The Southern California RLS Support Group Treatment Page

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RLS/PLMD Treatment Page

Comprehensive Review of Medications used in Treating RLS and PLMD


The information below is offered for patients with RLS and for medical professionals who may want more details about treating RLS. Patients with RLS should not use this information to adjust their own medicine or treat themselves. They should instead consult a physician who is knowledgeable in RLS to treat their problem. If a local physician knowledgeable in RLS is not available, then have your treating doctor use the information below as a guide for treatment.

The choice of medications should be individualized and most patients cannot be treated by using a simple formula. In general drugs are chosen from the 3 primary classes of medications first, and then if necessary, drugs from the secondary class of medications may be considered.


TABLE OF CONTENTS

    PRIMARY CLASS OF RLS MEDICATIONS

  1. Sedative/Hypnotic Medication - Benzodiazepines and related drugs
  2. Drugs used to treat Parkinson's Disease - Dopaminergic Drugs
  3. Analgesic (pain-killing) Medication - Opiates/Narcotics
     
  4. Anti-Seizure Medication

    SECONDARY CLASS OF RLS MEDICATION

  1. Hypertensive (High blood pressure) Medication
  2. Multiple Sclerosis Medication
  3. Antidepressant Medication
  4. Recreational Medication

    OTHER RLS/PLMD TREATMENTS

  1. Medication used to treat deficiency states associated with RLS
  2. Disease states associated with RLS
  3. Surgical treatment for RLS
  4. Non-drug treatment for RLS
  5. Non-conventional treatment for RLS
  6. Drugs and Foods to avoid to improve RLS
  7. Pregnancy and RLS
     
  8. Quinine
     
  9. Other RLS Information and Associations

PRIMARY CLASS OF RLS MEDICATIONS

(1) Sedative/Hypnotic Medication - Benzodiazepines and related drugs

This should be the first class of medication to be considered for mild RLS/PLMD problems which occur only at bedtime/sleep and do not regularly impair sleep. In the absence of significant daytime RLS symptoms, it is very appropriate to use sedative pills just before sleep time to induce sleep and sustain sleep until the morning. As such, the best drugs are ones that have a quick onset of action and a short half life so that the sedative effects are gone by the morning (so there is no persisting sleepiness in the daytime). In addition, these drugs should not have active metabolites (chemical formed when the drug is metabolized that are themselves active to cause sleepiness) which may cause excessive sleepiness during the daytime by prolonging the sleepy effects of the drug. The discussion of the different drugs below will concentrate on these beneficial and desirable features.

These drugs are also helpful in PLMS.  They do not consistently significantly decrease the amount of PLMS, but they do decrease the arousals from the PLMS, which improve the quality of sleep.

Side effects are generally quite similar in all the medications in this class. Addiction with tolerance and withdrawal problems can occur with almost all of them and therefore periodic drug holidays (generally 2 days off the drug every 2 weeks) should be considered (this is very strongly recommended!!). All the medications should be started at the lowest dose and increased only if necessary.

BENZODIAZEPINES SEDATIVES

(A) Benzodiazepine medications marketed for sleeping pills

Halcion (Triazolam)

This drug comes in 0.125 mg and 0.25 mg tablets. Doses range from 0.125 mg to 0.5 mg. It has a fast onset of action (15-30 minutes) and a very short half life, so that the duration of action is only 3-4 hours. This is also a popular sleeping pill and RLS medication.

The problems with Halcion (and short acting hypnotic drugs in general) is that of rebound insomnia (which is much worsened insomnia the night after using the drug). Another problem is that of short term amnesia. This occurs upon awakening, after taking Halcion, resulting in a loss of memory of previous recent events occurring after taking the Halcion.

Restoril (Temazepam)

Temazepam has a longer than usual onset of action of 45-60 minutes. It is therefore not as good for RLS problems that occur on going to sleep. It is good for RLS and especially PLMD that may occur after sleep onset. It has a reasonable duration of action of 6-8 hours, so that it should sustain sleep all night and generally not cause morning sleepiness.

The drug comes in 15 mg and 30 mg tablets and doses range from 7.5 mg to 30 mg.

