Restless leg syndrome (RLS) is a condition generally characterized by dysesthesia or paresthesia of the legs, motor restlessness, and an intense urge to move (Douglas, 2002). Patients may describe this sensation as a crawling, creeping, tingling, or even an aching sensation. The intensity of the sensation, frequency, and duration will vary from patient to patient. The upper limbs can also be affected. Although symptoms are typically worse or may only present at night, they can occur during the day, particularly while at rest. The urge to move as well as relief of symptoms with movement are cardinal signs of the condition. Symptoms may cause difficulty with sleep onset and sleep disruption (Thorpy, 2007). Severe RLS can affect patients during any time or day and may even affect the whole body.
Although studies suggest a prevalence of between 3% and 15% of the general population, only an estimated 3% of RLS sufferers require pharmacologic treatment (Thorpy, 2007). The diagnosis of RLS is typically based on clinical presentation. Although most patients will show more periodic limb movements during a sleep study, this alone does not confirm or exclude the presence of RLS (Douglas, 2002). Periodic limb movements may be noted in up to 80% of patients with RLS during a sleep study (Parker & Rye, 2002). Patients frequently have symptoms for many years before diagnosis with onset in childhood or early adulthood (Thorpy, 2007).
The diagnostic criteria for RLS were updated in 2003 by the International Restless Legs Syndrome (IRLS) Study Group. The diagnostic criteria are as follows: an urge to move the legs usually but not always accompanied by unpleasant sensations in the legs and, sometimes, the arms; the urge to move is worsened by rest or inactivity and is partially or totally relieved by movement at least while the movement occurs; symptoms are worse or present only during the evening or night; and the symptoms are not accounted for by any other medical or behavioral condition such as myalgias, leg edema, or positional discomfort (IRLS Study Group, 2013). The IRLS Study Group also developed a symptom rating scale, which is generally used in research.
The pathophysiology of RLS is not well understood, but links have been made to central dopaminergic as well as iron systems (Thorpy, 2007). Alterations in neurotransmitters such as hypocretins, endorphins, immune dysfunction, and genetic linkages have also been identified in the pathophysiology of RLS (Nagandla & De, 2013). Primary as well as secondary forms of RLS have been identified.
Primary RLS is generally determined to be present on the basis of clinical symptoms without the presence of an offending agent, iron deficiency, or other organic sleep disorder. A family history of the condition has been noted in 50%–92% of patients (Thorpy, 2007). Research has identified three loci on chromosomes: 12q, recessive mode of inheritance; 14q; and 9p with autosomal dominant mode of inheritance (Thorpy, 2007). These genes have been labeled RLS1, RLS2, and RLS3, respectively, but a causative mutation has not been identified (Dhawan, Ali, & Chaudhuri, 2006). A genome-wide association study in 922 cases with over 1,500 controls, all of European descent, found six loci, which identified RLS susceptibility: MEIS1, BTBD9, PTPRD, a locus encompassing MAP2K5, and SKOR1 as well as a region on chromosomes 2p14 and 16q12.1 (Winkelmann et al., 2011).
Secondary RLS has been noted in relation to multiple metabolic, medical, and neurologic conditions as well as particular medications. Conditions, which cause iron deficiencies, may also lead to secondary RLS; this includes renal disease and pregnancy (Thorpy, 2007). Diets, which do not allow for appropriate intake of iron, may also contribute. Conditions such as Parkinson disease (PD), rheumatoid arthritis, and neuropathies may also lead to secondary RLS (Thorpy, 2007). Medications such as antihistamines, selective serotonin reuptake inhibitors, tricyclic antidepressants, and dopamine receptor blockers may cause or worsen RLS (Thorpy, 2007). Primary sleep disorders such as sleep apnea may worsen primary RLS symptoms or lead to secondary RLS primarily because of sleep deprivation. Agents such as caffeine, nicotine, and alcohol may also worsen symptoms.Approximately a fourth of pregnant women experience RLS symptoms, primarily in the third trimester (Sethi & Mehta, 2012). Symptoms of RLS resolve as early as 2 weeks after delivery for some women, whereas others experience symptoms for several months after delivery (Sethi & Mehta, 2012). Medications used during pregnancy include gabapentin, opioids, and antiepileptics such as carbamazepine (Nagandla & De, 2013).
