Pain, opioids, and sleep: implications for restless legs syndrome treatment

Accepted Manuscript Pain, opioids, and sleep: Implications for restless legs syndrome treatment Claudia Trenkwalder, Walter Zieglgänsberger, Sam H. Ahmedzai, Birgit Högl PII:

S1389-9457(16)30238-6

DOI:

10.1016/j.sleep.2016.09.017

Reference:

SLEEP 3208

To appear in:

Sleep Medicine

Received Date: 15 March 2016 Revised Date:

27 September 2016

Accepted Date: 29 September 2016

Please cite this article as: Trenkwalder C, Zieglgänsberger W, Ahmedzai SH, Högl B, Pain, opioids, and sleep: Implications for restless legs syndrome treatment, Sleep Medicine (2016), doi: 10.1016/ j.sleep.2016.09.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Pain, opioids, and sleep: Implications for restless legs syndrome treatment

Claudia Trenkwalder a,b,*, Walter Zieglgänsberger c, Sam H. Ahmedzai d, Birgit Högl e

University Medical Center Goettingen, Goettingen, Germany

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Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Kassel,

Germany

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Max Planck Institute of Psychiatry, Munich, Germany

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Department of Oncology, The University of Sheffield, Sheffield, UK

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Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

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ARTICLE INFO

Received

Accepted

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Received in revised form

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Article history:

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Keywords: Opioid

Oxycodone

Restless legs syndrome Pain Pathomechanism Sleep Therapy 1

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* Corresponding author at: Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Klinikstr. 16, 34128 Kassel, Germany. Tel.: +49-561-6009-200; fax: +49-5616009-126.

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E-mail address: [email protected] (C. Trenkwalder).

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ACCEPTED MANUSCRIPT ABSTRACT

Opioid receptor agonists are known to relieve restless legs syndrome (RLS) symptoms, including both sensory and motor events, as well as improving sleep. The mechanisms of

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action of opioids in RLS are still matter of speculation. The mechanisms by which

endogenous opioids contribute to the pathophysiology of this polygenetic disorder, in which there are a number of variants, including developmental factors, remains unknown. A

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summary of the cellular mode of action of morphine and its (partial) antagonist naloxone via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the

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involvement of dendritic spine activation is described. By targeting pain and its consequences, opioids are the first-line treatment in many diseases and conditions with both acute and chronic pain and have thus been used in both acute and chronic pain conditions over the last 40 years. Addiction, dependence, and tolerability of opioids show a wide variability

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interindividually, as the response to opioids is influenced by a complex combination of genetic, molecular, and phenotypic factors. Although several trials have now addressed opioid treatment in RLS, hyperalgesia as a complication of long-term opioid treatment, or

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opioid−opioid interaction have not received much attention so far. Therapeutic opioids may act not only on opioid receptors but also via histamine or N-methyl-D-aspartate (NMDA)

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receptors. In patients with RLS, one of the few studies investigating opioid bindings found that possible brain regions involved in the severity of RLS symptoms are similar to those known to be involved in chronic pain, such as the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex, and orbitofrontal cortex). The results of this diprenorphine positron emission tomography study suggested that the more severe the RLS, the greater the release of endogenous opioids. Since 1993, when the first small controlled study was performed with oxycodone in RLS, opioids have been considered an efficatious off-label therapy in patients with severe RLS. A recent trial has proved the 3

ACCEPTED MANUSCRIPT efficacy of a combination of prolonged release oxycodone/naloxone in patients with severe RLS as second-line therapy, with a mean dosage of 10/5 mg twice daily (mean difference of IRLS between groups at 12 weeks: 8.15), and has now been licensed as the first opioid therapy in Europe. The current results from both short- and long-term trials and studies with

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opioids encourage optimism in alleviating RLS symptoms in patients with severe RLS, or

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possibly during or after augmentation.

