleep.2015.11.002

  View details for PubMedID 27198947

• Treatment response to sleep, pain, and mood disturbance and their correlation with sleep disturbance in adult patients with moderate-to-severe primary restless legs syndrome: Pooled analyses from 3 trials of gabapentin enacarbil ANNALS OF MEDICINE Bogan, R. K., Lee, D. O., Buchfuhrer, M. J., Jaros, M. J., Kim, R., Shang, G. 2015; 47 (3): 269-277

  Abstract

  This pooled analysis investigated the effects of gabapentin enacarbil (GEn) on clinical correlates of sleep disturbance in adults with moderate-to-severe primary restless legs syndrome (RLS) and no-to-moderate or severe-to-very severe baseline sleep disturbance.Co-primary end-points were mean change from baseline to week 12 in International Restless Legs Scale (IRLS) total score and proportion of responders ('much'/'very much' improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale (week 12). Pain, mood, individual IRLS items, and safety were assessed.The modified intent-to-treat population was 671 adults randomized to GEn 600 mg (n = 161), GEn 1200 mg (n = 266), or placebo (n = 244). GEn significantly improved least squares mean change in IRLS total score from baseline versus placebo for no-to-moderate (GEn 600 mg,- 12.3; 1200 mg, - 11.3; placebo, - 7.7) and severe-to-very severe (- 16.6; - 17.0; - 12.7) groups (all P < 0.01). Significantly more GEn-treated patients (both doses) were CGI-I responders (week 12) versus placebo in both sleep subgroups (all P < 0.01). GEn substantially improved mood and pain scores for both sleep subgroups versus placebo. The most frequent treatment-emergent adverse events were somnolence and dizziness.GEn (600 mg and 1200 mg) was effective and well tolerated in adults with moderate-to-severe primary RLS regardless of baseline sleep disturbance level.

  View details for DOI 10.3109/07853890.2015.1025825

  View details for Web of Science ID 000355562200011

  View details for PubMedID 25874578

• Sensory stimuli and the restless legs syndrome. Journal of clinical sleep medicine Burbank, F., Buchfuhrer, M. J. 2014; 10 (12): 1363-?

  View details for DOI 10.5664/jcsm.4306

  View details for PubMedID 25348247

  View details for PubMedCentralID PMC4237534

• Sleep improvement for restless legs syndrome patients. Part 1: pooled analysis of two prospective, double-blind, sham-controlled, multi-center, randomized clinical studies of the effects of vibrating pads on RLS symptoms JOURNAL OF PARKINSONISM AND RESTLESS LEGS SYNDROME Burbank, F., Buchfuhrer, M. J., Kopjar, B. 2013; 3: 1-10

  View details for DOI 10.2147/JPRLS.S40354

  View details for Web of Science ID 000215701900001

• Improving sleep for patients with restless legs syndrome. Part II: meta-analysis of vibration therapy and drugs approved by the FDA for treatment of restless legs syndrome JOURNAL OF PARKINSONISM AND RESTLESS LEGS SYNDROME Burbank, F., Buchfuhrer, M. J., Kopjar, B. 2013; 3: 11-22

  View details for DOI 10.2147/JPRLS.S40356

  View details for Web of Science ID 000215701900002

• Contemporary Challenges and Strategies for Improving Outcomes for Patients With Restless Legs Syndrome AMERICAN JOURNAL OF MANAGED CARE Buchfuhrer, M. J. 2012; 18 (12): S283-S290

  Abstract

  Restless legs syndrome (RLS) is a common neurological disease that is diagnosed solely based on clinical symptoms and may be treated via both nonpharmacologic and pharmacologic means. Despite its somewhat trivial-sounding name, this disease has a very significant impact upon the lives of RLS patients and imposes a substantial burden, as evidenced by direct and indirect costs and loss of productivity. After the introduction of US Food and Drug Administration (FDA)- approved drugs for the management of RLS in 2005, there has been an increase in the awareness of the disease. Increased awareness of RLS has resulted in a greater number of patients receiving treatment for RLS, and in turn, more patients presenting with refractory RLS, in part due to drug-emergent issues such as augmentation. Furthermore, management of the disease is still not optimal. Barriers to obtaining adequate treatment include healthcare providers' lack of knowledge, limited availability of specialists who can provide care to patients presenting with refractory RLS, and access to and cost of medications. Opportunities for managed care to enhance the recognition and treatment of RLS are discussed, with suggestions for improving outcomes in patients with RLS.

  View details for Web of Science ID 000312227100001

  View details for PubMedID 23327482

• Strategies for the Treatment of Restless Legs Syndrome NEUROTHERAPEUTICS Buchfuhrer, M. J. 2012; 9 (4): 776-790

  Abstract

  Restless legs syndrome (RLS) is a common neurological disorder of unknown etiology that is managed by therapy directed at relieving its symptoms. Treatment of patients with milder symptoms that occur intermittently may be treated with nonpharmacological therapy but when not successful, drug therapy should be chosen based on the timing of the symptoms and the needs of the patient. Patients with moderate to severe RLS typically require daily medication to control their symptoms. Although the dopamine agonists, ropinirole and pramipexole have been the drugs of choice for patients with moderate to severe RLS, drug emergent problems like augmentation may limit their use for long term therapy. Keeping the dopamine agonist dose as low as possible, using longer acting dopamine agonists such as the rotigotine patch and maintaining a high serum ferritin level may help prevent the development of augmentation. The α2δ anticonvulsants may now also be considered as drugs of choice for moderate to severe RLS patients. Opioids should be considered for RLS patients, especially for those who have failed other therapies since they are very effective for severe cases. When monitored appropriately, they can be very safe and durable for long term therapy. They should also be strongly considered for treating patients with augmentation as they are very effective for relieving the worsening symptoms that occur when decreasing or eliminating dopamine agonists.

  View details for DOI 10.1007/s13311-012-0139-4

  View details for Web of Science ID 000310325000009

  View details for PubMedID 22923001

  View details for PubMedCentralID PMC3480566