Periodic Limb Movement Disorder, Restless Legs Syndrome, and Pain

 US Pharm.2015;40(3)19-21.

Complaints of sleep disturbance in older adults are often attributed to pain associated with physical disorders (e.g., arthritis, cancer, herniated disks), and pharmacists may observe treatment that has a single focus, involving interventions such as analgesics and hypnotics in the absence of further followup or investigation. Most sleep disturbances are associated with medical and psychiatric conditions, medications, and primary sleep disorders.¹ This article will focus on two conditions that may interrupt sleep in older adults: periodic limb movement disorder (PLMD), and restless legs syndrome (RLS). Increased awareness of PLMD and RLS, including their potential iatrogenic etiology, may assist pharmacists in identifying, resolving, and preventing medication-related problems that contribute to interrupted sleep and pain.

PLMD leads to brief arousals and fragmented sleep. Thus, many patients with PLMD have complaints of insomnia, nonrestorative sleep, and excessive daytime sleepiness.¹ Both PLMD and RLS (in which 80% of patients also have PLMD) occur more commonly in midlife and older age.^2,3 RLS leads to considerable distress in and of itself and amplifies other physical symptoms, such as pain, by way of exacerbating sleep disturbance in affected patients.⁴

Age-Related Sleep Changes

Individual sleep requirements in adults vary widely. Generally, sleep ranges from 6 to 10 hours in a 24-hour period and progresses through three stages of depth (N1, N2, N3) typically followed by a brief interval of REM sleep, occurring cyclically five to six times a night.⁵ Brief periods of wakefulness (stage W) occur periodically. In the elderly, stage N3, deep sleep, may disappear altogether. Owing to these age-related sleep architecture changes, with both total sleep time and deep sleep tending to decrease, sleep becomes lighter and more interrupted. Although their clinical significance is unclear, these changes may account for the increasing fatigue and excessive daytime sleepiness (EDS)—difficulty maintaining wakefulness and an increasing propensity to fall asleep, even in inappropriate situations, despite the intention to remain awake—that occurs with aging.^5,6

Sleep disorders, while common in older adults, are not a function of age per se. When a sleep disorder is unrecognized or poorly treated, the severity of an underlying systemic disease may be worsened and its treatment may be not as effective.⁷

PLMD and RLS

PLMD, formerly called sleep myoclonus or nocturnal myoclonus, is characterized by rhythmic, abnormal motions of the limbs during sleep. These movements are repetitive (usually every 20 to 40 seconds) and are described as twitching or kicking of the lower or upper extremities during sleep.^2,8 They usually consist of extension of the big toe and flexion of the ankle, the knee, and the hip.³ Occurring periodically throughout the night, these movements tend to cluster in episodes that last from a few minutes to several hours and fluctuate in severity from one night to the next. PLMD movements are distinct from hypnic myoclonia, the normal spasms that are experienced upon sleep initiation.⁸ Patients often complain of interrupted nocturnal sleep and are typically unaware of the movements and brief arousals that follow. Patients with PLMD do typically complain of EDS; patients may not necessarily report EDS but may instead complain of feeling tired, fatigued, or irritable, or of experiencing other mood changes. Patients may report being unable to carry out usual activities of daily living without considerable effort; other manifestations of EDS that patients report include poor attention and concentration and difficulty with memory.⁹ These manifestations may be misinterpreted by a healthcare provider as a progressive cognitive decline in an elderly patient; family and caregivers may be fearful that they are an indication of dementia or Alzheimer’s disease. In a patient already diagnosed with dementia, EDS secondary to PLMD can potentially exacerbate behavioral problems.

RLS is considered a sensorimotor disorder in which patients feel a strong urge to keep their lower, and sometimes upper, limbs in motion and experience paresthesias described as creeping or crawling sensations in the calves, thighs, and arms. Pain in the extremities may be experienced by patients with RLS.^2,10 Symptoms of RLS tend to be more prominent during rest or inactivity (e.g., in a reclining position) and are at their most pronounced around bedtime. Stretching, kicking, or walking relieves symptoms; RLS interferes with falling asleep and/or may cause repeated nocturnal awakenings. Approximately 80% of patients with RLS also have PLMD. While the mechanism of both RLS and PLMD is unclear, it may involve abnormalities in dopamine neurotransmission in the central nervous system (CNS).²

Heredity may be involved in primary RLS; PLMD may be seen in patients with obstructive sleep apnea and during initiation of positive airway pressure (PAP) therapy.³ PLMD is common among people with narcolepsy and REM sleep behavior disorder. Isolated PLMD—the diagnosis of which requires periodic limb movements in sleep that disrupt sleep and are not accounted for by another primary sleep disorder including RLS —is thought to be rare.^2,3,6,10