Dalmane (Flurazepam)

This is the original benzodiazepine sleeping pill. It does have a rapid onset of action (15-30 min), but has a long half-life (8-10 hours) and in addition has active metabolites. These active metabolites (chemicals formed from the metabolism of the drug) occur after the Dalmane has lost in original effect and continue to act a sleep inducing chemicals, thus prolonging the hypnotic effect of the medication. Daytime sleepiness is thus a very significant problem with this medication.

Dalmane comes in 15 mg and 30 mg capsules. Doses range from 15 - 30 mg. It is not on our recommended list of RLS medications, but has been used successfully in a minority of patients.

Doral (Quazepam)

Doral comes in 7.5 mg and 15 mg tablets. Dosage ranges from 7.5 to 15 mg. It has a fast onset of action of 15-30 minutes. It's duration of action is 8-10 hours, so that morning sleepiness may be of some concern. It also has active metabolites which can lead to daytime sleepiness. This is one of the newer sleep medications and may have some benefit in a small percentage of RLS patients.

Prosom (Estazolam)

This comes in 1 mg and 2 mg tablets and is also one of the newer sleep medications. Dosage ranges from 0.5 mg to 2 mg. It has a rapid onset of action of 15-30 minutes and an intermediate duration of action of 6-8 hours. It may be quite a reasonable drug for RLS in patients who have the time and inclination to sleep a little longer (7-10 hours). It also has active metabolites which may cause increased daytime sleepiness in many individuals.

(B) Benzodiazepines marketed for anxiety

Xanax (Alprazolam)

This medication comes in 4 strengths; 0.25 mg, 0.5 mg, 1 mg and 2 mg tablets. Doses range from 0.25 mg to 2 mg. The drug has fairly quick onset of about 15-30 minutes and a duration of action of about 6-12 hours. Although not marketed as a sleeping pill, Xanax works quite well to control nighttime RLS problems without much daytime sleepiness in most users.

Valium (Diazepam)

This is one of the original sedative drugs. It has not been marketed for sleep but actually may work well in many patients. It has a rapid onset of action (less than 30 min). It's duration of action can be variable from 6-10 hours.

Valium comes in 2 mg, 5 mg, and 10 mg tablets. Effective dosages range from 5 mg to 10 mg.

Klonopin/ Rivotril (Clonazepam)

Klonopin comes in 0.5 mg, 1 mg, and 2 mg tablets. The usual dose range is 0.5 to 2 mg. This was the first drug used for RLS and PLMD. This is due to its previous use in myoclonic seizures. PLMD used to be called nocturnal myoclonus and thus this drug was tried for RLS/PLMD with great success.

The drug has a rapid onset of action (less than 30 min) but it has a very long half-life (30-40 hours) causing a duration of action of 8-12 hours or longer. Daytime sleepiness can be a problem in a large percentage of patients on Klonopin. We therefore do not recommend this drug for most patients with RLS. It is, however, very commonly prescribed for RLS due to its early association with the treatment of RLS.  It may work well in patients who do have morning RLS and do not get drowsy or sleepy due to the long lasting nature of this drug (which may persist at high  levels in the morning causing daytime sleepiness).  

Many physicians prescribe Klonopin, as this is the original drug used for RLS and is recommended by all the general medical textbooks that discuss RLS.  Some sleep specialists (and patients) prefer to use this drug for RLS, but our experience has been that the shorter acting sedatives work better for most RLS sufferers.

Ativan (Lorazepam)

Ativan is a tranquilizer that is used for stress rather than sleep. It is a very common benzodiazepine drug which is used during the daytime to help patients control anxiety. Like all the benzodiazepines, this drug will have some usefulness when taken at bedtime for sleep.

This drug comes in 0.5 mg, 1 mg and 2 mg tablets.  It has a half life of 12 hours, so there is a very significant concern about daytime sleepiness the morning after the medication is taken.  The long half life is more useful when Ativan is used for anxiety disorders, but may cause too much drowsiness when used for nighttime RLS/PLMD and as a sleeping pill.

Serax (Oxazepam)

Serax is actually not a benzodiazepine, but is in a closely related class of 3-hydroxybenzodiazepinones. This is a safer class of medication than the benzodiazepines (such as Valium).  It has a fairly rapid onset with rather long half life of 5.7 to 10.9 hours. This is a rather long half life which might result in daytime sleepiness, but many people who have tried it for sleep, find that morning drowsiness is often not a problem.