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1. Introduction

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The following short review on opioids and their implications for use in the treatment of

restless legs syndrome (RLS), can only highlight some aspects without going into depth. In particular, experimental studies on pain and opioids, which are a basis for this therapy in

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painful RLS, can only be mentioned and will not be covered in a systematic way.

Opioid receptor agonists provide symptomatic relief from dysesthesias and pain in patients

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with severe RLS or cases in which RLS patients experience problems with dopaminergic treatment. The mechanisms by which endogenous opioids contribute to the pathophysiology of this polygenetic disorder in which a number of variants, including developmental factors, contribute to the phenotype, remain unknown. Recent advances in pain research illustrate the

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analytical power of modern electrophysiological, molecular, and cellular biological techniques in a field previously accessible only to methods of systems biology [1−3]. Insights into pain physiology and neuropharmacology are required in order to better understand the

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complex mechanisms of action of opioid efficacy and safety in patients with pain and RLS; a synopsis of recent data suggests that numerous brain disorders are associated with abnormal

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dendritic spines. Dendritic spines serve as biochemical and electrical compartments. They typically receive input from one excitatory synapse and carry neurotransmitter receptors, organelles, and signaling systems essential for synaptic function and plasticity and thus serve as basic functional units of neuronal integration. Spine heads carry calcium channels and are invaded by action potentials and can thus individually detect the temporal coincidence of preand postsynaptic activity [4,5]. Recent long-term in vivo imaging studies of dendritic spines in animal models using a two-photon microscopy approach to visualize dendritic spines over a time course of weeks have revealed structural plasticity suggesting wiring changes within 5

ACCEPTED MANUSCRIPT neuronal networks. Such an approach may provide a powerful tool to analyze changes in neuronal network rewiring during health and disease. This may also apply to chronic neuropathic pain, which may partially contribute to the chronic pain experienced by some

remodeling may also contribute to RLS pain [6].

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RLS patients. At a conceptual level, a spinal memory mechanism that engages dendritic spine

By activating ubiquitously clustered opioid receptors in excitatory synapses, morphine causes

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the collapse of pre-existing dendritic spines and decreased synaptic α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors [7], whereas the opioid

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antagonist naloxone increases the density of spines. The effect of morphine on dendritic spines is absent in transgenic mice lacking µ-opioid receptors and is blocked by D-Phe-CysTyr-D-Trp-Orn-Thr-Pen-ThrNH2 (CYTOP), a µ-receptor antagonist.

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Chronic activation of µ-opioid receptors evokes the loss of dendritic spines and glutamate (AMPA) receptors via separate, but interactive, intracellular signaling cascades [8,9]. The initial steps of opioid action are mediated through the activation of G protein-linked (δ, κ, and μ) opioid receptors, which activate and regulate multiple second messenger pathways

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associated with effector coupling, receptor trafficking, and nuclear signaling. Differential receptor activation and the distinct distribution of receptor variants located regionally at the

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cellular level add to the complexity of intra- and interindividual variations in response to opioids.

Chronic morphine use and its abstinence for 2 months were accompanied by alterations in dendritic spine morphology in the frontal cortex and nucleus accumbens of mice. Such alterations were accompanied by significant upregulation of the postsynaptic protein Shank1 in synaptosomal enriched fractions. mRNA levels of Shank1 was also markedly increased during morphine treatment and during withdrawal. The authors of this study thus concluded that Shank1 plays an important role in the process of addiction with chronic morphine use via

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ACCEPTED MANUSCRIPT spine morphology [10].

Opioids alter the way in which the brain perceives and interprets nociceptive input. The use of opioids in the management of chronic pain remains somewhat controversial, as opioids are

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also known to be intensely addictive. Adding the opioid antagonist naloxone to orally

delivered opioid agonists combats only their gastrointestinal side effects. Further elucidation of the cellular mechanisms that are regulated by opioids is therefore necessary [11]. The

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response to opioids is influenced by a complex combination of genetic, molecular, and

phenotypic factors. Although some individuals are able to tolerate opioids for years without

develop hyperalgesia with regular use.

