Sensory symptoms in restless legs syndrome: the enigma of pain

Sleep Medicine xxx (2013) xxx–xxx

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Review Article

Sensory symptoms in restless legs syndrome: the enigma of pain John W. Winkelman a,⇑, Alison Gagnon b, Andrew G. Clair c a

Brigham and Women’s Hospital, Division of Sleep Medicine, 221 Longwood Ave, Boston, MA 02115, United States UBC Scientific Solutions, 3530 Post Road, Southport, CT 06890, United States c Pfizer Inc, New York, NY, United States b

a r t i c l e

i n f o

Article history: Received 29 November 2012 Received in revised form 12 April 2013 Accepted 18 May 2013 Available online xxxx Keywords: Restless legs syndrome Pain Neuropathy Periodic leg movements Gabapentin Pruritis Sleep disorders

a b s t r a c t Restless legs syndrome (RLS) is a common sensorimotor condition characterized by an urge to move the legs, worsening of symptoms at rest and during the evening/night, and improvement of symptoms with movement. Our review explores the role and impact of sensory symptoms in RLS. The phenomenology of RLS is discussed, highlighting the difficulty patients have in describing their sensations and in differentiating between sensory and motor symptoms. Sensory symptoms have a significant impact on quality of life but remain much less well understood than motor symptoms and sleep disturbances in RLS. Although RLS symptoms usually are not described as painful, sensory manifestations in RLS do share some similarities with chronic pain sensations, and RLS frequently occurs in chronic pain and neuropathic conditions. Peripheral neuropathies may account for some of the sensory disturbances in secondary RLS, while alterations in central somatosensory processing may be a more viable explanation for the sensory disturbances in primary RLS. The effectiveness of analgesics in treating RLS supports the concept of abnormal sensory modulation in RLS and suggests an overlap between pain modulatory pathways and sensory disturbances. Future studies are needed to better understand the experiential and biologic aspects of altered sensory experiences in RLS. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by abnormal sensations in the limbs that are both dependent on activity and time of day, such that symptoms are promoted by rest and relieved by activity and peak in the evening or at night. The majority of patients with RLS experience periodic leg movements during sleep, generally small extensor movements of the foot and lower leg, which occurs roughly every 15–30 s during sleep [1]. Impairments in sleep, daytime functioning, and health-related quality of life (HRQoL) are major consequences of RLS [1,2]. Two forms of RLS have been characterized: secondary RLS, which occurs in conjunction with another medical condition (e.g., renal disease, diabetes mellitus [DM]); and primary RLS, which is not associated with a known predisposing disorder and often is hereditary [3]. Resolution of the underlying condition in secondary RLS usually results in improvement of RLS symptoms, while primary RLS is thought to be a lifelong condition. RLS prevalence estimates in the general population vary depending on the method of ascertainment and the criteria used for diagnosis [4]. Using the validated diagnostic criteria, one study found that 7% of the general population in Europe and the United ⇑ Corresponding author. Tel.: +1 617 724 7426. E-mail address: [email protected] (J.W. Winkelman).

States reported all four diagnostic criteria of RLS, and 2.7% met the criteria for clinically significant RLS (moderate to severe symptoms at least twice a week) [1]. RLS more frequently occurs in women than in men and prevalence increases with age [1,5]. The diagnosis of RLS is based on patient report of the four essential hallmark symptoms of RLS: (1) urge to move the limbs, usually accompanied by unpleasant or uncomfortable sensations; (2) symptoms occur or worsen at rest; (3) symptoms occur or worsen in the evening or night; and (4) symptoms are relieved by movement [4]. By definition, all patients with RLS have the urge to move; however, the presence of distinct uncomfortable or unpleasant sensations are not required for the diagnosis, and thus are not consistently present. The objective of our review was to critically evaluate the role and impact of the sensory symptoms in RLS from both experiential and neurobiologic perspectives. These symptoms often may be described as pain, and although there are similarities the distinction between sensory symptoms in RLS and chronic pain sensations is highlighted. 2. Methods The International Association for the Study of Pain Terminology [6] was used to derive most of the terms for a search strategy for sensory symptoms. PubMed and Institute of Science Index databases were searched with the following search strategy (allodynia

1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.05.017

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J.W. Winkelman et al. / Sleep Medicine xxx (2013) xxx–xxx

OR analgesia OR causalgia OR central pain OR dysesthesia OR hyperalgesia OR hyperesthesia OR hyperpathia OR hypoalgesia OR hypoesthesia OR neuralgia OR neuritis OR neurogenic OR neuropathic OR neuropathy OR nocicep OR pain OR noxious OR paresthesia OR itch OR pruritus OR comorbid OR prevalence OR incidence OR symptom OR sensory OR central sensitization) AND (restless legs syndrome) and was limited to articles in the English-language literature published between January 1, 2000 and May 18, 2012. Articles from the authors’ libraries and citations from retrieved journal articles also were evaluated. Articles that described the prevalence, impact, treatment, or pathophysiology of the sensory aspects of chronic pain or RLS were selected. Additional articles published after May 18, 2012 and identified during the review process also were included. 3. Results 3.1. Neuroanatomy/neurobiology of pain pathways An understanding of normal pain processing is necessary before discussing how the sensory component of RLS relates to more typical pain sensations. Pain perception involves both ascending and descending neural pathways that transduce sensory information from the periphery to the central nervous system (CNS). Nociceptors and mechanoreceptors located in the periphery are activated in response to stimuli, such as pressure, impact, and temperature above a certain threshold. Peripheral nerves transduce signals from these sensory receptors to the spinal cord, which in turn transmits them to the ascending pathway to the brain for processing. The first painful stimulus is transmitted from high-threshold mechanoreceptors via dorsal horn A-d (myelinated) fibers to the CNS and provides qualitative (e.g., sharp, pricking, stinging) information and location of the sensation in an acute manner [7]. More prolonged stimuli are transmitted via nociceptors via unmyelinated C axons and result in more persistent sensations (e.g., burning) [7]. Acute pain arises from both first and second pain components, whereas chronic pain arises from the second pain component. Supraspinal mechanisms regulate pain perception at the level of the spinal cord [7], and pain amelioration via descending pathways occurs in normal pain processing [8]. Other spinal cord pathways are responsible for transmitting motor reflexes and movements as a result of noxious stimuli [9]. Repeated exposure to a pain stimuli leads to a reduced threshold for activation of the nociceptive neurons in the CNS, a process known as central sensitization [10]. As central sensitization involves a change to the properties of neurons in the CNS, the pain sensation becomes decoupled from the noxious peripheral stimuli itself [10]. The relationship between normal pain responses and the sensations in RLS is discussed below. 3.2. Phenomenology of RLS symptoms The essential feature of RLS, an urge to move the limbs, may be considered either as a sensory or as a motor symptom, depending on one’s perspective. In many cases, as elaborated in the diagnostic criteria [4], this urge to move may be associated with a dysesthesia in the affected limb, which is more clearly a sensory symptom. Many patients will not be able to distinguish these two features of their symptoms (37% of patients in one study [11]), reporting only a disagreeable feeling or ‘‘discomfort’’ in the limb that is relieved by movement. In fact, the most consistent feature of RLS sensory symptoms is that they are difficult to describe, leading to long lists of the words employed by patients to describe their symptoms (see Table 1). However, most patients report that RLS symptoms arise from deep in the limb, rather than superficially,

and feel like movement within the leg [4]. Analogies are commonly used to describe the sensory phenomena, such as creepy crawly, ants crawling, bubbling, electric current or discharge, tingling, worms moving, Elvis legs, jittery, fidgets, itching bones, grabbing, twitching, or squeezing [4,11–13]. A recent survey reported that electrical, prickling, burning, tingling, and itching sensations were the most commonly reported descriptors [11]. Although RLS symptom descriptions are varied, more RLS sufferers in the RLS Epidemiology, Symptoms and Treatment general population survey (45.7%) reported that at least one of these sensory symptoms (including the urge to move) was their most troublesome symptom, compared with associated RLS symptoms, including sleep-related symptoms (38%), disturbance of daytime function (6.9%), motor disturbances (3.4%), or mood (2.9%) [1]. In the companion RLS Epidemiology, Symptoms and Treatment survey in the primary care population, more RLS sufferers reported uncomfortable feeling in the legs (27%) as their most troublesome symptom compared with pain (21%), inability to stay still/urge to move (11.8%), or inability to get comfortable (11.1%) [14]. Whether RLS sensory symptoms are described as painful often is confounded by how this question is addressed. When specifically queried about pain, many patients will select it as a term to describe their RLS symptoms, and some report it as their most troublesome symptom [15]. In an effort to better understand the phenomenology of RLS symptoms, the standardized nomenclature of the McGill Pain Questionnaire (MPQ) [16] has been employed. Using the MPQ, RLS patients most commonly described their symptoms as tingling, nagging, annoying, tiring, gnawing, jumping, pricking, dull, and aching [17]. Of note is that pain scores do not correlate well with RLS severity ratings [17]. In one small study of patients with moderate to severe RLS, the average visual analog scale pain score, the gold standard of pain ratings, was only 18 mm (on a 0–100-mm scale) and did not correlate with RLS severity measured using the International Restless Legs Syndrome Study Group (IRLSSG) severity scale [16]. Similarly, in a clinical study of patients with mostly moderate to severe RLS, even ‘‘pain associated with RLS’’ ratings were only approximately four on a scale of 1–10, a rating considered to reflect mild to moderate pain [18]. The observed lack of correlation between RLS severity and pain scores could be partly related to how pain sensations are classified. Although the European Federation of Neurological Societies recommends that the intensity and unpleasantness of pain sensations be separately rated [19], this guidance is perhaps not always followed. As such, abnormal sensations in RLS may be inappropriately measured by intensity and not unpleasantness. At the same time, unpleasant sensations can be further differentiated into pain, an unpleasant sensory experience associated with actual or potential tissue damage, and dysesthesia, an unpleasant abnormal sensation, which is either spontaneous or evoked [6]. In practice dysesthesias also may be pain, but this is not necessarily the case, as the patient may subjectively experience the sensation as distinct from the typical qualities of pain [6]. Further characterization of the sensory sensations in RLS can assist in developing a deeper understanding of these symptoms. On the other hand, the number of words selected on the MPQ in patients with RLS did correlate with IRLSSG severity [17]. Of note is that the terms used to describe RLS corresponded to those used for neuropathic pain. However, these terms did not correspond to those used by lung cancer patients to describe their neuropathic pain [20]. This disparity of findings may reflect both that most patients with RLS lack conventionally described pain as well as the difficulty of describing RLS symptoms. For example, a study of 56 patients with RLS stressed the difficulty patients had in describing the quality of their sensations, often having to use analogies or emotive/affective words as descriptors [11]. Although the most commonly selected sensory words in this study (electrical, tingling,

Please cite this article in press as: Winkelman JW et al. Sensory symptoms in restless legs syndrome: the enigma of pain. Sleep Med (2013), http:// dx.doi.org/10.1016/j.sleep.2013.05.017

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J.W. Winkelman et al. / Sleep Medicine xxx (2013) xxx–xxx Table 1 Common descriptors for restless legs syndrome sensations. Bentley et al. [17] (n = 25)

Karroum et al. [11] (n = 56)

Kerr et al. [21] (n = 41)

MPQ

QDSA

MPQ

Spontaneous

Prompted

Tingling, 56% Nagging, 56% Annoying, 48% Tiring, 48% Aching, 32% Exhausting, 20%

Electrical, 43% Prickling, 30% Burning, 29% Tingling, 27% Irritating, 18% Itching, 14% Annoying, 11% Unbearable, 11%

Tingling, 56% Jumping, 54% Nagging, 51% Tiring, 44% Annoying, 41% Tugging, 39% Dull, 34% Gnawing, 29%

Irritating, 17% Painful, 17% Crawling, 15% Uncomfortable, 15% Discomfort, 12% Restless, 10% Tingling, 10% Twitching, 10%

Restless, 88% Uncomfortable, 78% Twitchy, 63% Unpleasant, 59% Irritating, 56% Nagging, 56% Fidgety, 46% Jerky, 46%

Abbreviations: MPQ, McGill Pain Questionnaire; QDSA, Questionnaire Douleur de Saint-Antoine (a validated French reconstruction of the MPQ).

3.2.1. Relationship between the sensory and motor component of RLS There has been some debate regarding the relationship between the uncomfortable/unpleasant sensations and the urge to move and periodic leg movements while awake in RLS. In a clinical series of patients who reported uncomfortable RLS sensations, 55% experienced these sensations exclusively before the urge to move the legs [11]. Another 37% of patients could not distinguish the sensations from the urge to move the legs [11]. The relationship between these sensory and motor manifestations of RLS has been simultaneously assessed in real time using the Suggested (or Forced) Immobilization Test. One study found that in patients with primary RLS, 49% of periodic leg movements during the Forced Immobilization Test were not associated with a patient-reported sensory event (within 5 s) [23]. However, all patients reported a sensory event at some point during the Forced Immobilization Test, with most (96%) sensory events associated with a motor event. Sensory events occurred before but more com-

monly after the onset of leg movement, as well as in the absence of leg movement (Fig. 1). These findings suggest that the sensory and motor components of RLS are independent phenomena arising from a common dysfunction [23]. Similarly, there was a temporal dissociation between sensory events and periodic leg movements in RLS patients during a Suggested Immobilization Test [24]. However, another study found that all patients experienced a sensory event several minutes before the leg movement [25]. The discrepancy between these findings may be from the latency allowed between sensory and motor events or possibly varying criteria used to define a sensory event. Nevertheless, this discrepancy highlights the difficulty in defining the relationship between sensory and motor components in RLS. 3.3. RLS in chronic pain conditions The prevalence of RLS in patients with various chronic pain or sensory disorders is shown in Table 2. In patients with migraine, the prevalence of RLS, though still within the range of that found among the general population [4], was significantly higher than that observed in other headache disorders [26]. In another study, 34% of patients with chronic headache conditions (chronic or episodic migraine and cluster, persistent, or posttraumatic headaches) had RLS [27]. Interestingly, dopamine receptor–blocking agents used to treat symptoms of chronic headache increased the likelihood of development of drug-induced akathisia (motor restlessness) in patients with RLS compared to those without RLS [27]. In a study of two different pain conditions, RLS was more common in patients with fibromyalgia (31%; P < .001) and rheumatoid arthritis (15%; P = .023) compared with healthy controls (2%) [28]. More patients with rheumatoid arthritis and comorbid RLS had neurophysiologic abnormalities than patients with rheumatoid arthritis without RLS [29]. One study of patient-reported

Percent of sensory events

and burning) were selected by 70% of patients, up to 16 words were required to cover 95% of the patients [11]. However, it has been observed that patients’ spontaneous descriptors can differ from the basic terminology used in the RLS diagnostic criteria (see Table 1), suggesting that expanding these criteria to include more commonly used descriptors may improve the diagnostic accuracy of RLS [21]. In one study of 41 patients with RLS, it was determined that just four words (restless, uncomfortable, twitchy and creepy-crawly) and four phrases (legs need to stretch, urge to move, legs want to move on their own, need to kick out legs) were sufficient so that at least one was selected by every participant to describe their symptoms [21]. Of note was that the mean number of descriptive words selected spontaneously was 2.6, compared with 21.8 for prompted words and 10.1 for words from the MPQ, suggesting the difficulty patients may have in spontaneously selecting words and the importance of prompting with appropriate descriptors [21]. Although RLS perhaps is not painful in the strict sense, it still has considerable impact on HRQoL. Decrements in HRQoL primarily are from sleep disturbance and periodic leg movements during sleep but also may be partly related to sensory symptoms [2]. In RLS patients, all Short Form-36 Questionnaire scales and summary measures are lower than those in a healthy population [2,22]. The burden of RLS on HRQoL was greatest on physical health domains, most notably bodily pain and the physical component summary [22]. Increased symptom bother but not frequency was associated with greater decrements in physical domains [2]. A greater proportion of patients with RLS (63%) reported that ‘‘bodily pain’’ interfered a little bit or more with normal work in the past 4 weeks compared with the US general population (44%) [22]. The HRQoL impairments were greater in patients with RLS than those observed in patients with type 2 DM and comparable to those in patients with osteoarthritis [22].

100 80

76.9%

60 40 18.8%

20

4.3% 0 After motor event

Before motor event

No motor event

Fig. 1. The relationship between sensory and motor events. Pelletier et al. [23] studied the temporal relationship between sensory and motor events in patients with RLS. Patients underwent electromyogram recording during a 60-min Forced Immobilization Test. Patients used a hand switch to indicate when they felt an uncomfortable sensation in their legs. The bar chart displays the proportion of sensory events (N = 465) recorded before or after initiation of the motor event or in absence of a motor event.

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symptoms accompanying fibromyalgia found that two-thirds of these patients reported RLS symptoms [30], and another study found patients with fibromyalgia were more likely to report having RLS and abnormal leg movements during sleep than patients without fibromyalgia [31]. RLS was the major manifestation in 4 of 12 patients with cryoglobulinemia and peripheral neuropathy [32]. RLS was more common in patients with Charcot-Marie Tooth syndrome type 2 vs Charcot–Marie–Tooth syndrome type 1, and those patients with comorbid Charcot–Marie–Tooth syndrome type 2 and RLS had more sensory symptoms compared to those without RLS (P = .026) [33]. Patients with somatoform pain disorder appeared to experience more severe pain if they had comorbid RLS [34]. However, these studies are limited by the varying definitions and means of diagnosing RLS, which often can be difficult in patients with widespread pain or multiple somatic complaints. The relationship between peripheral neuropathy and RLS remains unclear. Among patients with type 2 DM, nearly all patients with RLS had comorbid peripheral neuropathy [35]. RLS was more common in patients with painful peripheral neuropathy than nonpainful neuropathy [36], and treatment of neuropathic pain in patients with diabetic peripheral neuropathy may improve symptoms of RLS [37]. However, other data fail to support a link between peripheral neuropathy and RLS. Higher rates of RLS were observed in patients with peripheral neuropathy vs controls, based on an RLS screening questionnaire; however, after diagnostic confirmation of RLS, no significant difference in prevalence was observed between patients with peripheral neuropathy (12.2%) and

controls (8.3%; P = .14).[38] However, in the same study, the prevalence of RLS was higher in patients with hereditary neuropathies (14.2%) vs acquired neuropathies (9.2%; P = .014) and controls (8.2%; P = .033) [38]. As with other studies of different disorders with prominent painful symptoms, criteria for defining or diagnosing RLS and the fact that neuropathy itself may confound diagnosis of RLS [39], pose challenges for defining the relationship between peripheral neuropathy and RLS. Furthermore, the data on RLS prevalence in patients with pain syndromes must be cautiously interpreted. Primary pain symptoms of these disorders could be misdiagnosed as RLS, or conversely RLS could be interpreted as a primary pain disorder. Given the varied descriptions of RLS symptoms and the absence of an objective gold standard for diagnosis, misdiagnosis is likely to be common, particularly in studies in which only questionnaires and not interviews by clinicians experienced in RLS form the basis of diagnosis. This issue has been documented in patients with end-stage renal disease who were assessed by both questionnaire and clinical interview with the questionnaire shown to have low sensitivity and low specificity, suggesting that questionnaires are not sufficient to diagnose or even screen for RLS in these patients [40]. It also has been proposed that questionnaires could be updated to help exclude mimics of RLS [41]; for example, some recent studies have employed supplementary questions for patients who satisfy the four diagnostic criteria for RLS including questions on family history [42].

Table 2 Prevalence of restless legs syndromea in chronic pain and sensory disorders. Condition

RLS, (%)

Migraine/chronic headache Chen et al. [26] 11.1 Young et al. [27] 34

Characterization of RLS

Notes

IRLSSG criteria and physician diagnosis via telephone 4 IRLSSG criteria

Patients with clinically relevant RLS, 4.3% Chronic or episodic migraine and cluster, persistent or posttraumatic headaches

Cryoglobulinanemic neuropathy Gemignani et al. 30 Patient history according to minimal ICSD criteria [110] [32] Rheumatoid arthritis Salih et al. [29] 15 Yunus et al. [28] 25 Fibromyalgia Shaver et al. [31] Yunus et al. [28] Zoppi and Maresca [30] Stehlick et al. [112]

20 31 66

Patient report of being diagnosed with RLS Symptom questionnaire Patient report of RLS

64

4 IRLSSG criteria

Peripheral neuropathy Gemignani et al. 40 [36] Gemignani et al. 16 [36] Mold et al. [113] 31 Nineb et al. [114] 54 Gemignani et al. [37] Gemignani et al. [42]

Gibb and Lees criteria [111] Symptom questionnaire

4 of 12 patients

vs 2% of HC (P < .023)

vs 2% of HC (P < .001)

Structured interview, 4 IRLSSG criteria

Painful neuropathy

Structured interview, 4 IRLSSG criteria

Nonpainful neuropathy

Symptom questionnaire IRLSSG criteria

30

Structured interview using IRLSSG

Older patients (age P65 y) in family practice setting Patients with Dx of PN; vs 56% of patients with suspect PN but not with Dx of PN; vs 10% in HC Painful diabetic peripheral neuropathy

36

Semistructured interview using EFNS guidelines [19]

Distal symmetric polyneuropathy

Charcot Marie Tooth Syndrome II Gemignani et al. 37 IRLSSG criteria [33] Somatoform pain disorder Aigner et al. [34] 42

Physician screen using IRLSSG and ICSD criteria [115]; clinical diagnosis

Mild RLS symptoms were not diagnosed as RLS

Abbreviations: IRLSSG, International Restless Legs Syndrome Study Group; RLS, restless legs syndrome; EFNS, European Federation of Neurological Societies; ICSD, International Classification of Sleep Disorders; HC, healthy controls; y, years; Dx, diagnosis; PN, peripheral neuropathy. a Clinically relevant RLS symptoms P2 days/week over last 12 months and moderate to severe impact on quality of life.

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RLS symptoms share important features with other sensorimotor disorders, including motor tics with premonitory urges, neuropathic pain disorders, and itch. In patients with Tourette syndrome (TS) or simple motor tic syndromes, complex and simple motor tics and compulsions are preceded by urges to move or a need to perform the desired behavior [43]. As with the urge to move in RLS, patients with TS report that the urges are relieved by performance of the tic [44]. Higher urge ratings are observed when tics are suppressed [44], a phenomenon similar to the increased leg discomfort reported during the suggested immobilization testing in RLS [45]. Patients with TS reported that the urges were more bothersome than the tics themselves [46], consistent with the observation that RLS patients were more likely to be troubled by sensory disturbances/urge to move than motor abnormalities [1]. Comorbidity between TS and RLS has been noted [47], suggesting that their underlying pathophysiology may be related. To that point, the BTB (POZ) domain containing 9 (BTBD9) single-nucleotide polymorphism is associated with both disorders [48,49], and both disorders are modulated by dopaminergic agents [50,51]. As with the circadian rhythm of RLS symptoms, pain intensity in several chronic pain conditions, including painful diabetic neuropathy, postherpetic neuralgia, and phantom limb pain, is most pronounced in the evening and at night [52–54]. For instance, 52% of patients with painful diabetic neuropathy reported that pain was worse at night, whereas only 17% had worse pain in the morning [55]. To what extent this is related to a true circadian rhythm, as with RLS (Fig. 2) [56,57], vs other confounding features (e.g., time awake, distraction) is uncertain, as the appropriate studies have not been performed in these pain conditions. Patients with phantom limb pain experience paresthesias at night while at rest or lying down, an urge to move the phantom or residual limb, and spontaneous movements while awake or asleep [54]. Physical or cognitive stimulation (e.g., rubbing, arguing, social stimulation, distraction) improves RLS symptoms and lessens phantom limb pain [4,13,54]. As with RLS, these chronic pain conditions negatively impact sleep, worsening the underlying sensory symptoms of the disorder. Although RLS shares characteristics with chronic pain conditions, there also are notable differences between RLS and these disorders. Several nontraditional analgesics effective for treating chronic pain also improve RLS symptoms (see below, Evidence for effective agents for RLS working as analgesics); however, tricyclic antidepressants and selective serotonin norepinephrine reuptake inhibitors, which are effective for neuropathic pain, may induce or worsen the symptoms of RLS [58]. Furthermore, movement generally results in partial relief of symptoms in patients with RLS [4,54], whereas movement does not substantially improve pain in chronic neuropathic pain conditions. Finally, pruritus has a number of strong analogies to RLS. In the former, the sensory component of itch and the compelling need to scratch is analogous to the essential symptoms of an urge to move and relief with movement of RLS. Further, the circadian nature of pruritus in many systemic diseases has been well-documented, though little fundamental investigation of this phenomenon exists [59]. However, physiologic, brain imaging, and molecular studies suggest similar mechanisms between itch and pain processing [60,61]. 3.5. RLS as a sensory modulation disorder Evidence has emerged supporting a dysfunction in sensory modulation in the pathophysiology of primary RLS. Patients with RLS have heightened evoked pain responses to pinprick (static mechanical hyperalgesia) but not dynamic mechanical hyperalge-

3

7 6 5

2

4 3 1

2 1 0

Subjective RLS rating score

3.4. Comparison of sensory symptoms in RLS to other chronic sensory disorders

Pain intensity in neuropathic pain

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0 Day 1 Day 1 Day 1 Day 2 Day 2 Day 2 Day 3 Day 3 Day 3 8:00 16:00 20:00 8:00 16:00 20:00 8:00 16:00 20:00

Fig. 2. Circadian rhythm of symptoms in restless legs syndrome (RLS) and neuropathic pain. The well-established circadian rhythm of RLS symptoms with increased symptoms in the evening and at night is similar to that observed in several chronic pain conditions. This figure plots subjective RLS rating score (a patient ranked measure from 0 [no symptoms] to 10 [the worst RLS symptoms ever experienced]; mean data for 1 day are replicated in triplicate) [57] alongside pain intensity in patients with painful diabetic neuropathy over 3 days (reported on a subjective numerical rating scale from 0 [no pain] to 10 [worst possible pain]) [53]. Adapted with permission from Odrcich et al. [53] and Trenkwalder et al. [57].

sia (allodynia) when compared with healthy controls [62]. This effect was most pronounced in the evening and was more apparent in the feet, consistent with RLS symptoms. Static mechanical hyperalgesia has been confirmed in both primary and secondary RLS [63]. This more recent study found that patients with primary RLS also had vibratory hyperesthesia and hyperalgesia to blunt pressure, while those with secondary RLS with small fiber neuropathy also had thermal hypoesthesia [63]. Secondary RLS may at least in part be a consequence of abnormal peripheral small fiber function [36,64], particularly in patients with comorbid diabetic neuropathy [37]. In early studies in patients with primary RLS, no alterations in thermal detection thresholds [63,64] or deficits in peripheral C-fiber function, A-d fibers, or spinothalamic tracts were observed [12,64], suggesting an absence of peripheral abnormalities in primary RLS. A more recent study demonstrated significant increases in the warm detection thresholds of the hands and feet and in the cold detection threshold of the feet in idiopathic RLS patients compared with healthy controls [65]. This study showed no differences between the groups in sudomotor axon reflex tests, suggesting that the abnormal sensory perception in RLS may result from impairment of central somatosensory processing and not small fiber neuropathy [65]. However, one study did find subclinical small sensory fiber loss associated with late-onset primary RLS with painful symptoms [66]. Improvements in static mechanical hyperalgesia in patients with primary RLS have been observed following long-term dopaminergic therapy, which suggests the involvement of central sensitization to afferent Ad-fiber mechanoreceptors or altered descending inhibition [62]. Further support for the concept that RLS may arise from loss of supraspinal inhibition comes from a study showing enhanced spinal cord excitability in patients with primary RLS [67]. Together these findings suggest a central process in the pathophysiology of both primary and secondary RLS, with some contribution from peripheral nerve fiber deficits in secondary RLS. Although the ability of peripheral nociceptor hyperactivity to induce central changes in the spinal cord dorsal horn has been documented in neuropathic pain [68,69]; this phenomenon has not been clearly shown in RLS. However, the ability of pharmaceutical agents to selectively disrupt periodic leg movements and arousals in RLS patients may suggest an indirect mutual relationship between these symptoms [70]. It was hypothesized that a biologic process in the sympathetic branch of the

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autonomic system may drive this process, suggesting the importance of the peripheral nervous system in RLS symptoms [70]. Alterations in central opioid pathways also have been observed in patients with RLS. Although no differences between patients with RLS and healthy controls were observed, opioid receptor availability in medial pain areas was inversely correlated with severity on the IRLSSG Rating Scale in those with primary RLS [71]. Additionally, this inverse relationship was found between opioid receptor availability in the orbitofrontal cortex and anterior cingulate gyrus and scores on the affective component of the MPQ [71]. One interpretation of these findings was that endogenous opioids may be increased in patients with RLS in response to uncomfortable sensations/dysesthesias, leading to higher levels of receptor occupancy in medial pain areas in the brain [71]. Furthermore, the endogenous opioids b-endorphin and methionine-enkephalin were reduced in sensory (thalamus) but not motor (substantia nigra) pathways in RLS patients compared with controls in another study [72]. Neuroanatomic studies of somatosensory brain regions have been performed to better understand the pathophysiology of RLS. Reductions in gray and white matter in the primary somatosensory cortex support the role of altered somatosensory pathways in the pathophysiology of RLS [73,74]. Alterations in thalamic gray matter have been investigated in several studies with conflicting results. One study found increased thalamic gray matter in patients with primary RLS compared with age-matched healthy controls [75]. However, other studies have failed to replicate this finding [76,77]. This discrepancy could be a consequence of the dopaminergic treatment of patients in the first study, with patients in the subsequent studies being unmedicated. 3.6. Evidence for effective agents working as analgesics in RLS Dopamine agonists are the current first-line treatment for RLS [51]. Their use is supported by clinical evidence showing their efficacy for improving RLS symptoms [51,78,79] and has led to the theory that the spinal hyperexcitability observed in RLS may be a consequence of dopaminergic dysfunction [80]. Dopamine has been proposed to function as a nonclassical analgesic with evidence for the involvement of dopaminergic transmission in supraspinal pain modulation [81]. Analgesics commonly used to treat chronic pain conditions also have shown efficacy in RLS, including the opioids oxycodone [82], methadone [83], and tramadol [84]; the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine [85]; and the anticonvulsants gabapentin [86,87], gabapentin enacarbil (XP13512) [18,88–90], and pregabalin [91–93]. The analgesic effects of opioids in chronic pain have been attributed to hyperpolarization, reduced neurotransmitter release, and depression of excitatory postsynaptic potentials in postsynaptic neurons [94,95]. Ketamine reduces neuropathic pain by blocking activation of NMDA receptors by glutamate [96]. In chronic pain states, excitatory amino acids such as glutamate and aspartate are released by prolonged stimulation of C-fibers. Glutamate activates NMDA receptors in the spinal cord to produce a heightened state of pain sensitivity [96,97]. At low doses, ketamine also may function to reduce pain via direct effects on dopamine D2 receptors [81,98]. The ability of ketamine to act as an analgesic is attenuated by either dopamine- or opioid-receptor blockade, suggesting a role for both of these pathways in NMDA antagonist-mediated analgesia [81]. The analgesic effects of methadone in chronic pain states have been attributed to both activation of mu-opioid receptors and inhibition of NMDA receptors [99]. The mechanism of action of gabapentin, gabapentin enacarbil, and pregabalin in neuropathic pain has been attributed to binding to the a2d subunit of voltagegated calcium channels at the dorsal horn of the spinal cord, modulating the influx of calcium ions, subsequently reducing excitatory neurotransmitter release (e.g., substance P and glutamate),