Serax comes in 10 mg, 15 mg and 30 mg capsules.

 

NON-BENZODIAZEPINES SEDATIVES

Ambien (Zolpidem)

This is the first drug in this class. It is not a benzodiazepine, but it does work selectively on some of the benzodiazepine nerve receptors (only the omega 1 receptor of the 3 omega receptors). Because of this selectivity, Ambien appears to have fewer side effects than other drugs in this class. It is unique in sedative pills as it does not alter the sleep stages. Most drugs in this class decrease stages 1, 3, and 4 (and possibly even REM sleep) to increase stage 2 sleep. There have been as yet, no reported tolerance or withdrawal problems with long term usage of Ambien. There are also no problems with rebound insomnia (increased problems falling asleep the night after using the drug) which occurs in short acting sedative. Amnesia (loss of memory when awakening in the morning) does not occur as it does with Halcion (see below).

Ambien comes in 5 mg and 10 mg tablets. Doses are 2.5 to 10 mg, doses greater than 10 mg are no more effective than the 10 mg maximum dose. This drug has very quick onset of action (less than 30 minutes), in fact it is recommended that you should go to bed immediately after taking the medication. The half-life of the medication is about 2.5 hours, which means that daytime sleepiness is extremely unusual. Time will tell, but Ambien may be an excellent choice for long term use in patients who get relief with this drug.

 Sonata (Starnoc in Canada) (Zaleplon)

This is a new non-benzodiazepine drug from the pyrazolopyrimidine class of drugs. It is similar in many ways to Ambien in that there is no tolerance/addiction or withdrawal problems demonstrated yet and it acts on the same omega 1 receptors in the brain.  It also does not affect the sleep stages. It works very quickly and should be taken as one goes to bed.  There are also no problems with amnesia or next day sleepiness.

Sonata comes in 5 and 10 mg tablets.  It can be taken up to 20 mg, but the starting dose is 10 mg for most adults, and 5 mg for elderly patients or very small people.  It should not be taken after a meal that is high in fat, as that will delay absorption and cause a significant decrease in its effectiveness. Care should be taken when used with Tagamet (cimetidine), as it will cause higher levels of Sonata (therefore, start with 5 mg for patients on Tagamet).

One major difference from Ambien is that this drug has a half life of only 1 hour (compared with 2..5 hours for Ambien), which makes this the fastest metabolized sedative that is prescribed. It is suggested that due to this short half life, that Sonata will only result in about 4 hours of sleep.  Some clinical studies suggest that the actual sleep times with this drug will only be minimally shorter than with Ambien.   This may be a good drug to take in the middle of the night when quick relief is need for RLS insomnia, but when one needs to be awake and alert a few hours later (there are no studies yet to show whether or not this will be the case). 

As this drug is quite new, only time will tell how well it works for RLS and for sleep in general.

Imovane (Zopiclone) Available only in Canada - can not get this in the USA

Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic agent. Imovane belongs to a novel chemical class which is structurally unrelated to existing hypnotics. This drug is similar to Ambien (which is not available in Canada). The half-life of zopiclone ranges from 3.5 to 6.5 hours. In the elderly, the elimination half-life is prolonged to approximately 7 hours and in patients with liver insufficiency it was substantially prolonged to11.9 hours.

Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines and benzodiazepine-like agents (i.e. cimetidine or erythromycin). Side effects are similar to the shorter acting benzodiazepines, but tolerance/addiction should be less common.

Imovane comes only in 7.5 mg tablets. That is the starting dose for most adults. Older patients should start at 1/2 tablet and only increase the dose to a full tablet if necessary.

Lunesta (Eszopiclone)

This is very similar to the drug Imovane described above.  It is a purer form of Imovane in that only the S isomer is in this drug.  Most all drugs come in a 50/50 mixture of a S and R enantiomers (mirror image molecules) but only one of them is active.  In the case of Lunesta only the active S isomer is used providing for a purer form of the drug which may make it more active and possibly have less side effects.

This drug is not a benzodiazepine and should act similar to Ambien except for having a longer duration of action.  Its half-life is 6 hours (compared to 2.5 for Ambien) which may provide for longer sleep times but may also result in more early morning sleepiness (after waking up).

Lunesta is the only drug that has been studied for long term (6 months or longer) use is now the only sleeping pill that has been proven to be non-addictive or cause tolerance.

Lunesta comes in 1 mg, 2 mg and 3 mg capsules.  It is recommended to start with 2 mg for most people but 1 mg may be more appropriate for older patients.

 

(2) Drugs used to treat Parkinson's Disease - Dopaminergic Drugs

This class of drugs should be considered when the symptoms are not easily relieved by intermittent use of the above sedative medications or for daytime complaints which would preclude the use of sedatives. There is generally a good response (about 90% of patients will respond to these medications) to this class of pills, so it makes a good second choice to try on RLS patients.

Sinemet (Carbidopa/LevoDopa)

This medication has 2 components; LevoDopa (L-Dopa), the active Parkinson's medication (this is a precursor drug and turns into dopamine in the brain), and Carbidopa, an inhibitor of the enzyme (decarboxylase) which inactivates L-Dopa. The short acting form of this medication comes in 3 strengths: 25-100, 10-100, and 25-250. The first number indicates the amount of Carbidopa and the second number is the amount of L-Dopa in the pill. The Sinemet pill most often used for RLS is the 25-100.

Sinemet can be started at half a pill (25-100) 30-60 minutes before bedtime. It can be increased to about 3 tablets before bedtime, and will last about 3-4 hours. For early morning awakenings, another half to one pill can be added to help finish the night's sleep. Keep the nighttime total dose to a maximum of 3 pills. The medication generally works better for nighttime RLS than on daytime RLS symptoms.

Sinemet also comes in a sustained release long acting formulation called Sinemet CR, in both 25-100 and 50-200 strengths. This slow release tablet comes to peak action in two hours, so it is often combined with a short acting Sinemet to get relief within 30 minutes. Sinemet CR can be used in the morning also (in patients who get daytime benefit from this medication) for sustained daytime relief.

The main side effects of Sinemet include nausea, mental effects (confusion, hallucinations, dizziness), and dyskinesia (abnormal involuntary movements which occur with long term usage). The nausea can be avoided often if the medication is taken with food (this can however delay absorption of the drug). Dyskinesias are the most common serious side effect to occur in Parkinson's disease patients taking this drug, but occurs rarely in RLS patients. Periodic monitoring of CBC, hepatic and renal function is suggested.

Two main problems for patients with RLS using Sinemet are rebound and augmentation. Rebound occurs as the drug's action is wearing off with the symptoms coming back even worse than they were before treatment. Augmentation is an increase in RLS problems in general, not just as the drug's effects are wearing off and is the most common reason for discontinuing Sinemet. With augmentation, the intensity of the RLS symptoms can increase, can onset earlier and even spread to the upper limbs. Raising the dose of Sinemet may temporarily help the augmentation symptoms, but in a short while the increased dose just leads to further augmentation. Keeping the Sinemet 25-100 dose at no more than 2-3 tablets per day reduce the chances of getting augmentation (it is rarely seen with 1-2 tablets). Augmentation occurs more readily when RLS symptoms are present before 6:00 p.m. (off therapy).

Sinemet CR generally prevents the rebound problem but does not avoid augmentation. The augmentation effect of worsening RLS symptoms lasts for several days after discontinuing the medication. Mirapex or Requip (see below) can be used to treat Sinemet augmentation by giving one of the lowest strength tablets at bedtime, then adding another tablet every 2 days to that dose if needed.  The Sinemet can be discontinued abruptly (especially at the lower doses), but may cause an increase in RLS symptoms for a few days as noted above. Mirapex or Requip (as above) will prevent some of this, or the Sinemet can be tapered off over several days.

NOTE: Due to the problems of  augmentation which may occur in 50-80% of patients, Sinemet is likely better for mild intermittent cases of RLS, in which the dose of medication can be kept low enough or on an intermittent basis to avoid these side effects.  Another use might be in cases where the other medications do not last through the night, a dose of Sinemet CR added to the other Parkinson's disease drugs at bedtime (and only at that time) may provide all night relief from RLS. Now that there are other better Parkinson's disease drugs available, Sinemet should not be used for RLS (except by RLS specialists who are very well versed with the problems with this drug).

Permax (Pergolide) This drug has been voluntarily removed from the US market as of March 2007

This medication is a dopamine agonist (acts like dopamine on the dopamine D1 and D2 receptors). Permax may work better than Sinemet for daytime RLS symptoms and for more severe RLS. Permax has been shown in a recent study to help patients (73%) who failed Sinemet. Compared to Sinemet it has a longer duration of action of up to 10-12 hours ( Sinemet's duration is only 5-6 hours). It can be added to Sinemet (the Sinemet dose should be reduced as this is done). This drug does usually does not cause significant rebound or augmentation problems as described above with Sinemet. Permax comes in 0.05 mg, 0.25 mg, and 1.0 mg.

Start with Permax .05 mg, 1/2 - 1 tablet 1-2 hours before bedtime. If symptoms start in the evening, another 1/2 - 1 tablet can be taken at dinner time. The medication should be taken 1 hour before the symptoms occur. A middle of the nighttime dose can be added in addition if necessary. For daytime symptoms, Permax .05 mg can be added at breakfast and lunch time. Increase the dose every 3 - 7 days by 1/2 - 1 tablet prior to the times of day with persistent symptoms until the RLS symptoms are under control or up to 0.5 mg (10 times the starting dose) for each single dose or to a maximum of 1.5 mg per day. Most patients can be controlled with Permax 0.5 - 1.0 mg per day.

Go slow with Permax to avoid side effects which include nasal stuffiness, hypotension (low blood pressure), nausea, headache, and lightheadedness. The problem with hypotension can be very bothersome if the dose is increased too quickly. Dyskinesia (involuntary movements) as with Sinemet, seem to occur mostly in Parkinson's disease patients, but not in RLS patients. 

A minority of RLS patients on Permax may get tolerant of the drug and need higher doses.  This tolerance problem is not generally as bad a with other drugs, such as the sedatives or narcotics, as most will still be controlled by the higher dose. There is little or  no cross tolerance with the other dopamine agents (Mirapex or Requip), so a change can be made to another drug once tolerance to Permax becomes a problem.

Augmentation has been reported in some studies with Permax in about 10-22% of patients.  The problem is not similar to the augmentation seen with Sinemet as giving more of the medication earlier in the day to treat the RLS symptoms work well, rather than worsening the problem as with Sinemet.

   A new study published in the Mayo Clinic Proceedings (Mayo Clin Proc, 2002;77:1280-1286) has just revealed 3 cases of valvular heart disease from Permax.  This is similar to what was seen in the past with the diet drug Phen Fen (from the fenfluramine part).  Permax is an ergot-derived drug which is a class of drug that has been known to cause valvular heart disease. Although it is to early to know whether there is a significant concern for all patients taking this drug, patients on this drug should see their doctor and an echocardiogram (the best test to see if any valvular heart damage is occurring) should be considered.

In addition, there are several case reports of Pulmonary Fibrosis (scarring of the lungs) caused by Permax.  The latest article is in Clinical Neuropharmacology, Vol 25, No. 5, pages 290-293.  This problem with Pulmonary Fibrosis should also be considered when using Permax for long periods of time.

Parlodel (Bromocriptine)

This medication, which is also a dopamine agonist (acts like dopamine on the dopamine receptors), has been used with some success in some medical centers. Others have not found Parlodel to be as effective as the other 2 Parkinson's medication above. Parlodel comes in 2.5 mg and 5 mg tablets and should be given in divided doses before bedtime. The usual dose range is 5 - 15 mg per day. Side effects are similar to Permax.

Eldepryl/Deprenyl (Selegiline)

This medication is different than the other Parkinson's medication listed above. It does not work directly through the dopamine system, but is a MAO (Monoamine Oxidase) inhibitor. The MAO type B enzyme (which is inhibited) is responsible for the breakdown of dopamine in the brain. In Parkinson's patients, this medication is given only to patients who are on Sinemet and need additional help (the Sinemet dose is usually then decreased) . Eldepryl comes in 5 mg tablets, and the dose is generally one tablet once or twice daily (maximum dose).  We do not have much (if any) experience using this medication for RLS.

Mirapex (Pramipexole) 

This is a new Parkinson's medication which is a dopamine agonist. It has more complete and specific binding to the D2 and D3 receptors. It is therefore, a full (not a partial agonist, like the 3 above dopamine agonists) dopamine agonists. The other dopamine agonists do not bind to the D3 receptors, but the function of the D3 receptor is still unknown.  The side effect profile is similar to the other dopamine agonists; visual hallucinations, insomnia or sleepiness, fatigue, malaise, nausea (less if taken with meals) and abnormal dreams.  These side effects generally occur mostly with the higher doses of the drug. Several studies have shown this drug to be effective in over 90% of RLS sufferers.

Drug interactions may occur with Tagamet (cimetidine) which can increase the blood levels of Mirapex.  This drug is metabolized mostly in the kidneys.

Mirapex comes in 0.125 mg, 0.25 mg, 1.0 mg, or 1.5 mg tablets.  It should be started at 0.125 mg (the smallest tablet) at 1/2 or one tablet taken 30-60 minutes before the onset of symptoms. For mild RLS, one can start with 1/2 or one pill 30-60 minutes before bedtime, but other doses (of the same 1/2 or one .125 mg tablet) can be added (up to three doses per day).  Each of the starting 1/2 or one .125 mg doses can be increased if necessary every 5 days to a total .75 mg to 1 mg (6-8 of the .125 mg tablets) per dose.  In a recent study, most patients were controlled by doses between 0.2 - 0.4 mg per day.  The maximum dose for most RLS sufferers is about 3 mg per day.  Higher doses usually do not add additional benefit.

This medication is new, but experience with its usage in RLS in increasing. Two studies, (Effect of Pramipexole in Treatment of Resistant Restless legs SyndromeSiong-Chi Lin, M.D. et al, Mayo Clinic Proceedings, June 1998;73:497-500, Encouraging Initial Response of Restless Legs Syndrome to Pramipexole, Philip M. Becker, M.D., et. al., Neurology, Oct.1998;51:1221-1223 and Restless legs syndrome improved by pramipexole, a double-blinded randomized trial. Montplaisir J., et al, Neurology  1999;52:938-943) have shown that this drug can be very effective in RLS and PLMD.   In some cases of Sinemet augmentation, that were not relieved by Permax, this drug was found to be successful.

Just as in its use in Parkinson's disease, Mirapex  should be started at low doses and increased slowly until the RLS symptoms are mostly relieved. Augmentation has been reported in some studies with Mirapex in about 10-22% of patients.  The problem is not similar to the augmentation seen with Sinemet as giving more of the medication earlier in the day to treat the RLS symptoms work well, rather than worsening the problem as with Sinemet.

WARNING!!!  Mirapex has been associated with falling asleep while engaged in activities of daily living.   This is common at doses of 1.5 mg/day (12 of the .125 mg tablets or 6 of the .25 mg tablets), but is much less common at the lower doses used to treat RLS patients.  Do not drive your car until you are sure that you are not having increased daytime sleepiness while on Mirapex (even at low dose)

Requip (Ropinirole) 

This is a new Parkinson's medication which is a more specific dopamine agonist similar to Mirapex (binds to the D2 and D3 receptors).  Requip is available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 4 mg and 5 mg tablets.   The starting dose should be 0.25 mg, which can be given if needed up to three times per day.  The 0.25 mg dose can be increased by 0.25 mg each week for the first four week. Then the dose can be increased by 0.5 each week up to 3 mg three time per day (9 mg per day).  

If necessary, the dose can then be increased by 1 mg per dose each week to a maximum of 8 mg three times per day (total of 24 mg per day), but doses greater than 6-9 mg per day rarely add additional benefit.  RLS sufferers will generally need between .25 mg and 1.5 mg per day.  Parkinson's disease patients generally need between 10-16 mg per day.

The antibiotic Cipro (ciprofloxin) increases the blood levels of Requip.  Requip is metabolized in the liver so may be a better choice for dialysis patients.

Side effects with Requip include nausea (can be prevented by taking the medication with food), dizziness, and sleepiness (similar to Mirapex above, but usually at higher doses than most RLS patients tend to need.).

  Dostinex/{Cabaser outside the USA} (Cabergoline)

This is the latest of the dopamine D2 (also works on D1 receptors) agonist medications (like Mirapex and Requip above), but is only approved in the USA for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas. 

A recent study in the journal SLEEP (May 2000, Vol 1;23, pages 349-54) showed that this drug worked very well for patients with severe RLS who developed augmentation under LevoDopa therapy.   Nausea was noted due to the drug, but Domperidone (the only anti-nausea drug that does not bother RLS and is not available in the USA) was used to take care of it.  The average dose of cabergoline was 2.1 mg, with a range of 1-4 mg. In another study (presented at the June 2002 Sleep meeting) it was found that .5 mg of the drug helped nighttime RLS and a dose of 2 mg would give 24 hour relief.  Another 2004 study found that an average dose of 1.5 mg per day worked very well in patients with fairly severe RLS.

Dostinex is supplied in .5 mg tablets. It should be given 2 hours before sleep. The most common side effects have been headache and nausea/vomiting.

More on this drug as reports become available and we gain experience her in the USA. This drug is used in much smaller doses for hyperprolactinemic disorders and is extremely expensive in the USA if used in the higher doses necessary for the treatment of RLS.

  There have been reports of valvular heart disease occurring with Dostinex (Mov Disord 2004 Jun;19(6):656-62)  similar to those caused by Permax.  Both of these drugs are ergot derivatives (unlike Mirapex and Requip) and have been now linked to these problems.

 

 Tasmar (Tolcapone) 

This is one of the newest Parkinson's disease medications.  It is not clear whether or not this will be a useful drug for RLS. Tasmar inhibits an enzyme known as COMT (catechol-O-methyl transferase). This enzyme breaks down LevoDopa, and by inhibiting it, more LevoDopa remains in the body - specifically in the nervous system. Therefore, Tasmar works only when taken in conjunction with a LevoDopa containing medication such as Sinemet.   We have already described the problems with Sinemet, so it remains to be shown what benefit Tasmar will have for RLS.

Tasmar can be administered orally three times daily starting with 100 mg per dose (it comes in 100 mg and 200 mg tablets). The first dose of the day of Tasmar should be taken together with the first dose of the day of a LevoDopa preparation (Sinemet), and the subsequent doses should be given approximately 6 and 12 hours later. Tasmar may be taken with or without food. The maximum therapeutic dose of 200 mg three times daily should not be exceeded as there is no evidence of additional efficacy at higher doses. Patients with moderate liver impairment should not be increased to 200 mg Tasmar three times daily

Dyskinesia, nausea and other LevoDopa-associated adverse reactions may increase. These adverse reactions may often be mitigated by reducing the dose of LevoDopa. It is recommended that liver transaminases be monitored when starting Tasmar treatment and monthly for the first six months. NB There have been cases of severe liver failure (1 per 20,000) causing the withdrawal of this drug in many countries, except the USA. Other side effects include sleep disorder, dystonia, excessive dreaming, anorexia, orthostatic complaints, somnolence, diarrhea (quite common), dizziness, confusion, headache, hallucination, vomiting, constipation, upper respiratory tract infection, increased sweating , xerostomia, abdominal pain, syncope, urine discoloration, dyspepsia, influenza, chest pain. 

We will wait to see if any reports occur in the medical literature on the use of this drug in RLS.  Until then, it is best that this drug not be used on RLS patients. This drug is really useful for Parkinson's disease patients who suffer from the "wearing-off" phenomenon (about 50% of Parkinson's disease patients after 2-5 years) where as the disease progresses, Sinemet therapy tends to lose its effectiveness, generally shortening the duration of the therapeutic effect.  At the end of the Sinemet dose effectiveness, there is a wearing-off of the drug that is made better by Tasmar.

 Comtan (Entacapone)

This medication is the newest of the COMT inhibitors, just like Tasmar above. Since the only function it has is to help prolong the effects of Sinemet, it will likely have no role in the treatment of RLS. The only role of this drug is to help Parkinson's disease patients who have the wearing off effect (when the Sinemet dose gets metabolized too quickly by COMT) of Sinemet. There is no problem with liver disease with this drug (as with Tasmar above) and liver tests do not need to be followed.

Comtan comes in 200 mg tablets and can be taken to a total of 8 per day.

As with Tasmar above, no reports have been noted using this drug for RLS, nor do we expect to see any.

 Symmetrel (Amantadine)

This drug is normally used for Parkinson's disease or treating influenza A.  A recent trial of this drug was published in the journal Movement Disorders (2000;15:324-327) in which they tested 21 patients with this drug. Half the patients had improvement with this drug and 6 had almost complete resolution of their RLS symptoms. This drug should be started at 100 mg per day and increased by 100 mg (to a maximum of 300 mg/day) until RLS symptoms are better or side effects limit its usage. Side effects in this study were drowsiness, fatigue and insomnia.