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any adverse effects, others may become physically dependent, develop tolerance, and even

Pain appears to be the strongest predictor for pain-associated cognitive decline, which affects all other aspects of life. Chronic pain is a stressful life event, commonly producing anxiety

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and depression. Stress-induced dysfunction of glutamatergic neurotransmission is considered to be a core feature of stress-related mental illnesses. Furthermore, behavioral deficits caused

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by stress exposure are associated with structural changes in dendrites and spines in brain regions such as the amygdala, hippocampus, and prefrontal cortex. The negative impact of

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stress hormones such as corticotropin-releasing hormone (CRH) and neurotransmitters on the density and organization of spines is thought to contribute to the behavioral deficits caused by stress exposure and is reversed by antidepressants. With the cessation of stress, these alterations are usually reversible but may persist in some structures. Elucidation of the signaling pathways and molecular mechanisms that control spine synapse assembly and plasticity will contribute to a better understanding of the pathophysiology of depression. Dendritic spine abnormality may provide a new perspective for investigating pain, and the identification of specific molecular players in RLS. The substantial remodeling of spines during the sleep state supports the notion that sleep plays an important role in the 7

ACCEPTED MANUSCRIPT development and plasticity of synaptic connections [12]. New spines are formed on different sets of dendritic branches in response to different learning tasks and are protected from being eliminated when multiple tasks are learned. These findings indicate that sleep plays a key role in promoting learning-dependent synapse formation and maintenance on selected dendritic

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branches that contribute to memory storage [12]. However, the challenge also consists in disentangling alterations due to the formation of declarative/relational memories from those

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developing in the same regions in relation to non-memory functions [13].

By targeting pain and its consequences, opioids are the first-line treatment in many

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diseases/conditions associated with both acute and chronic pain. The scientifically driven introduction of therapeutic opioids in the past 40 years has been one of the most important advances in medical care. However, opioids also have multiple therapeutic actions apart from pain reduction, and these can be either helpful or harmful. For example, classical opioids can

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cause spasms of the smooth musculature in the sphincter of Oddi, and are therefore contraindicated/or to be used with caution in acute pancreatitis or cholecystitis. The constipating action of morphine is also a burden for patients who take it for pain relief or

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dyspnea in terminal illness, but for a person who has life-threatening diarrhea from gastrointestinal infection or inflammation, the same drug (or rather an analogue) may be life

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saving. An issue of potential concern is the development of opioid-induced hyperalgesia, which is recognized in pain management but may also become significant if these drugs are increasingly used in the future in RLS.

Looking at opioids from an evolutionary perspective, the very primitive invertebrates such as the edible mussel and parasitic worm make opioids and express opioid receptors; in the former, opioids regulate internal muscle activity, whereas in the latter they could benefit the organism by slowing gastrointestinal passage. In fish, opioid receptors are associated with 8

ACCEPTED MANUSCRIPT regulating aversive behavior, which could be analogous to pain avoidance. In higher vertebrates, especially mammals, a large number of naturally produced opioid receptors and their ligands have been described that regulate a wide range of actions from immunomodulation, respiratory control, eating behavior, and gastrointestinal function—and

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of course, their better known actions on pain and sleep induction. The phylogenetic

relationship between opioids and dopamine implicates the reward-center−stimulating action of opioids, which determines their pleasure response but also their addictiveness.

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In higher mammals, there are three main classes of opioid receptors—μ, κ, and δ—for which the molecular and crystalline structures are becoming understood, and for which there are

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many endogenous opioid ligands and their precursors targeting these receptors. Many of these receptor classes also have subtypes, with several expressing different splice variants that add to the variety of effects that the naturally occurring opioids, and therapeutic drugs, can have. Some opioids and receptors may be associated with different effects determined by the sex of the subject, notably with the κ receptor. There is also an opioid-like receptor, ORL-1, which shares some opioid properties but has others too; again, animals also produce endogenous

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ligands that bind to ORL-1, and therapeutic drugs are now available that target it (for further details on the various receptors, their structure and binding properties, see Suratt and Adams [14]).

