Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients

doi:10.1016/S1389-9457(00)00025-3

Sleep Medicine

Volume 2, Issue 1, January 2001, Pages 57-61

https://doi.org/10.1016/S1389-9457(00)00025-3 Get rights and content

Abstract

Background: The restless legs syndrome (RLS) is a common sensomotor disorder associated with severe sleep disturbances. Symptoms clearly improve following treatment with dopaminergic or opioidergic agonists.

Objective: To further elucidate the involvement of opioidergic and dopaminergic mechanisms in the pathophysiology of RLS, the effects of specific antagonists on motor (periodic leg movements) and subjective (sensory) RLS-symptoms during daytime were assessed.

Methods: A modified suggested immobilization test was performed in eight drug-naive RLS-patients. An infusion of either naloxone, metoclopramide or placebo was administered. In addition, the hormonal levels of adrenocorticotropic hormone, cortisol, prolactin and growth hormone were determined, to elucidate a possible involvement of the hypothalamic-pituitary-adrenocortical (HPA) system in RLS.

Results: RLS sensory or motor symptoms could not be provoked. Hormonal responses showed no abnormal profiles.

Conclusions: Rather than a general alteration of the opioidergic/dopaminergic tone and an involvement of the HPA system, it is more likely that specific neuronal dopaminergic or opioidergic pathways are altered in the pathophysiology of RLS.

Introduction

The restless legs syndrome (RLS) is a common cause of sleep disturbances. Patients complain about unpleasant sensory symptoms, mainly affecting the legs. Symptoms typically appear at rest, inducing an irresistible urge to move the limbs, which is temporarily relieved by motor activity. The patients also suffer from periodic leg movements (PLM): these consist of repetitive flexions at the hips and knees during stage 1 and 2 of non-REM-sleep, causing frequent awakenings. PLM are not restricted to night sleep, but can also occur at relaxed wakefulness during daytime [1]. Thus far, little is known about the pathophysiology of this syndrome. The prompt response to opioidergic or dopaminergic agonists [1], [2], [3], [4] suggests that these systems may be involved in RLS pathophysiology. The therapeutic benefit of the μ-opioid receptor agonist codeine could be blocked by the dopamine receptor antagonist pimozide [5]. This finding shows evidence in favour of a close functional interaction between the two systems. The opioid antagonist naloxone did not block the effect of the dopamine receptor agonist bromocriptine, suggesting that the effect of the dopaminergic agonist is not mediated through an opioidergic mechanism [6].

A synopsis of recent studies suggested that hormones of the hypothalamic-pituitary-adrenocortical (HPA) system are also strongly associated with the regulation of human sleep under physiological and pathophysiological conditions [7]. These hormones are altered during various central nervous system (CNS) disorders associated with sleep disturbances, including depression [8]. Naloxone administration increases the plasma concentration of adrenocorticotropic hormone (ACTH), cortisol (CORT), and growth hormone (GH), and metoclopramide decreases prolactin (PRL) and GH plasma concentration in normal subjects [9], [10]. This provides evidence in favour of a tonically active opioidergic and dopaminergic control of the HPA system.

In the present randomized cross-over study we investigated two hypotheses. First, never-treated RLS-patients may display a primarily altered endogenous opioidergic or dopaminergic tone and may therefore be susceptible to the respective antagonists concerning their RLS symptoms. Therefore, in order to block endogenous opioidergic or dopaminergic mechanisms, the effect of naloxone (opioid antagonist) and metoclopramide (dopamine antagonist), respectively, were compared with a placebo.

Second, we wanted to elucidate the possible involvement of the HPA-axis in RLS, since an alteration in other CNS diseases with sleep disturbances has been shown previously [7]. Therefore, profiles of hormonal responses were also determined before and after the drug challenges.

Section snippets

Methods

Eight patients with idiopathic RLS and no history of dopaminergic or opioidergic medication were included. All patients fulfilled the diagnostic criteria of the International RLS-Study Group and gave written informed consent. Patients were only included if they did not report daytime RLS-symptoms and had no additional medical disorders.

All patients underwent two polysomnographic recordings according to standardized guidelines, including an electromyogram (EMG) of both anterior tibialis muscles

PLM

Polysomnography: the PLMS-arousal indices of all but one patient were >20 PLMS/h. The one patient (patient #4) had almost no PLM during sleep. Sleep efficiency of all patients was 79.9%±1.4 (mean±SEM). SIT: PLM/h indices were calculated for the time interval after the infusion (14:30–16:00 h). All patients showed a continuous increase of movements and PLM during the 90 min of the SIT with a maximum in the last 30 min. Patient #7 and #8 negated the SIT at 1 day of the study (both placebo).

The

Discussion

This study investigated the involvement of endogenous opioidergic/dopaminergic systems in the pathomechanism of drug-naive RLS patients. For this purpose the opioid antagonist naloxone and the dopamine antagonist metoclopramide were applied. In the eight RLS patients performing SIT during daytime, no RLS-symptoms could specifically be provoked by naloxone or metoclopramide administration in comparison with placebo. The results of motor (PLM/h) and subjective RLS-symptoms were similar for all

Acknowledgments

The authors would like to thank Elisabeth Kappelmann for her excellent work and continuous assistance while performing SITs and taking blood samples.

References (15)

C Trenkwalder et al.
Periodic limb movements and restless legs syndrome
Neurol Clin
(1996)
E Friess et al.
The hypothalamic-pituitary-adrenocortical system and sleep in man
Adv Neuroimmunol
(1995)
J Volavka et al.
Short-term hormonal effects of naloxone in man
Psychoneuroendocrinology
(1980)
A.S Walters et al.
Clinical presentation and neuropharmacology of restless legs syndrome
Clin Neuropharmacol
(1987)
T.C Wetter et al.
A randomized controlled study of pergolide in patients with restless legs syndrome
Neurology
(1999)
W.A Hening et al.
Dyskinesias while awake and periodic movements in sleep in restless legs syndrome: treatment with opioids
Neurology
(1986)
J Montplaisir et al.
Restless legs syndrome and periodic movements in sleep: The primary role of dopaminergic mechanism
Eur Neurol
(1991)

There are more references available in the full text version of this article.