Evaluation of patients with RLS should include efforts to identify and manage treatable causes of the condition. Nonpharmacologic interventions such as decreases in caffeine intake and adjustments or cessations of offending agents should be considered.
Multiple agents including dopamine agonists such as carbidopa/levadopa, ropinirole, and pramipexole as well as gabapentin, clonazepam, and opioids have been used in the management of RLS symptoms. Some of these treatment options are further discussed. The effectiveness of dopaminergic agents in the treatment of RLS was described as early as 1982 (Thorpy, 2007). Ropinirole was approved for the treatment of RLS in 2005; at the time being, it is the only medication indicated for the condition. Before this, treatment often involved opioids or benzodiazepines (Byrne, Sinha, & Chadhuri, 2006).
The pharmacokinetics of ropinirole show that it is active at the dopamine D2 and D3 receptors and has a bioavailability of 55% (Kushida, 2006). Although the details of how these medications work in RLS may not be clear, the effectiveness of dopaminergic agents in RLS has been shown in multiple studies (Byrne et al., 2006).
One of the most common challenges of ongoing treatment of RLS with dopaminergic agents is augmentation and rebound. Augmentation is noted based on factors such as the time of day the symptoms begin, the number of body parts involved, the severity of symptoms, and the effects of dopaminergic agents with a diagnosis of augmentation requiring either a 4-hour advancement in the start of symptoms or a combination of the other factors (Garcia-Borreguero et al., 2007). Augmentation is not considered to be a part of the natural course of RLS (Kurlan, Richard, & Deeley, 2006). Rebound refers to a recurrence of symptoms when the effect of an individual dose ends and may involve a worsening in leg movements during sleep (Allen & Earley, 1996). Essentially, rebound refers to a return of symptoms, whereas augmentation refers to a worsening of symptoms because of medication.
Augmentation has been noted to occur with use of levadopa for over 15 years, may affect 82% of patients with RLS, and was more likely to occur at larger doses (Allen & Earley, 1996). Because of its high risk of augmentation, this is usually less preferred (Nagandla & De, 2013). Long-acting formulations may help avoid rebound symptoms (Byrne et al., 2006).
In a 66-week study using ropinirole in patients with no history of augmentation, it was found that 3% of patients experienced augmentation, and 50% of those patients discontinued treatment because of this (Garcia-Borreguero et al., 2012).
A 6-month double-blind study of 234 patients using pramipexole found that 9.2% of patients had confirmed augmentation versus 6% of patients on placebo; the rate of augmentation was noted to increase over the 6-month period (Högl et al., 2011). Over the course of 4 years of therapy, the efficacy of pramipexole dropped, and side effects including augmentation and sleepiness increased with time (Lipford & Silber, 2012). A community-based sample of 266 patients on long-term dopaminergic treatment of RLS found that 20% of patients had definitive or highly suggestive indications of augmentation with a rate of about 8% per year for at least the first 8 years (Allen et al., 2011). It is significant to note that this study did not differentiate between the various dopaminergic agents. These studies help indicate that, although not all patients experience augmentation, it can lead to discontinuation of treatment, as is more likely to occur with ongoing treatment of dopaminergic agents.
A class effect of dopamine agonists that is important to be aware of is the possibility of impulse control disorders. Behaviors such as compulsive shopping, eating, gambling, and sexual behaviors are a known complication of dopamine agonist use in PD (Weintraub & Nirenberg, 2013). This is more likely to occur in a person with factors such as impulsive personality traits, bipolar disorder, substance abuse, male gender, and younger age (Weintraub & Nirenberg, 2013). This is also more likely to occur at higher dosages (Weintraub & Nirenberg, 2013). Although the doses of dopamine agonists used in RLS are generally lower than the doses used in PD, this may still occur. A small survey-type study completed on 94 patients with RLS who were treated with standard-dose dopamine agonists found that 12.4% of them developed a new compulsive behavior (Pourcher, Remillard, & Cohen, 2010).
Gabapentin has been found to be effective in relieving the symptoms of RLS; however, its use is limited by tolerability and a high variability in doses needed for symptom control. Doses studied and found to be effective range from 300 to 2400 mg daily (Thorpy, 2007). Gabapentin has been shown to have similar efficacy as ropinirole, although augmentation was not observed (Byrne et al., 2006).
Opioids such as oxycodone, methadone, and sustained-release morphine have been used in the management of RLS (Byrne et al., 2006). The side effects of these medications are well known and, of course, include the possibility of overuse and addiction. Stronger opioids such as methadone should be considered in patients who do not respond to dopaminergic agents and are in pain or have severe symptoms (Byrne et al., 2006).