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Not surprisingly, genomic mutations occur in this range of opioid receptors, and many of

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these have been characterized and associated with phenotypic variations in the actions that therapeutic opioids have on them. For example, the common A118G variation in the molecular structure of the important μ-1 receptor induces a significantly different pain response between wild-type and homozygous genetic variants. Interestingly, the same genetic variation is also associated with susceptibility to addictive behavior. A further level of understanding is needed to explain why therapeutic opioids have such a wide range of effects in humans. These drugs can act as ligands on non-opioid receptor classes. Thus, the histamine receptor is targeted by many opioid drugs, inducing itching and

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ACCEPTED MANUSCRIPT asthma. In some cases, the non-opioid receptor activity is beneficial, for example, drugs such as methadone also target the N-methyl-D-aspartate (NMDA) channel on sensory neurons, which can help with the reduction of chronic pain and sensory hypersensitivity. Furthermore, allosteric receptor binding on opioid receptors may be responsible for some unpredictable

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effects of certain drugs.

The foregoing review of the molecular diversity of opioids and opioid receptors that are

expressed in higher mammals including humans, gives an insight into how therapeutically

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used drugs can have such powerful actions, both beneficial and harmful. The pain relieving

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effects of most opioid analgesics are without doubt, although there is increasing debate about their relative potencies and benefits for pain management in chronic conditions. In recent years, the over-prescription of opioids for pain relief has exposed their ‘dark side’, which includes tolerance, hypersensitivity and paradoxical hyperalgesia, as well as addiction. It is not known, but important to know to what extent these adverse effects may arise with the

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chronic use of opioids in other clinical indications, such as RLS. The side effects of opioids are likely to be important in how patients receiving these drugs

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experience and ultimately balance their benefit and harm. Patients with cancer-related pain benefit from opioids given for analgesia, and yet they can rate their quality of life as being

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lower because of the adverse effects [15]. In cancer patients with a short prognosis, they may regard this as an acceptable trade-off; however, in those with a longer survival, or in chronic non-cancer conditions, the adverse effects of opioids may eventually cause the patient to stop taking them.

Therefore, when beginning use of opioid drugs in non-malignant and especially chronic conditions, there is a duty to remember the phylogenetic history of these drugs and their receptors, their propensities to target non-opioid receptors and for allosteric actions, and to treat them with great respect. When used by experienced clinicians and with constant 10

ACCEPTED MANUSCRIPT monitoring of benefit versus harm, opioid use can be one of the most rewarding tools of medicine. However, when used casually and without regard to their potential toxicity, they

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can be destructive and even lethal.

2. Sleep–pain interaction

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When examining pain and RLS, it may be of particular interest to consider sleep deprivation as one mechanism and to study the importance of sleep as a modifier of pain. The

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bidirectional interactions of sleep, sleep deprivation, and pain have been addressed in multiple animal and human studies, both experimental and clinical. Different types of painful stimulation have been used, as well as exposure to chronic pain. Total, partial, and selective sleep deprivation procedures have been applied, and sleep or proxy markers of sleep have

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been assessed with polysomnography (PSG) and actigraphy.

2.1. Animal studies of sleep, sleep deprivation, and circadian rhythms

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Multiple animal studies have addressed the connection between sleep deprivation and hypersensitivity to pain. Sleep deprivation protocols have included acute and chronic, total

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and partial, global and selective sleep deprivation as well as insufficient or poor-quality sleep. The results of these studies help to clarify how different types of sleep deprivation affect the perception of different types of pain, and to elucidate contributing mechanisms. Rapid eye movement (REM) sleep deprivation has been used to induce hypersensitivity to mechanical stimuli (but also other effects, eg, visceral hyposensitivity) and to study the attenuating or antagonizing effect of various substances acting at different levels [16,17]. Although 5 days of sleep deprivation alone have not been shown to induce mechanical hypersensitivity, when

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ACCEPTED MANUSCRIPT combined with previous musculoskeletal sensitization, using acidified saline injections, mechanical hypersensitivity occurs [18].