Diagnosis

Diagnosis of a sleep disorder requires a thorough sleep and medical history; inquiry into medication use must include prescribed and OTC agents, vitamins, and nutritional and herbal remedies. Diagnosis of RLS requires history alone. Diagnosis of PLMD may be suggested by history reported by the patient or bed partner; confirmed diagnosis for PLMD is based on clinical history and overnight polysomnograph (PSG); a neurological examination is also recommended to rule out other potential causes, such as peripheral neuropathy. Furthermore, respiratory monitoring during the PSG allows for ruling out sleep-disordered breathing as a cause for the disrupted sleep and excessive muscle activity.³ While PSG is not necessary for the diagnosis of RLS, it may be performed after RLS is diagnosed to determine whether patients also have PLMD.² Patients with either disorder should be evaluated medically for conditions and history that can contribute to the disorder, such as iron deficiency anemia (TABLE 1).² Recommended testing includes bloodwork for ferritin, folic acid, vitamin B12, and magnesium levels, as well as tests for thyroid function, renal function, and hepatic function.³

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Treatment for RLS and PLMD

While newer nonpharmacologic therapies for RLS such as cognitive behavioral therapy or exercise therapy are still being investigated, the use of pharmacotherapy has been more widespread.¹⁰ Interestingly, the magnitude of the placebo effect in RLS studies has been estimated at 40% by Fulda and Wetter, based on a meta-analysis¹¹; Aurora et al indicated that this meta-analysis reinforced the need for placebo-controlled studies to determine the true effect of any treatment for RLS.¹⁰

For PLMD, there are no specific treatments, but the treatments for RLS are usually used and often help to provide palliative therapy to optimize comfort and normalize sleep patterns; however, treatments require further study.^2,4,5 According to the American Academy of Sleep Medicine, there is insufficient evidence to comment on the use of pharmacologic intervention in isolated PLMD. Existing data in RLS therapy do, in some cases, support some medical interventions in both RLS and PLMD; they indicate that clinical judgment must be used regarding any pharmacologic intervention in PLMD.¹⁰

Generally, for RLS, a variety of agents (e.g., dopaminergic drugs, benzodiazepines, anticonvulsants, vitamins and minerals) are used; the dopamine agonists have replaced levodopa as first-line therapy in RLS and have been found to reduce the number of kicks and associated arousals.^12,13 Specifically, with regard to FDA approval and high-level evidence, these are recommended: pramipexole, ropinirole, rotigotine (as a transdermal patch), or gabapentin enacarbil.^2,10 As an option, clinicians may use supplemental iron to treat RLS patients with low ferritin levels (<50 ng/mL); some experts recommend supplementation with ferrous sulfate 325 mg, plus 100 to 200 mg of vitamin C at bedtime.^2,10  

In addition to the agents noted above, pain relief with gabapentin supports consideration of its use in patients with both RLS and pain (off-label use). While pregabalin, a nondopaminergic alpha-2-delta ligand, has exhibited a low level of evidence with regard to effectiveness in the treatment of moderate-to-severe RLS, it may be useful for RLS accompanied by pain (off-label use).^2,10 Benzodiazepines (e.g., clonazepam) may improve sleep continuity but do not reduce limb movements and should be used cautiously to avoid tolerance and daytime sleepiness; clonazepam is not recommended as a first-line agent in the treatment of RLS.^2,10 Of note, benzodiazepines are considered to be potentially inappropriate in the elderly population; based on high- quality evidence, the Beers Criteria strongly recommend avoiding the use of these agents, when possible, in this population.¹⁴

Opioids may be beneficial for patients with RLS and pain; however they are generally reserved as a last resort because of tolerance, adverse effects, and abuse potential.² The elderly may be particularly susceptible to CNS depression and confusion as well as to the constipating effects of opioids.¹⁴ Patients with RLS or PLMD should exercise good sleep hygiene and should be reassessed regularly to evaluate EDS, tolerance, efficacy, and adverse effects of medication therapy. 

Aurora et al, who conducted the systematic literature review and meta-analyses (where appropriate) that provided the 2012 update to the American Academy of Sleep Medicine practice parameters on the treatments of RLS and PLMD state that¹⁰

• Therapies with a standard level of recommendation include pramipexole and ropinirole. (Of note, rotigotine was removed from the market in 2008; a new formulation was approved and came back into the U.S. market in July, 2012).

• Therapies with a guideline level of recommendation include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which has additional caveats for use)

• Therapies with an option level of recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for patients with low ferritin levels, iron supplementation.

Pharmacists are referred to this document for therapies for RLS secondary to end-stage renal disease, neuropathy, and superficial venous insufficiency.¹⁰ Additional guidance with regard to special geriatric dosing of the above medications may be found in Reference 14.

Conclusion

Both PLMD and RLS occur more commonly in midlife and older age, with the prevalence of PLMD increasing significantly with advancing age. Evidence-based guidance on practice parameters, especially in light of the high rate of placebo response and potential adverse effects of therapeutic options, is welcomed to guide pharmacists in their efforts to evaluate for treatable causes, avoid unnecessary prescribing cascades, and better tailor effective pharmacotherapy to the individual.

 

REFERENCES

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