Newer medications provide options that may avoid some of the major side effects of previously available therapies.
Neupro (Rotigotine Transdermal System)
Rotigotine was approved for the treatment of primary moderate-to-severe RLS in August 2012. The studies to support this indication were published in 2008 and 2010. The total number of patients was 963, with age range of 18–75 years. One of the studies was completed in Europe, whereas the other was completed in the United States. Both studies were placebo-controlled, double-blind studies with maintenance phases of 6 months. Both studies used standard RLS scales including the IRLS Rating Scale, which consists of 10 questions rating symptoms from none to very severe and assigning points to the answers (www.IRLSSG.org). Primary end points of both studies included decrease in severity scores on the IRLS scale. Mean change in score from baseline was found to be statistically significant versus placebo at the two highest doses tested, 2 mg/24 hours and 3 mg/24 hours (Hening et al., 2010).
The European study found statistically significant changes in IRLS scores with doses of 1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours (Trenkwalder et al., 2008). Open-label follow-up shows clinically relevant and stable improvements over 3 years of maintenance treatment (Hening et al., 2010). Improvement in IRLS score of 50% from baseline was found in twice as many patients who received rotigotine as compared with those who received placebo (Trenkwalder et al., 2008).
Recommended starting dose is 1 mg/24 hours, increased as needed by 1 mg/24 hours at weekly intervals, up to 3 mg/24 hours (UCB, 2013). Neupro was approved by the Food and Drug Administration at doses up to 3 mg/24 hours with an initial dose of 1 mg/24 hours. There was a significant improvement not only in night-time symptoms but also in RLS symptoms that occurred during the day (Trenkwalder et al., 2008).
The mechanism of action of rotigotine is unknown (UCB, 2013). Neupro is a pregnancy category C medication, meaning that there are no adequate and well-controlled studies in pregnant women. About the older adults, 26% of patients enrolled in the trial were aged 65 years or over (UCB, 2013). Plasma levels of rotigotine in patients aged 65–80 years were not noted to be different than plasma levels in younger patients (UCB, 2013).
There is no recommendation for dosage adjustments in patients with mild-to-severe renal or moderate hepatic impairment; information for severe hepatic impairment is not available (UCB, 2013). The primary elimination of rotigotine occurs through the urine as inactive conjugates (UCB, 2013). Neupro is also indicated for PD. It is significant to note that the recommended doses of Neupro for the management of PD are significantly higher. The mechanism of action in both RLS and PD is not known but is thought to be because of its ability to affect dopamine receptors (UCB, 2013).
Common Side Effects
The most common adverse reactions in doses used for RLS were application site reactions, nausea, somnolence, and headache. Nausea and headache did not appear to be dose-related reactions (Hening et al., 2010). Application site reactions were noted in 40% of patients, with most reactions being mild to moderate and discontinuation occurring in 10% of patients (Trenkwalder et al., 2008).
Augmentation and rebound are considered possible with the use of rotigotine because this has been noted with other dopaminergic agents as mentioned. A 5-year open-label extension study with 126 patients found an augmentation rate of 5% (Oertel et al., 2011).
Sleep attacks were noted in both pivotal trials. Among 963 patients, there were 12 patients who experienced this adverse effect; trial discontinuation occurred in three cases (Hening et al., 2010; Trenkwalder et al., 2008). Rotigotine is labeled as pregnancy category C (UCB, 2013). Labeling for rotigotine includes impulse control behaviors as possible adverse effects (UCB, 2013). Adverse effects listed as having occurred during trials include events that occurred with higher than a 2% frequency; this list does not include behavior changes (UCB, 2013).
Horizant (Gabapentin Enacarbil)
Horizant (gabapentin enacarbil) was approved by the Food and Drug Administration for the treatment of moderate-to-severe primary RLS in June 2011. It is the only nondopaminergic agent currently on the market with an indication for RLS. Gabapentin enacarbil is available as long-acting, once-daily medication with one approved dosage for RLS. This is likely to make Horizant easier to use than gabapentin from a practical standpoint.
The absorption of gabapentin occurs in a limited area of the small intestine and leads to individual responses to doses; gabapentin enacarbil is a prodrug with a novel mode of transport that allows absorption throughout the length of the intestine (Cundy et al., 2008). Data show superior bioavailability of gabapentin enacarbil, particularly when taken with food, over gabapentin (Cundy et al., 2008).