Increased pain perception and attenuated opioid antinociception in paradoxical sleep-deprived

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rats, associated with reduced tyrosine hydroxylase staining in the periaqueductal gray matter (PAG) and reversed by levodopa, suggests the involvement of dopaminergic functionality in PAG, leading to a decrease in endogenous analgesic mechanisms [19]. Although spinal D-

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amino acid oxidase (DAAO), which is expressed in astrocytes, promotes tonic pain, DAAO inhibitors cause a dose-related antihypersensitivity to otherwise increased mechanical pain

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perception in REM sleep−deprived rats (presumably due to a reduction in reactive oxygen species) [20]. The hyperalgesic response to mechanical noxious stimuli in rats subjected to paradoxical sleep deprivation seems to be modulated by nitric oxide, as nitric oxide synthase (NOS) activity is increased in the dorsolateral PAG, and NOS inhibitors reverse the

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hyperalgesic response [21]. A different line of research has used capsaicin treatment to investigate the function of transient receptor potential vanilloid 1 (TRPV1), a cation channel that detects noxious stimuli. Capsaicin is considered a tool to investigate sensory fiber

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functions. Mediated by TRPV1, capsaicin treatment in neonatal rats decreased TRPV1 expression in the S1 dorsal root ganglia, induced noxious heat sensation, and abnormal

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circadian body temperature, and changed the expression of circadian clock genes such as Hsf1 and Per2 [22].

2.2. Human studies in health and disease: Sleep and circadian influences In humans, the interaction between pain and sleep, or the influence of sleep and different types of sleep deprivation on pain perception, have been studied using various methods. In healthy humans, a diurnal time course of infrared laser−induced heat pain perception can be observed when measured in close intervals every 2 hours from morning to nighttime hours 12

ACCEPTED MANUSCRIPT with an increase of pain scores in the evening and at night [23]. Autonomic pain responses to nociceptive stimulations are significantly reduced in all sleep stages. The R-R interval decreases even when there is no arousal, but is even more marked with arousal [24]. Lateral and medial pain systems are thought to be functionally dissociated during sleep. It has been

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suggested that this dissociation between sensory and orienting–motor networks might explain why nociceptive stimuli can be neglected or incorporated into dreams without awakening the individual [25]. In contrast to the findings presented above [23], another study has reported

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that thermal pain scores are lower in the morning; however, this study covered only 10 hours of the day, divided into three blocks [26]. The authors demonstrated that the time-of-day

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modification of pain perception is modality dependent, so although there were no significant diurnal differences in mechanically induced pain parameters, there were diurnal changes for cold and heat-related pain [26]. In healthy young volunteers, sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain

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ratings. Sleep reduction could lead to an impairment of activation in the ascending pathway (and reduced laser-evoked potentials [LEPs]) and boost pain perception, perhaps by lack of

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pain control [27].

Self-reported short sleep duration (<6.5 hours/night) after heat−capsaicin treatment in 28

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healthy participants has been shown to be associated with more secondary hyperalgesia and skin flare, but reduced analgesic effect of distraction [28]. Acevedo et al. found that hyperalgesic pain perception and concomitant LEP threshold increased following total sleep deprivation, and changes were cumulative over several days [29]. Schuh-Hofer et al. performed quantitative sensory testing after a normal night and a night of total sleep deprivation, in random order. One night of total sleep deprivation was found to induce generalized hyperalgesia. It modulated nociception, whereas detection thresholds of nonnociceptive modalities remained unchanged [30]. 13

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Bastuji et al. recorded intracortical field potentials to pain during sleep and wakefulness [25]. Dynamics of responses differed among recording locations according to sleep stage. Although the lateral operculo-insular system (supervising sensory analysis of somatic stimuli) remained

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active during non-REM sleep, mid anterior cingulate processes relating to orienting and

avoidance behavior were suppressed. It is thought that this functional dissociation of lateral and medial pain systems during sleep might explain why nociceptive stimuli can be neglected

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or incorporated into dreams without awakening the subject [25].

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2.3. Clinical context

Pain exacerbation through sleep deprivation has also been shown in patients with rheumatoid arthritis [31], juvenile arthritis, and dermatomyositis [32], in whom subjective sleep disturbance has been shown to be associated with increased pain and decreased quality of life

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[32]. In chronic somatoform pain, sleep deprivation has been shown to affect both pain regulation and mood [33]. In a heterogeneous chronic pain patient sample, it has been shown that previous pain is not a reliable predictor of subsequent sleep, but sleep quality is a

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consistent predictor of pain the next morning [34]. A comprehensive clinical review has addressed the effect of postoperative sleep deprivation:

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the release of specific cytokines—interleukin-1 (IL-1), tumor necrosis factor−α (TNF-α), and interleukin-6 (IL-6)—are known to disturb sleep, increase sleep fragmentation, and decrease slow-wave sleep (SWS) and REM sleep, although sympathetic overactivity and stress hormone levels could also disturb sleep [35].

3. Use of opioids in RLS

Opioids have been used for some time to treat patients with severe RLS for whom other drugs 14

ACCEPTED MANUSCRIPT have failed. Prolonged release (PR) oxycodone−naloxone is currently the only licensed opioid product (secondline treatment for severe inadequately controlled RLS in Europe), although tramadol, methadone, morphine sulfate, and other oxycodone formulations are often used in clinical practice for RLS therapy. The basis for combining PR oxycodone and PR naloxone is

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to prevent the otherwise inevitable constipating effect of the opioid on the gut, without

affecting the central beneficial effects. Evidence-based data for opioids are scarce, as apart from very small randomized controlled trials [36], open studies or retrospective cohort

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observations [37−39], data from only one large multi-center randomized controlled trial with PR oxycodone/naloxone are available [40]. Results from clinical trials and observational

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cohorts show a general improvement of RLS including subjective sensory symptoms and restlessness, motor symptoms as far as assessed, and a possible restoration of sleep.

3.1. Pre-clinical data on opioids in RLS

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Only a few pre-clinical studies are available that investigate the possible role of opioids in RLS. One pilot study looked into post-mortem quantification of β-endorphin, Met-enkephalin, and Leu-enkephalin in the thalamus and the substantia nigra in five brains of RLS patients

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compared with five brains of matched controls. Only a significant decrease of β-endorphin in the thalamus was observed, suggesting an altered central processing of pain in RLS with

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involvement of the μ-receptor. The small number of brains, the long-term pre-treatment with opioids in the majority of patients, and some methodological issues limit the conclusions of this study. Interestingly, there was no decrease of tyrosine hydroxylase in the substantia nigra in RLS brains, although one of the main hypotheses for pathogenesis has been that there is a dopaminergic hypofunction in RLS, which cannot be confirmed by these results and is also no longer favored by a recent pathophysiological hypothesis [41]. A correlation of decreased iron levels and thalamic opioid hypofunction has been postulated by Walters et al. [42]. An earlier study looked into the possible protection of opioids against 15

ACCEPTED MANUSCRIPT nigral cell death induced by apoptosis induced by iron deficiency, and proposed this as an animal model for RLS [43]. Finally, there is the hypothesis that there is an “intimate relationship between iron, dopamine and opioids in the pathogenesis of RLS” [43]. Molecular

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mechanisms, however, have not yet been established to confirm this hypothesis.

3.2. Mode of action of opioids in RLS: Possible dopamine−opioid interaction

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From studies on opioids, addiction, and the reward system, we know that the rewarding effect of pain relief requires opioid signaling in the anterior cingulate cortex (ACC), activation of

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midbrain dopamine neurons, and the release of dopamine in the nucleus accumbens (NAc) [44] Activation of opioid receptors, which include the μ, δ, and κ subtypes, results in Gi  coupled inhibition of adenylyl cyclase and cAMP formation in the postsynaptic neuron. It also starts the suppression of voltagegated calcium currents and activates the outward potassium currents, resulting in hyperpolarization, reduced neurotransmitter release, and inhibition of dorsal horn neurons with depression of excitatory postsynaptic potentials. Therefore, the

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longterm use of opioids leads to an inhibition of the dorsal and ventral horn, compared with an excitation of the same system with dopaminergic substances [45]. A further important action may be caused by the expression of opioid receptors on sympathetic preganglionic neurons in the spinal cord. An overview on the interaction between opioids and other

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neurotransmitters such as dopamine or serotonin investigates the current status of the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of

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endogenous mediators in the living brain [46]. At first sight, there seems to be no difference between oxycodone and dopamine agonists as far as efficacy in improving sensory and motor symptoms of RLS is concerned, although comparative studies are not available. Larger sleep studies, however, which look into time of wakefulness, as recorded on PSG, and sleep stages of RLS patients, have yet to elucidate whether opioids improve sleep itself or only reduce periodic limb movements in sleep (PLMS). Subjective sleep evaluation during therapy with oxycodone/naloxone has been shown to significantly improve when assessed with the Sleep Scale from the Medical Outcomes Study (MOS), without an increase in somnolence or drowsiness, and even daytime alertness and daytime naps improved [40]. From existing data, it is possible only to speculate whether opioids improve sleep solely by reducing PLMS, or whether there is an additional direct mode of action of opioids on sleep. In healthy adults, 16

ACCEPTED MANUSCRIPT acute administration of morphine sulfate or methadone significantly reduces deep sleep and increased stage 2 sleep, but does not alter sleep efficiency [47]. However, it is known that dopamine D3receptor−acting agents, such as pramipexole and cabergoline, increase wakefulness, arousals, or stage shifts [48] at night, thereby disturbing sleep, confirmed by electroencephalography (EEG) spectral analysis of the D1/D2 receptor agonist pergolide [49].

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Most probably, a dose relation may explain daytime sleepiness with dopamine agonist and nighttime sleep disturbance [50]. Similar results have been reported in animal experiments, even for dopamine-D4−receptor agonists. These agonists increased waking duration, and

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conversely, reduced non−rapid eye movement (NREM) sleep duration in rats [51].

Another lesson learned from clinical trials is the possible lack of augmentation during

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treatment with opioids, although two reports [52,53], which have not been confirmed in clinical trials, report augmentation with tramadol. Tramadol has, in addition to its opioidergic action, some serotonergic (agonistic) properties, which may explain a worsening of RLS with higher dosages [53]. The lack of augmentation with other opioids may be explained by the

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specific interactions of opioid and dopamine receptors in the spinal cord. Although only opioids show sustained long-term inhibitory responses, dopaminergic stimulation induces short-term spinal inhibitory responses, and induces excitatory responses with longterm

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therapy [54]. This mode of action has been explained in more detail by Clemens’ group [55].

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Besides the spinal action of opioids in RLS patients, the medial pain system could be involved in RLS. A rationale for this hypothesis may be derived from a PET study with diprenorphine. Fifteen patients with RLS and 12 controls were studied using diprenorphine. There were no mean group differences in opioid receptor binding between patients and controls; however, an inverse correlation was detected for ligand binding, both for RLS severity investigated with the IRLS and pain scores investigated with the McGill Pain Questionnaire. The regions were attributed to the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex, and orbitofrontal cortex) (Fig. 1). In this population of moderately to severely affected RLS patients, the results suggest that the more severe the RLS, 17

ACCEPTED MANUSCRIPT the greater the release of endogenous opioids. Opioid receptor availability in the medial affective pain system in the brains of RLS patients was similar to receptor bindings in patients

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with chronic pain disorders [56].