Cited by (108)

Emerging Concepts of the Pathophysiology and Adverse Outcomes of Restless Legs Syndrome
2020, Chest
Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common neurological disorder affecting up to 5% to 10% of the population, but it remains an underdiagnosed condition. RLS/WED is characterized by uncomfortable sensations, mainly in the legs, which appear during inactivity and worsen in the evening or at night. The prevalence of RLS/WED and periodic leg movements (PLMs) is increased in patients with sleep-disordered breathing, particularly in those with OSA, the most common sleep disorder encountered in sleep centers.
New advances in the pathophysiology of RLS/WED have shown important implications for various genetic markers, neurotransmitter dysfunction, and iron deficiency. A practical approach to RLS/WED management includes an accurate diagnosis, the identification of reversible contributing factors, and the use of nonpharmacological therapies, including iron substitution (oral or IV) therapy. Many pharmacological agents are effective for the treatment of RLS/WED. Until recently, the first-line treatment of RLS/WED consisted of low-dose dopamine agonists (DA). However, given the fact that DAs cause high rates of augmentation of symptoms, international guidelines recommend that whenever possible the initial treatment of choice should be an α2δ ligand, and avoidance of dopaminergic agents unless absolutely necessary. If necessary, the lowest effective dose should be used for only the shortest possible time. The symptoms of RLS/WED can disrupt the quality of sleep as well as the quality of life. IV iron therapy may be considered in patients with refractory RLS. A better understanding of RLS/WED pathophysiology will allow patients to receive tailored therapy, resulting in an improved quality of life.
Occupational Health and Sleep Issues in Underserved Populations
2019, Physician Assistant Clinics
The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome
2018, Mayo Clinic Proceedings
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.
Occupational Health and Sleep Issues in Underserved Populations
2017, Primary Care - Clinics in Office Practice
Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation
2017, Sleep Medicine
Citation Excerpt :
Levodopa and dopamine D2/3 receptor (D2/3R) agonists significantly improve the primary symptom of restless legs syndrome (RLS), which is defined as focal, akathisia involving the lower extremities [1,2]. Dopamine (DA) antagonists, on the contrary, can trigger or worsen akathisia [3–5]. From these findings, it has been deduced that the dopaminergic system is involved in the development of RLS/akathisia and that decreased DA function is at the heart of RLS [6–8].
Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact induce a hyperdopaminergic state are summarized. On the basis of these data, the concept of a dynamic nature of the dopamine effects in a circadian context is presented. The possible interactions of cell adhesion molecules expressed by the dopaminergic systems and their possible effects on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally distinct dopamine receptor subtypes can reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these interactions can extend to the adenosine A₁ and A_2A receptors, which are also prominently expressed in the striatum. Interactions between adenosine and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets for treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to consider dynamic changes in the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes in the connectome based on alterations in cell adhesion molecules, and receptor interactions that may extend beyond the dopamine system itself.
Association of restless legs syndrome with oxidative stress and inflammation in patients undergoing hemodialysis
2015, Sleep Medicine
Restless legs syndrome (RLS) is a common comorbidity in patients undergoing hemodialysis, but clinical factors predictive of RLS risk and severity have not been identified. The aims of this multicenter cross-sectional study were to document RLS prevalence and severity in patients undergoing hemodialysis and to identify associated risk factors.
One-hundred and fifty-nine stable patients on maintenance hemodialysis were enrolled (113 men, 46 women; mean age: 68 ± 11 years; mean duration of dialysis: 54 ± 60 months). Diagnosis of RLS was based on the criteria proposed by the International Restless Legs Syndrome Study Group (IRLSSG), and RLS severity was assessed using the IRLSSG Severity Scale. Potential factors associated with RLS and IRLSSG Severity Scale score were assessed by univariate and multivariate regression analyses.
RLS affected 22% of the study population. The RLS subgroup had a significantly longer duration of hemodialysis and higher cardiothoracic ratio compared to the non-RLS subgroup. The RLS subgroup also had significantly higher serum levels of high-sensitivity C-reactive protein, interleukin-6, ferritin, N-terminal pro-B-type natriuretic peptide, and 8-hydroxy-2′-deoxyguanosine (8-OHdG), and a significantly lower transferrin saturation level compared to the non-RLS subgroup, suggesting a chronic inflammatory state and associated oxidative stress in comorbid patients. Serum 8-OHdG level was an independent risk factor for high IRLSSG Severity Scale score.
This study confirms the high prevalence of RLS among hemodialysis patients and identifies the oxidative stress marker serum 8-OHdG as a significant independent predictor of RLS severity. Further studies are needed to identify detailed risk factors and the pathophysiological role of oxidative stress in RLS.

View all citing articles on Scopus

View full text

Brief communicationOpioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients

Abstract

Introduction

Section snippets

Methods

PLM

Discussion

Acknowledgments

Neurol Clin

Adv Neuroimmunol

Psychoneuroendocrinology

Clinical presentation and neuropharmacology of restless legs syndrome

Clin Neuropharmacol

A randomized controlled study of pergolide in patients with restless legs syndrome

Neurology

Dyskinesias while awake and periodic movements in sleep in restless legs syndrome: treatment with opioids

Neurology

Restless legs syndrome and periodic movements in sleep: The primary role of dopaminergic mechanism

Eur Neurol

Brief communication
Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients