Restless legs syndrome: Update on evaluation and treatment

Restless legs syndrome (RLS) is a very common disease affecting about 10% of Caucasian adults with about one third of them having RLS symptoms severe enough to require treatment.

Although many patients still go undiagnosed or misdiagnosed, the diagnosis is easily established with the five diagnostic criteria that are simplified by the acronym URGES:

1. Urge to move the legs associated with unpleasant leg sensations.

2. Rest induces symptoms.

3. Gets better with activity.

4. Evening and nighttime worsening.

5. Solely not accounted by another medical or behavioral condition.

The diagnosis is based completely upon the history. However, supplemental tests can be helpful to rule out underlying conditions that increase the risk of RLS. Routine lab tests, such as serum creatinine (to rule out renal disease), TSH (to rule out thyroid disease), and a CBC/ferritin/iron with transferrin saturation (to rule out low iron stores) should be ordered if not done recently.

A polysomnographic sleep study should not be ordered unless there is a strong suspicion that sleep apnea is present. Even very frequent PLM (periodic limb movements) are not that helpful in confirming the diagnosis of RLS since they are nonspecific and often occurring with drug treatment (SSRIs, SNRIs) and many medical conditions such as sleep apnea, narcolepsy, and REM behavior disorder.

The paradigm for treating RLS has been presented in the consensus article published in 2013 (Silber MH, et al. Mayo Clin Proc. 2013 Sep;88[9]:977). Since 2013, there has been a gradual shift of that paradigm that recommended starting an approved dopamine agonist (pramipexole, ropinirole, or rotigotine) or an alpha-2-delta ligand (gabapentin enacarbil, gabapentin, or pregabalin) as first-line treatment. Although dopamine agonists provide excellent relief of RLS symptoms initially, with time, they tend to markedly worsen RLS. This process is called RLS augmentation and has become one of the most common causes of refractory RLS and difficult-to-treat patients.

RLS augmentation typically onsets a few months to several years after starting a short-acting dopamine agonist (DA) like pramipexole or ropinirole. It presents with symptoms occurring a few hours earlier than prior to starting the medication, symptoms becoming more intense with less rest time needed to trigger RLS symptoms, drugs becoming less effective both in effectiveness and duration of action, and spread of symptoms to other body parts (arms, trunk, and even head). The majority of physicians mistake this worsening of RLS for the natural progression of the disease and, thus, increase the dose of the DA, which provides temporary improvement. Further increases become progressively necessary until the patient is receiving very large doses, often exceeding 10 times the FDA maximum recommended doses. Eventually, further dose increments provide minimal additional benefit, leaving patients with severe, around the clock RLS symptoms causing extreme misery. To be more aware of augmentation, physicians should consider augmentation may be occurring whenever a patient who has been on a regimen of stable dopamine agonist treatment for at least 6 months requests more medication.

 

The incidence of augmentation for patients taking short-acting DA drugs is about 7% to 8% per year so that by 10 years, the vast majority of these patients with RLS are experiencing augmentation. Since it has been over 13 years since pramipexole and ropinirole have been approved for treating RLS, currently, over 75% of patients referred to national RLS experts are referred due to augmentation (although the actual referral diagnosis is often “refractory RLS”). Despite the concerns about augmentation, the short-acting DA drugs are by far the most commonly prescribed medications for initial treatment of RLS.

To help educate doctors about RLS augmentation, a consensus article was published in 2016 promoting guidelines for the prevention and treatment of RLS augmentation (Garcia-Borreguero D, et al. Sleep Med. 2016;21:1-11). Since augmentation occurs only with dopaminergic drugs (with the exception of tramadol), considering the use of nondopaminergic drugs for first-line therapy of RLS would dramatically decrease the occurrence of augmentation. This is a clear shift in the paradigm of choosing equally amongst the approved RLS drugs.

Unless contraindicated, the alpha-2-delta drugs should be the first consideration for treating new RLS patients. These drugs can be as effective as the DA drugs but cannot cause augmentation and, also, do not cause Impulse control disorders, which occur with the use of DAs. Furthermore, they reduce insomnia and anxiety that are both associated with RLS. The use of these drugs may be limited by their side effects, which include CNS depressive effects (sedation, dizziness, decreased balance or cognition) or depression.

When the alpha-2-delta ligands can’t be used due to lack of efficacy, side effects or cost, the DA drugs may then be appropriate. The rotigotine patch has the lowest incidence of augmentation, especially at the approved doses of up to 3 mg. If the rotigotine patch cannot be used (most often due to skin side effects or cost), then the short-acting DA drugs may be employed. Augmentation may be prevented or significantly delayed by starting these drugs at their lowest dose (.125 mg for pramipexole and .25 mg for ropinirole) and increasing the dose as little as possible, definitely not exceeding the approved RLS limits of .5 mg for pramipexole and 4 mg for ropinirole. My personal suggestion is not to exceed .25 mg for pramipexole and 1 mg for ropinirole as augmentation is dose-related but may occur at even the lowest doses. When patients need and request increased treatment for their RLS, rather than increasing the dose of the DA, instead, consider adding other medications, such as the alpha-2-delta ligands or even low dose opioids.

Managing augmentation is typically a very challenging problem for both the physician and patient; this is described in detail in the augmentation article referenced above. Decreasing, or better yet eliminating , the short-acting DA is the preferred method for treating augmentation. However, upon elimination of the DA, there is a short period of 1 to 4 weeks (average of 10-12 days) when the RLS symptoms get dramatically worse. Patients typically experience extremely severe RLS symptoms around the clock and may not be able to sleep at all until the RLS calms down. Most often, only low dose opioid treatment will enable them to get through this transition. The augmentation article (with its algorithm) may help physicians manage augmentation, but patients with severe augmentation may need referral to an RLS specialist who is experienced in this area and who is comfortable managing the disease with opioids.

Low iron levels are often associated with RLS, cause RLS symptoms to worsen, and increase the risk of augmentation (Allen RP, et al, and the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2018;41:27). We typically suggest that patients with ferritin levels under 100 mcg/L should get supplemental iron. However, oral iron absorption is very limited when the patient’s ferritin is above 50 mcg/L and, therefore, most patients may require IV iron to improve their RLS symptoms. There are several IV iron preparations but only iron dextrose, iron carboxymaltose, and ferumoxytol are effective. When the ferritin level is increased to over 200 µg/L, RLS symptoms may be dramatically improved.

With the currently available treatment options, most patients should have their RLS symptoms well controlled without developing augmentation.


Dr. Buchfuhrer is with Stanford University, Department of Psychiatry and Behavioral Sciences in the School of Medicine, Division of Sleep Medicine, Stanford, Calif.

Restless legs syndrome (RLS) is a very common disease affecting about 10% of Caucasian adults with about one third of them having RLS symptoms severe enough to require treatment.

Although many patients still go undiagnosed or misdiagnosed, the diagnosis is easily established with the five diagnostic criteria that are simplified by the acronym URGES:

1. Urge to move the legs associated with unpleasant leg sensations.

2. Rest induces symptoms.

3. Gets better with activity.

4. Evening and nighttime worsening.

5. Solely not accounted by another medical or behavioral condition.

The diagnosis is based completely upon the history. However, supplemental tests can be helpful to rule out underlying conditions that increase the risk of RLS. Routine lab tests, such as serum creatinine (to rule out renal disease), TSH (to rule out thyroid disease), and a CBC/ferritin/iron with transferrin saturation (to rule out low iron stores) should be ordered if not done recently.

A polysomnographic sleep study should not be ordered unless there is a strong suspicion that sleep apnea is present. Even very frequent PLM (periodic limb movements) are not that helpful in confirming the diagnosis of RLS since they are nonspecific and often occurring with drug treatment (SSRIs, SNRIs) and many medical conditions such as sleep apnea, narcolepsy, and REM behavior disorder.

The paradigm for treating RLS has been presented in the consensus article published in 2013 (Silber MH, et al. Mayo Clin Proc. 2013 Sep;88[9]:977). Since 2013, there has been a gradual shift of that paradigm that recommended starting an approved dopamine agonist (pramipexole, ropinirole, or rotigotine) or an alpha-2-delta ligand (gabapentin enacarbil, gabapentin, or pregabalin) as first-line treatment. Although dopamine agonists provide excellent relief of RLS symptoms initially, with time, they tend to markedly worsen RLS. This process is called RLS augmentation and has become one of the most common causes of refractory RLS and difficult-to-treat patients.

RLS augmentation typically onsets a few months to several years after starting a short-acting dopamine agonist (DA) like pramipexole or ropinirole. It presents with symptoms occurring a few hours earlier than prior to starting the medication, symptoms becoming more intense with less rest time needed to trigger RLS symptoms, drugs becoming less effective both in effectiveness and duration of action, and spread of symptoms to other body parts (arms, trunk, and even head). The majority of physicians mistake this worsening of RLS for the natural progression of the disease and, thus, increase the dose of the DA, which provides temporary improvement. Further increases become progressively necessary until the patient is receiving very large doses, often exceeding 10 times the FDA maximum recommended doses. Eventually, further dose increments provide minimal additional benefit, leaving patients with severe, around the clock RLS symptoms causing extreme misery. To be more aware of augmentation, physicians should consider augmentation may be occurring whenever a patient who has been on a regimen of stable dopamine agonist treatment for at least 6 months requests more medication.

 

The incidence of augmentation for patients taking short-acting DA drugs is about 7% to 8% per year so that by 10 years, the vast majority of these patients with RLS are experiencing augmentation. Since it has been over 13 years since pramipexole and ropinirole have been approved for treating RLS, currently, over 75% of patients referred to national RLS experts are referred due to augmentation (although the actual referral diagnosis is often “refractory RLS”). Despite the concerns about augmentation, the short-acting DA drugs are by far the most commonly prescribed medications for initial treatment of RLS.

To help educate doctors about RLS augmentation, a consensus article was published in 2016 promoting guidelines for the prevention and treatment of RLS augmentation (Garcia-Borreguero D, et al. Sleep Med. 2016;21:1-11). Since augmentation occurs only with dopaminergic drugs (with the exception of tramadol), considering the use of nondopaminergic drugs for first-line therapy of RLS would dramatically decrease the occurrence of augmentation. This is a clear shift in the paradigm of choosing equally amongst the approved RLS drugs.

Unless contraindicated, the alpha-2-delta drugs should be the first consideration for treating new RLS patients. These drugs can be as effective as the DA drugs but cannot cause augmentation and, also, do not cause Impulse control disorders, which occur with the use of DAs. Furthermore, they reduce insomnia and anxiety that are both associated with RLS. The use of these drugs may be limited by their side effects, which include CNS depressive effects (sedation, dizziness, decreased balance or cognition) or depression.

When the alpha-2-delta ligands can’t be used due to lack of efficacy, side effects or cost, the DA drugs may then be appropriate. The rotigotine patch has the lowest incidence of augmentation, especially at the approved doses of up to 3 mg. If the rotigotine patch cannot be used (most often due to skin side effects or cost), then the short-acting DA drugs may be employed. Augmentation may be prevented or significantly delayed by starting these drugs at their lowest dose (.125 mg for pramipexole and .25 mg for ropinirole) and increasing the dose as little as possible, definitely not exceeding the approved RLS limits of .5 mg for pramipexole and 4 mg for ropinirole. My personal suggestion is not to exceed .25 mg for pramipexole and 1 mg for ropinirole as augmentation is dose-related but may occur at even the lowest doses. When patients need and request increased treatment for their RLS, rather than increasing the dose of the DA, instead, consider adding other medications, such as the alpha-2-delta ligands or even low dose opioids.

Managing augmentation is typically a very challenging problem for both the physician and patient; this is described in detail in the augmentation article referenced above. Decreasing, or better yet eliminating , the short-acting DA is the preferred method for treating augmentation. However, upon elimination of the DA, there is a short period of 1 to 4 weeks (average of 10-12 days) when the RLS symptoms get dramatically worse. Patients typically experience extremely severe RLS symptoms around the clock and may not be able to sleep at all until the RLS calms down. Most often, only low dose opioid treatment will enable them to get through this transition. The augmentation article (with its algorithm) may help physicians manage augmentation, but patients with severe augmentation may need referral to an RLS specialist who is experienced in this area and who is comfortable managing the disease with opioids.

Low iron levels are often associated with RLS, cause RLS symptoms to worsen, and increase the risk of augmentation (Allen RP, et al, and the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2018;41:27). We typically suggest that patients with ferritin levels under 100 mcg/L should get supplemental iron. However, oral iron absorption is very limited when the patient’s ferritin is above 50 mcg/L and, therefore, most patients may require IV iron to improve their RLS symptoms. There are several IV iron preparations but only iron dextrose, iron carboxymaltose, and ferumoxytol are effective. When the ferritin level is increased to over 200 µg/L, RLS symptoms may be dramatically improved.

With the currently available treatment options, most patients should have their RLS symptoms well controlled without developing augmentation.


Dr. Buchfuhrer is with Stanford University, Department of Psychiatry and Behavioral Sciences in the School of Medicine, Division of Sleep Medicine, Stanford, Calif.

Restless legs syndrome (RLS) is a very common disease affecting about 10% of Caucasian adults with about one third of them having RLS symptoms severe enough to require treatment.

Although many patients still go undiagnosed or misdiagnosed, the diagnosis is easily established with the five diagnostic criteria that are simplified by the acronym URGES:

1. Urge to move the legs associated with unpleasant leg sensations.

2. Rest induces symptoms.

3. Gets better with activity.

4. Evening and nighttime worsening.

5. Solely not accounted by another medical or behavioral condition.

The diagnosis is based completely upon the history. However, supplemental tests can be helpful to rule out underlying conditions that increase the risk of RLS. Routine lab tests, such as serum creatinine (to rule out renal disease), TSH (to rule out thyroid disease), and a CBC/ferritin/iron with transferrin saturation (to rule out low iron stores) should be ordered if not done recently.

A polysomnographic sleep study should not be ordered unless there is a strong suspicion that sleep apnea is present. Even very frequent PLM (periodic limb movements) are not that helpful in confirming the diagnosis of RLS since they are nonspecific and often occurring with drug treatment (SSRIs, SNRIs) and many medical conditions such as sleep apnea, narcolepsy, and REM behavior disorder.

The paradigm for treating RLS has been presented in the consensus article published in 2013 (Silber MH, et al. Mayo Clin Proc. 2013 Sep;88[9]:977). Since 2013, there has been a gradual shift of that paradigm that recommended starting an approved dopamine agonist (pramipexole, ropinirole, or rotigotine) or an alpha-2-delta ligand (gabapentin enacarbil, gabapentin, or pregabalin) as first-line treatment. Although dopamine agonists provide excellent relief of RLS symptoms initially, with time, they tend to markedly worsen RLS. This process is called RLS augmentation and has become one of the most common causes of refractory RLS and difficult-to-treat patients.

RLS augmentation typically onsets a few months to several years after starting a short-acting dopamine agonist (DA) like pramipexole or ropinirole. It presents with symptoms occurring a few hours earlier than prior to starting the medication, symptoms becoming more intense with less rest time needed to trigger RLS symptoms, drugs becoming less effective both in effectiveness and duration of action, and spread of symptoms to other body parts (arms, trunk, and even head). The majority of physicians mistake this worsening of RLS for the natural progression of the disease and, thus, increase the dose of the DA, which provides temporary improvement. Further increases become progressively necessary until the patient is receiving very large doses, often exceeding 10 times the FDA maximum recommended doses. Eventually, further dose increments provide minimal additional benefit, leaving patients with severe, around the clock RLS symptoms causing extreme misery. To be more aware of augmentation, physicians should consider augmentation may be occurring whenever a patient who has been on a regimen of stable dopamine agonist treatment for at least 6 months requests more medication.

 

The incidence of augmentation for patients taking short-acting DA drugs is about 7% to 8% per year so that by 10 years, the vast majority of these patients with RLS are experiencing augmentation. Since it has been over 13 years since pramipexole and ropinirole have been approved for treating RLS, currently, over 75% of patients referred to national RLS experts are referred due to augmentation (although the actual referral diagnosis is often “refractory RLS”). Despite the concerns about augmentation, the short-acting DA drugs are by far the most commonly prescribed medications for initial treatment of RLS.

To help educate doctors about RLS augmentation, a consensus article was published in 2016 promoting guidelines for the prevention and treatment of RLS augmentation (Garcia-Borreguero D, et al. Sleep Med. 2016;21:1-11). Since augmentation occurs only with dopaminergic drugs (with the exception of tramadol), considering the use of nondopaminergic drugs for first-line therapy of RLS would dramatically decrease the occurrence of augmentation. This is a clear shift in the paradigm of choosing equally amongst the approved RLS drugs.

Unless contraindicated, the alpha-2-delta drugs should be the first consideration for treating new RLS patients. These drugs can be as effective as the DA drugs but cannot cause augmentation and, also, do not cause Impulse control disorders, which occur with the use of DAs. Furthermore, they reduce insomnia and anxiety that are both associated with RLS. The use of these drugs may be limited by their side effects, which include CNS depressive effects (sedation, dizziness, decreased balance or cognition) or depression.

When the alpha-2-delta ligands can’t be used due to lack of efficacy, side effects or cost, the DA drugs may then be appropriate. The rotigotine patch has the lowest incidence of augmentation, especially at the approved doses of up to 3 mg. If the rotigotine patch cannot be used (most often due to skin side effects or cost), then the short-acting DA drugs may be employed. Augmentation may be prevented or significantly delayed by starting these drugs at their lowest dose (.125 mg for pramipexole and .25 mg for ropinirole) and increasing the dose as little as possible, definitely not exceeding the approved RLS limits of .5 mg for pramipexole and 4 mg for ropinirole. My personal suggestion is not to exceed .25 mg for pramipexole and 1 mg for ropinirole as augmentation is dose-related but may occur at even the lowest doses. When patients need and request increased treatment for their RLS, rather than increasing the dose of the DA, instead, consider adding other medications, such as the alpha-2-delta ligands or even low dose opioids.

Managing augmentation is typically a very challenging problem for both the physician and patient; this is described in detail in the augmentation article referenced above. Decreasing, or better yet eliminating , the short-acting DA is the preferred method for treating augmentation. However, upon elimination of the DA, there is a short period of 1 to 4 weeks (average of 10-12 days) when the RLS symptoms get dramatically worse. Patients typically experience extremely severe RLS symptoms around the clock and may not be able to sleep at all until the RLS calms down. Most often, only low dose opioid treatment will enable them to get through this transition. The augmentation article (with its algorithm) may help physicians manage augmentation, but patients with severe augmentation may need referral to an RLS specialist who is experienced in this area and who is comfortable managing the disease with opioids.

Low iron levels are often associated with RLS, cause RLS symptoms to worsen, and increase the risk of augmentation (Allen RP, et al, and the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2018;41:27). We typically suggest that patients with ferritin levels under 100 mcg/L should get supplemental iron. However, oral iron absorption is very limited when the patient’s ferritin is above 50 mcg/L and, therefore, most patients may require IV iron to improve their RLS symptoms. There are several IV iron preparations but only iron dextrose, iron carboxymaltose, and ferumoxytol are effective. When the ferritin level is increased to over 200 µg/L, RLS symptoms may be dramatically improved.

With the currently available treatment options, most patients should have their RLS symptoms well controlled without developing augmentation.


Dr. Buchfuhrer is with Stanford University, Department of Psychiatry and Behavioral Sciences in the School of Medicine, Division of Sleep Medicine, Stanford, Calif.