Chapter 27 Is the Manifestation of the Restless Legs Syndrome Related to a Pain Mechanism?
Pain is a sensory and emotional experience that is distinctly subjective and personalized according to each individual patient’s beliefs, past pain experience, and genetic background.1,2 Physiologically, pain sensations are triggered by a complex cascade of events referred to as nociception that arises as a consequence of tissue injury or immune reaction. This sensory information can be carried from the spinal cord to the brain via six major ascending pathways: the spinothalamic, spinoreticular, spinomesencephalic, spinoparabrachial, spinohypothalamic and spinocervical tracts.3 Briefly, nociception comprises three steps: (1) activation of sensory nerve endings of Aδ and C first-order neurons; (2) activation of ascending projection neurons located in the dorsal horn of the spinal cord or trigeminal nucleus, that project to higher brain areas (several nuclei in the thalamus, reticular formation of the pons and periaqueductal gray matter of the midbrain); and (3) activation of third-order neurons that project to the cortical mantle (e.g., primary and secondary somatosensory, insular, anterior cingulate cortices).4
A myriad of diverse chemical entities are known to activate (e.g., K+, serotonin, histamine, bradykinin) or sensitize (e.g., prostaglandins, substance P, leukotrienes) nociceptors.5,6 These events are important players in initial pain transmission and maintenance. From a physiological viewpoint, perceived pain results from the balance of the activity in nociceptive and non-nociceptive afferents. This concept is referred to as the gate control theory. This hypothesis is based on the involvement of inhibitory interneurons able to modulate projection neurons, by integrating the respective activity of the myelinated non-nociceptive afferent and nonmyelinated nociceptors.7
Pain perception can also be modulated via descending pathways originating from the dopaminergic periaqueductal gray of the midbrain, noradrenergic locus ceruleus, and serotoninergic neurons of the nucleus raphe magnus.8 These descending pathways can inhibit projection neurons directly or indirectly by activation of enkephaline-containing interneurons in the superficial layers of the dorsal horn. A more diffuse way of modulating pain has also been identified and referred to as the DNIC (diffuse noxious inhibitory controls).9–12
Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder that is often associated with pain complaints and severe insomnia.13,14 Recently, some evidence proposed a dysfunction of the endogenous opioid system in RLS sufferers as a possible primary cause of RLS.15,16 On the other hand, the abnormalities in somatosensory processing observed in RLS patients could be mediated by other consequences of sleep. Both the sensory discomforts of RLS and the associated periodic movements in sleep can lead to frequent arousals or awakenings, with a consequence of major sleep deprivation. Sensory hyperexcitability in patients as measured by hyperalgesia16 could be a consequence of this sleep loss.17 In this chapter, we review some of the emerging knowledge on sleep and pain interaction to better understand the mechanisms by which pain becomes prevalent in RLS, and to evaluate the possible involvement of the opioid system as a causal factor in the pathogenesis of RLS.
Restless Legs Syndrome and Pain
RLS is characterized by an often irresistible urge to move usually accompanied by or caused by unpleasant, sometimes even painful, sensations in the lower limbs. These symptoms are worse at night, or during periods of inactivity, and can be partially or totally relieved by movement.18 RLS patients often exhibit stereotyped and recurring movements of the lower limbs and these periodic limb movements (PLMs) occur during both sleep and wakefulness.19 Recent clinical evidence suggests that pain is a relatively frequent complaint of patients suffering from RLS. In an international study performed in a primary care setting, 21.4% of 23,052 patients reported pain as a concomitant symptom of their RLS.13 In a genetic study encompassing 300 patients, pain was reported among RLS-related symptoms by 61% of cases with a positive familial history of RLS and by 85% of patients with no family history of RLS.20 In another study of over 218 RLS patients, painful disorders such as rheumatoid arthritis, disorders of the back, and arthropathy were concurrently reported by 2.6% to 49.6% of the female subjects and by 1.0% to 35.9% of male subjects.18 To our knowledge, none of these reports estimated the pain intensity quantitatively (e.g., using a numerical scale of 0 to 100 mm, a visual analogue scale [VAS]) nor the time course of worst pain, from onset to its peak. To diagnose RLS patients, sleep clinicians are using the terms dysesthesia (i.e., altered perception of sensory inputs) and paresthesia (i.e., partial lost of sensation, numbness or tingling sensations), which are typically used for neuropathic pain assessments.21
Pain: Definition and Sleep Interaction
Pain manifestations can be described according to two major components. The sensory-discriminative aspect of pain is a function of the intensity of the perceived stimuli, and the emotional dimension is related to the unpleasantness of the painful experience. These qualities can be investigated separately in a clinical as well as an experimental setting with the use of simple objective and subjective psychophysical tools.9 Pain can be acute (days, weeks) or chronic (>3 months) or can be recurrent with variable durations of pain-free periods. The International Association for the Study of Pain (IASP) developed an extensive classification similar to the International Classification of Sleep Disorders.9 However, for practical reasons in clinics, the day-to-day classification of pain is categorized into three groups: musculoskeletal pain, neuropathic pain, and pain with psychological components.22 The prevalence of chronic pain in the general population is between 11% and 29%, depending on the population surveyed and types of questions used.23–25
According to a survey from the National Sleep Foundation in 2000, “20% of American adults reported that pain or physical discomfort disrupted their sleep” a few nights a week.26 Poor sleep quality, frequently defined as an unrefreshing sleep or fatigue on awakening, is reported by two thirds of chronic pain patients, and pain is most often the primary trigger of poor sleep complaints.27–35
Because sleep is a state with altered vigilance and with a partial disconnection from the external milieu, pain perception and processing during sleep are probably better described by the term nociception, because no voluntary reaction is expected if no sleep arousal toward a behavioral wake state is present.10,35,36
Pain Assessment Tools in the Clinic and Laboratory
Questionnaires
In the clinical setting, patients use words that describe both the intensity and emotional aspects of the noxious stimulus (e.g., Melzack scale).37 When a patient reports pain with words such as dull, diffuse, or cramp-like, this typically refers to muscle pain. In opposition, when pain is reported with words such as sharp, pins and needles, electric shock, or burning, clinicians are prone to classify the complaints as neuropathic pain. However, in the clinic, it is the use of a 0 (no pain)-to-10 (most intense pain imaginable) numerical scale that is most frequently used by clinicians to estimate pain intensity. This scale is easily understood by patients and is an effective means of collecting data rapidly by clinicians, but it is not very accurate in estimating pain relief, since pretreatment pain intensity can be overestimated or underestimated by patients.38 Moreover, with patients who are too young or too old, under medication (e.g., psychoactive), or with cognitive or mental dysfunction, scales with graded colors or faces (from smiling to unhappy) are very useful. In the clinical research environment, the gold standard is the use of the VAS with anchor words at both extremities of the scale: from no pain to the most intense pain imaginable. Sophisticated questionnaires also assess the impact of pain in relation to quality of life, mood alterations, and fatigue (see the McGill Pain Questionnaire [MPQ], the Multidimensional Pain Inventory [MPI], and Neuropathic Pain Symptom Inventory [NPSI] for examples).22,39,40 For neuropathic pain, 10 descriptors were used in a recent study to evaluate the intensity of neuropathic pain and the efficacy of treatments. These descriptors included burning, pressure, squeezing, electrical shocks, stabbing, pin and needles, tingling, and pain induced by brushing, pressure, or cold.41 The descriptors are presented with numerical 0-to-100 scales. Such scales need further validation and replication but add a quantitative dimension rarely used in RLS symptom assessments.
Psychophysical Quantitative Testing
Several reviews describe the psychophysical methods to assess sensory changes in humans, for various sensory disorders, and at different body sites.10,42–46 These methods are known under the name of Quantitative Sensory Testing (QST). In summary, the pain threshold is estimated experimentally from stimulations that cause pain in 50% of trials, and the pain tolerance is estimated as the maximal pain a subject can tolerate (Table 27-1). The measured variables are pain intensity, unpleasantness scores, tolerance measures, amplitude of stimulation (e.g., current, temperature), and/or latency of response. Pain can be evoked experimentally using stimuli of various nature, to access the reactivity of different sensory pathways. Thermal stimulations (cold or heat) are used to assess either Aδ (heat) or C (cold) sensory fibers, mechanical pressure tests (pressure, von Frey hair, two points, brush, vibration) are used to assess tactile reactivity of all A and C fibers, and chemical stimulation (hypertonic saline, glutamate, capsaicin) usually challenge the roles of free nerve endings and C fibers. Superficial thermal cold (0° to 4° C) or heat (43° to 50° C) pain test is often administered by a water bath or a Peltier bridge. Laser stimulation is another way of causing superficial heat pain. The duration of thermal stimulation ranges from 60 milliseconds (laser) up to 60 seconds (Peltier bridge) and is usually harmless. Deep tissue pain is estimated with a mechanical pain device or graded finger palpation displaced slowly; data are expressed in Newton or in kg/cm2. Touch discrimination and two-point discrimination using von Frey hairs, grade scale, or pin-prick tests are used to assess the presence of allodynia. Subcutaneous pain perception and muscle pain can be mimicked by injection of algesic substances such as capsaicin, glutamate, or hypertonic saline (5%). Electrical stimulations that trigger motor reflexes or brain-evoked potentials have also been used during sleep; however, these are not considered as being representative of clinical pain in comparison with other means of stimulation.36,47–52 Even though the data obtained with these assessment techniques are quite reproducible, the function of sensory fibers is modified in conditions like sensitization and allydonia, where activation of a non-nociceptive touch fiber may be interpreted as a painful stimulus.
| Algesia | Any pain experience following a stimulus |
| Allodynia | Pain due to an innocuous stimulus that does not normally provoke pain (e.g., skin touch after a sunburn) |
| Causalgia | Pain after a trauma to a nerve (could be associated with vasomotor dysfunction) |
| Habituation | A decrease or loss of response in nerve receptors or nerve cells following repetitive stimulations |
| Hyperalgesia | Increased pain response to a nociceptive stimulus |
| Hypoalgesia | Diminished pain response to a nociceptive stimulus |
| Hypoesthesia | Decreased sensitivity to stimulation that feels similar to the effect of local anesthesia |
| Neuroma | The mass of a peripheral neurons formed by a healing scar at the level of a damaged nerve preventing regeneration. It can cause hyperexcitability of neurons or spontaneous discharge also termed ectopic discharge. |
| Neuropathic pain | The aberrant pain reaction induced by an injury to a sensory nerve or neuron. The aberrant reaction may be evoked by thermal, mechanical, or chemical stimuli or may be secondary to a disease (e.g., diabetes, post-herpetic neuralgia), or may also be central. |
| Nociception | The reception, transmission, and perception of noxious sensory input |
| Pain | An unpleasant sensory, emotional, and motivational experience associated with actual or potential tissue damage |
| Pain threshold | The lowest level of stimulation perceived as painful by a subject (in 50% of trials) |
| Pain tolerance | The highest level of pain that a subject is able to tolerate |
| Paresthesia/dysesthesia | An abnormal sensation that is termed dysesthesia when it becomes unpleasant |
| Sensitization | Nerve receptors or nerve cells that, over time, become activated or hyperexcitable by stimulation of a lower magnitude. Can be peripheral, central, or both. |
| Sprouting | The excessive regeneration of nerve endings over surrounding tissue following nerve damage |
Adapted from Lavigne GJ, McMillan D, Zucconi M. Pain and sleep. In: Kryger MH, Roth T, Dement WC (eds). Principles and Practice of Sleep Medicine. Philadelphia, WB Saunders, 2005, pp 1246-1255.
Assessment of Sensory Dysfunction in Restless Legs Syndrome During Wakefulness
The estimation of the leg discomfort of RLS patients, as assessed on the VAS in the evening, discriminated RLS patients from age-matched asymptomatic subjects.53 Over a period of 60 minutes of immobilization, the leg discomfort rose up to 50 mm over the 100-mm scale, and this was highly correlated with the number of periodic leg movements (PLMs). An early study investigated peripheral neuropathy in RLS patients and found significant changes in electrical, psychophysiological, and/or morphological characteristics of axonal neuropathy. These results were confirmed for secondary RLS in a recent study, where sensory deficits seem at least in part caused by small fiber neuropathy.54 In opposition, idiopathic RLS seems to depend more on central somatosensory processing impairments.55 In addition, pin-prick ratings in 11 patients with RLS were significantly elevated, compared with 11 age- and gender-matched healthy control subjects, whereas pain to light touch (allodynia) showed no difference.16 Furthermore, hyperalgesia in RLS patients can be reduced by long-term dopamineric treatment.16 In this light, dysfunction of supraspinal pain modulatory pathways involving the basal ganglia and/or descending dopaminergic pathways might be involved in the pathophysiology of RLS.
Although the pin-prick test is a validated method to assess tactile sensory dysfunction, it is not frequently used in the clinical assessment of pain.56,57 Use of thermal (heat or cold), touch (pin-prick [so far, the only one tested]), deep tissue chemical, or mechanical (hypertonic saline or pressure, respectively) tests may be more comprehensive approaches to further discriminate sensory symptoms of RLS subjects and, eventually, to predict treatment efficacy (sensitivity changes).
Assessment of Sensory Dysfunction in Restless Legs Syndrome During Sleep
To our knowledge, only a few studies have assessed RLS sensory perception in patients during sleep. One sleep study tested motor excitability with a flexion reflex and revealed an increase in spinal cord excitability in RLS patients.58 A similar reflex-testing paradigm was used to assess whether changes in pain perception occurred during sleep in normal subjects.49 The threshold of the RIII polysynaptic nociceptive flexion reflex is higher in all stages of sleep compared with wakefulness, and its latency is prolonged during stage 4 and REM (rapid eye movement) sleep, suggesting that sleep decreased pain perception.49 However, electrical stimulation is considered an aversive method that may trigger a hypervigilance reaction and does not represent the usual sensory complaints of pain patients or of RLS patients. Hence, the question of “ecological validity” is raised. Moreover, during sleep, the duration of stimulation seems critical to trigger a clinically relevant response. Brief pain stimulations (6 to 12 seconds) trigger microarousal, whereas longer ones (90 to 120 seconds), such as infusion of hypertonic saline, seem more representative of natural painful experiences and often induce awakenings—in 40% of hypertonic infusions in stage 2, 26.7% in slow-wave sleep (SWS) and 45.8% in REM sleep.36,52 In other words, the reactivation of the reticular system needed to interpret inputs as painful in a sleeping brain needs sufficient time to assess a threat to the body’s integrity. It seems apparent that during sleep, the presence of pain can trigger either a brief and unconscious microarousal response accompanied by a sleep stage shift, or an awakening with a rise in consciousness/vigilance, that may interfere with sleep continuity.
Fatigue
The assessment of pain in patients with sleep complaints needs to be controlled for other confounding influences. In clinics, it is important to assess the type of fatigue that is reported. A fatigue complaint due to sleep fragmentation in patients with RLS or sleep apnea is probably very different from the one experienced in a context of low motivation associated with lack of outside stimulations. Several questionnaires are available to assess fatigue,59–62 but again their validity in investigating the sleep and pain interaction in RLS patients needs to be evaluated.