inhibiting aberrant excitatory synapse formation, or modulating descending inhibition, resulting in reduced neuronal network hyperexcitability [8,100–105]. The relationship between the mechanism of action of dopaminergic agonists and analgesics in RLS is not clear. It is apparent that there is considerable interplay among dopamine and traditional analgesics in producing analgesia in chronic pain states. In RLS, available evidence suggests that the effects of opioids may be via effects on dopaminergic neurotransmission, as dopamine-blocking agents inhibit the effects of both opioids and dopamine agonists, but opioid receptor blocking drugs only inhibit the effects of opioids [106–109]. Whether or not other analgesics alleviate the symptoms of RLS via modulation of dopaminergic neurotransmission is not known. The fact that some therapies for chronic pain improve the symptoms of RLS suggests an overlap between pain modulatory pathways and the sensory disturbances in RLS. 4. Discussion Most patients with RLS experience uncomfortable sensory symptoms that are difficult for them to describe, and although some may call their symptoms ‘‘pain’’ or ‘‘painful’’ most patients deny that these are accurate terms for their sensations. In fact, pain scores do not correlate well with RLS severity ratings in patients with RLS, which suggests that there is a meaningful distinction between them. Nevertheless, the sensory manifestations of RLS share some similarities with chronic pain, and differential diagnosis of the two conditions can be difficult at times. RLS frequently occurs in chronic pain and neuropathic conditions, making the distinction even more difficult. It appears that most patients with RLS lack conventionally described pain and often have to use analogies or emotive/affective words as descriptors. An improved understanding of those descriptors preferred by patients with RLS may help to improve diagnostic criteria and questionnaires for the identification of patients. At the same time, rating the intensity and unpleasantness of pain sensations separately and differentiating between pain and dysesthesia can improve the characterization of sensory sensations in RLS. Sensory symptoms in RLS have a significant impact on quality of life but remain much less well understood than other aspects of RLS, such as motor symptoms and sleep disturbances. Indeed, the relationship between sensory and motor symptoms is not well-defined. Although some studies have reported that sensory events may drive subsequent motor events, other studies have been less able to differentiate between the two symptoms. Peripheral neuropathies account for some sensory disturbances in secondary RLS, but perhaps less so in primary RLS in which altered central somatosensory processing may be more relevant. However, determining the relationship between peripheral neuropathy and RLS is challenging, as the neuropathy itself may confound the diagnosis and evaluation of RLS. At the same time, a pain condition may be misdiagnosed as RLS or RLS misdiagnosed as a pain condition, particularly in studies in which questionnaires by clinicians experienced in RLS in the absence of interviews form the basis of diagnosis. The effectiveness of analgesics in treating RLS supports the concept that abnormal sensory modulation may be part of the pathophysiology of RLS. For many patients, sensory symptoms and the urge to move are their most troublesome RLS symptom. Further study is needed to better understand the experiential and biologic aspects of altered sensory experiences in RLS. Financial disclosures All authors participated in developing the content of this manuscript, preparing and reviewing the draft versions, and approving

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the final version. Dr. Winkelman was not paid in conjunction with development of this manuscript. He has received consultancy fees from Pfizer, Sunovion, UCB, and Zeo Inc.; and research support from GSK and Impax. Dr. Gagnon is a fulltime employee of UBC Scientific Solutions, who were paid consultants to Pfizer Inc. in the development of this manuscript. Dr. Clair is an employee of Pfizer Inc. This review article contains information concerning a use of pregabalin and gabapentin that is not approved by the US Food and Drug Administration.

Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.05.017.

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