Studies for RLS and Horizant (gabapentin enacarbil) included doses of 600 and 1200 mg/day. The IRLS scores significantly improved in both dose groups versus placebo over a 12-week period (Lee et al., 2011). The proportion of patients with over 50% of improvement in IRLS scores versus baseline was as follows: 64% for 600-mg dose, 57.7% for 1200-mg dose, and 39.6% for placebo (Lee et al., 2011). Improvements in IRLS scores were seen as early as week 1 (Lee et al., 2011). Subjective improvement in time awake because of RLS symptoms, quality of sleep, and ability to function were noted in patients who received gabapentin enacarbil (Kushida et al., 2009).
The recommended dose for the management of RLS is 600 mg once per day to be taken at 5 P.M. with food (Xenoport, 2013). Gabapentin enacarbil is primarily excreted as unchanged gabapentin by the kidneys and is effectively removed by hemodialysis (Xenoport, 2013). Dose adjustment is needed for patients with severe renal impairment, and use of gabapentin enacarbil by patients who are on dialysis should be avoided (Xenoport, 2013).
Doses available are 300 and 600 mg once per day. Gabapentin enacarbil is also indicated for the treatment of postherpetic neuralgia with a dose of 1200 mg/day. Gabapentin enacarbil carries a class warning related to its parent compound regarding mood changes, depression, and suicidal thoughts (Xenoport, 2013). The pregnancy category for gabapentin enacarbil is C (Xenoport, 2013).
Common Side Effects
The most common adverse reactions were somnolence or sedation and dizziness. A 52-week study found that somnolence and dizziness led to withdrawal of the drug in 1.4%–1.6% of patients with dose ranges from 600 to 1800 mg/day (Ellenbogen et al., 2011).
A 12-week study with over 300 patients found that dizziness occurred in 10.4% of patients who took 600 mg of gabapentin enacarbil versus 5.2% of patients on placebo (Lee et al., 2011). Somnolence was noted in 2.1% of patients on placebo versus 21.7% of patients on 600 mg of gabapentin enacarbil (Lee et al., 2011). As with all possibly sedating medications, patients should avoid driving until they know how the medication will affect them. Despite achieving higher peak concentrations of gabapentin with the use gabapentin enacarbil, side effects were similar to those seen with gabapentin (Cundy et al., 2008). In a 52-week study, there were no clinically relevant changes in laboratory parameters, vital signs, or electrocardiograms in patients taking gabapentin enacarbil (Ellenbogen et al., 2011).
Both agents are long acting. As usual, the patient’s comorbidities must be considered when choosing to add a new medication. Previous response medications may not be indicative of a limited response to the new agents because side effects differ from one class to the other. Gabapentin enacarbil is not associated with augmentation, and data on rotigotine suggest that augmentation is not likely to be a significant issue.
Remember to educate patients who receive rotigotine to look out for skin reactions. If a patient is to undergo magnetic resonance imaging or a cardioversion, removal of the rotigotine patch is advised because it could cause a burn on the application site (UCB, 2013).
If patients have not responded to dopamine agonists or prefer to avoid this class of medications, gabapentin enacarbil is likely a good option. It is important to instruct patients to take this with food because medication absorption can be significantly affected. Patients should be aware of possible somnolence and should avoid driving until they are aware of how the medication will affect them.
If hospitalized, these medications should be continued or resumed if the patient’s condition allows. Sudden cessation of these agents is likely to trigger a return of RLS symptoms.
The management of RLS typically requires individualized consideration of each patient’s situation. Nonpharmacologic interventions including decreases in caffeine and nicotine should be part of all treatment plans.
New pharmacologic agents provide options for a condition that can significantly interfere with quality of life. Medications approved for the treatment of RLS are specifically for primary RLS. Addressing the causes of secondary RLS is pivotal to the successful treatment of the condition in patients in whom a cause can be identified.
Horizant (gabapentin enacarbil) provides a nondopaminergic, generally well-tolerated, once-daily option that is not associated with augmentation or rebound. Neupro (rotigotine) allows for once-daily application of a patch, which is less likely to cause augmentation as compared with other dopamine agonists. Both agents may improve daytime symptoms, particularly as Neupro is designed to absorb over 24 hours.
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