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3.3. Clinical trials with opioids in RLS Some early clinical studies of opioids and dopamine blocking substances point to the hypothesis that opioids work through indirect dopamine activation [57]. Since 1993, when the first small controlled study was performed with oxycodone in RLS [36], opioids have been considered an efficient off-label therapy in patients with severe RLS. Divided doses of standard oxycodone formulations have been shown to significantly improve subjective sleep, as measured by visual analogue scales, and PLMS, as measured by PSG [36]. Several open-label studies [58] and case series followed, consistently showing benefit of RLS, even in long-term therapy with methadone [37,38]. 18

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Prolonged release oxycodone/naloxone has recently been studied in a multicenter placebo controlled trial in 495 patients with severe, treatment-refractory RLS [59]. Treatment with a mean dosage of 10/5 mg prolonged oxycodone/naloxone twice daily was efficacious in

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significantly reducing RLS severity compared to placebo (mean difference in IRLS score between groups at 12 weeks: 8.15) (Fig. 2). Secondary outcomes such as the RLS-6 scale score during the daytime, the MOS Sleep Scale score, and quality-of-life scale scores also

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improved. Treatment-related adverse events were similar to those from other opioid studies, and included constipation and nausea. The controlled 12-week period was followed by an

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open-label trial in 197 patients using the same dosages up to 1 year. At the end of this period, IRLS scores were stable, and even further reduced compared to baseline and week-12 scores. Interestingly, the dosages needed were smaller compared to those used in pain studies, similar to the low dopamine agonist dosages that are efficacious in RLS. Furthermore, the prolonged

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release effect may have been important as well, when looking at the lack of augmentation cases in this trial. The pulsatile versus the continuous mode of action of both dopaminergic

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and opioidergic agents should be further elucidated in the pathophysiology of RLS [60].

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Along these lines, another possible mode of action has arisen from observation of opioid pump systems in patients with severe RLS. Case studies have been performed with intrathecal morphine [61]; in this way, the dosage of morphine can be significantly reduced, and the

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systemic side effects of opioids can almost completely be avoided. Even longterm

observations using these small doses are available, with a further dose reduction over time,

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and no loss of efficacy has been reported so far.

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4. Conclusion and future directions

The involvement of spinal opioid receptors in RLS, possibly via spinal dopamine receptors, seems likely and needs further therapeutic consideration. The efficacy of low dosages of opioids in treatment studies, especially when combined with naloxone, points towards an

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indirect mechanism via the dopamine receptors, which are known to require only small dosages in RLS patients. The current results from both short- and long-term trials and studies with opioids, especially with prolonged release oxycodone/naloxone, provides an optimistic

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view of alleviating RLS symptoms in severe RLS patients, who are sometimes treatment refractory to dopaminergic agents, or possibly during or after augmentation. Although

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subjective sleep data are promising, and insomnia and subjective sleep quality are definitely improved, how opioids may modify sleep and breathing in RLS needs to be studied with PSG. Further research is also needed to describe the primary site of the action of opioids, including answering the question of how the circadian rhythm of RLS plays a role. New perspectives are opening up with the discovery of a new structure-based opioid analgesic PZM21, with fewer side effects such as respiratory depression but with similar analgesic efficacy [62].

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Endogenous opioids, like dopamine, are ancient signaling molecules that are expressed in many tissues and that give a wide range of effects through many opioid receptor systems. Opioid receptor agonists are known to relieve symptoms of restless legs syndrome (RLS). Therapeutic opioids can provide beneficial effects but may also cause harm through activation of “off-target” opioid or non-opioid receptors. Differential receptor activation and distribution at the cellular level add to the complexity of opioid response. Pathomechanisms of action for opioids in RLS are not fully understood but may involve the medial pain system and dopamine system in RLS. RCTs are now available to prove the efficacy of oxycodone in RLS.

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