Moreover, because some patients with chronic pain tend to report more impairment in memory and attention,63–65 RLS patients might present cognitive alterations due to fatigue and these changes need to be further estimated. To our knowledge, the influence of RLS on cognitive functions has not yet been systematically studied; however, one study has shown that the sleep deprivation of RLS can cause frontal lobe dysfunction.66
Circadian Pattern for Pain
In normal volunteers, some studies shows circadian variation in objective and subjective measures of sensitivity to experimental acute pain,67,68 whereas others fails to reveal any differences.69,70 A more recent study by Roehrs and colleagues17 showed a time-of-test difference in finger withdrawal latency, being shorter at 2:30 P.M. than at 10:30 A.M. These divergent findings may be due to methodological differences, as pain was produced by different techniques and many parameters were used to quantify pain intensity. In addition, the presence of circadian fluctuation in pain sensitivity could be linked to altered vigilance and/or motivation, and not to changes in pain processing per se. On the other hand, a circadian pattern of pain is often found in chronic pain patients suffering from different diseases.71 Symptoms can be low in the morning or in the evening depending on the pain syndrome. Musculoskeletal pain complaints show two main patterns: arthritic pain that is worst at waking time, with subsequent movement alleviating discomfort, and fibromyalgia and various myofascial pains that gradually increase in intensity from morning to evening.28,70,72–74
Interestingly, RLS symptoms, leg or limb discomfort, and motor restlessness increase in intensity from morning to evening and are paroxysmal around midnight.53,75 The study from Michaud53 suggested that the downregulation of central dopamine secretion by melatonin may play a role in the nocturnal manifestation of RLS symptoms. Furthermore, dysfunction or atrophy of dopaminergic A11 neurons could be involved in the generation of circadian rhythms of symptoms, because these cells are in close proximity to the hypothalamic circadian pacemaker.
Sleep and Pain Interaction
In humans, acute pain perception during sleep depends mainly on the intensity, the duration and the nature of the sensory stimulation, as well as the depth of sleep. Indeed, although short (60 milliseconds) laser stimulation is ineffective in producing an evoked cortical response in stage 2 sleep,47 a mid-duration (6 to 12 seconds) thermal pain stimulation triggers more microarousals during stage 2 sleep than during SWS or REM sleep.36 Furthermore, infusion of hypertonic saline (5%) that mimics a muscle cramp for more than 70 seconds causes clear awakening responses with possible recall the following morning, similarly across all sleep stages.52 These experimental models underlie the involvement of pain in poor sleep quality, with respect to fragmentation of sleep continuity, lower sleep efficacy, and numerous sleep stage shifts (stages 3 and 4 toward stages 1 and 2). In addition, certain chronic pain patients present abnormal sleep architecture, intrusions of arousal in clusters, or cardiac sympathetic overactivation in sleep.35
RLS as an undeniable influence on the sleep quality of patients, sometimes leading to severe insomnia.14,76 Because sleep loss has consequences on many physiological processes and cognitive functions, the morbidity of RLS, including altered pain perception, could be a result of modified sleep architecture, sleep fragmentation, or sleep stage shifts. Indeed, studies of total or specific sleep stage deprivation underlie the effect of sleep on subsequent noxious stimuli processing. REM sleep deprivation in rats has been shown to increase the behavioral responses to painfull stimuli.77 In the human, Roehrs and colleagues17 observed a linear decrease in finger withdrawal latency after radiant heat stimulus, as a function of either total or REM sleep deprivation. Early studies showed that SWS deprivation influences the magnitude of pain on the following day.78 On the other hand, delta wave sleep interruption in healthy subjects has been shown, in another study, to cause no significant lowering of pain thresholds compared with a control group.79 Interestingly, a recent publication showed that healthy female subjects with the shortest REM sleep latency and longest REM duration reported highest suprathreshold pain ratings, suggesting that a REM-related mechanism may be associated to hyperalgesia.80
Patients reporting chronic pain seem to have been free of major sleep complaints before the initial occurrence of pain, suggesting a linear relation in which pain preceded poor sleep. Indeed, with acute pain, the poor sleep complaints do not usually continue after pain clearance.35 This linear relation was noted in approximately two thirds of patients with various musculoskeletal types of pain.29,
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