Symmetrel comes in 100 mg tablets or a syrup with each teaspoon containing 50 mg.

This drug has been used for many years for Parkinson's disease and influenza, and its use for RLS seems promising.  We will wait for other studies and reports to see how this drug works for RLS.

new.gif (980 bytes) Neupro (Transdermal Rotigotine patch)

Rotigotine just got approved for use in RLS on April 3, 2012. It had been available in 2008 for Parkinson's disease but was taken off the market here in the USA (but not in Europe) because the drug crystallized on the patch when stored at room temperature.  This problem has now been solved and the new patches should not have any problems.

After the patch is applied, there is a lag-time of about 2-3 hours before the drug reaches the body's circulation and about 24 hours until it reaches peak concentrations. Blood levels are stable at 2-3 days. Rotigotine is metabolized in the liver then excreted mostly through the kidneys.

Rotigotine is available in three patch doses; 1, 2, and 3 mg daily and should be on the pharmacy shelves in June 2012. Initially, the drug should be started at 1 mg/24 hours, increased as needed by 1 mg/24 hours at weekly intervals, up to 3 mg/24 hours.

Side effects were mild with nausea, headache and skin irritation being the more common problems. As this was a fixed dose study without any titration, the correct dosing and titration of this drug has yet to be determined. Several clinical trials are in progress that should answer these questions and its long-term effectiveness and safety for RLS.

(3) Analgesic (pain-killing) Medications - Opiates/Narcotics

These medications are very helpful for treating RLS. Many patients will get relief from this class of drugs. Many physicians have significant fears about patients getting addicted to these mainly narcotic derived drugs (derived from opium, hence the term opiates). This generally does not happen if the medications are used to just blunt the majority of the RLS symptoms, rather than increasing the dose to completely eradicate all symptoms and possibly "overshoot" using more drug than really needed. Intermittent use and drug holidays (using other medication in place of the narcotic for a few days) can often insure that no tolerance/dependence will occur. In patients who use the opiates daily and cannot stop them, keeping them at the lowest dose to relieve most of the symptoms should greatly reduce the chance of addiction. There are many patients who have been using these medications daily for years without problems. A recent study (Walters, A.S. et al, Long-term follow-up on restless legs syndrome patients treated with opioids.  Mov Disord 2001;16:1105-1109) which found the narcotics to be very safe even when used for long -term use in RLS patients.

Constipation can also occur with this class of drugs. This may limit the use of this class of medication, but adding fiber (Metamucil, for example) may help this problem. Nausea can also be a significant problem and can be overcome by adding an anti-nausea pill before taking the opioid.

Below is a chart comparing equianalegesic doses (doses that have the same pain relieving effect) of the different narcotic pain medications. These doses are calculated for the relief of severe post-surgical pain and may not be accurate for their effect when used to treat RLS.  The combination drugs (Propoxyphene, Codiene, Hydrocodone, and Oxycodone) have considerably more effect for post surgical pain due to the added aspirin or acetaminophen.  Since aspirin and acetaminophen have no effect on RLS, these drugs are less potent than listed when used for RLS treatment.  This chart is just a rough reference guide to the potency of the narcotics.

DRUG APPROXIMATE EQUIANALGESIC ORAL DOSE
Morphine 30-60 mg every 3-5 hours
Morphine, controlled-release (MS Contin) 60-120 mg every 12 hours
Hydromorphone (Dilaudid) 7.5 mg every 3-4 hours
Levorphanol (Levo-Dromoran) 4 mg every 6-8 hours
Meperidine (Demerol) 300 mg every 2-3 hours
Methadone (Dolophine) 20 mg every 6-8 hours
Propoxyphene (Darvon, Darvocet N-100, etc.) 270-300 mg every 3-4 hours
Codeine (with aspirin or acetaminophen) 180-200 every 3-4 hours
Pentazocine (Talwin) 150-170 mg every 3-4 hours
Hydrocodone (Hycodan, Lorcet, Lortab, Maxidone, Norco, Vicodin, Vicoprofen, Zydone) 30 mg every 3-4 hours
Oxycodone (OxyContin, OxyFast, OxyIR, Percolone, Percodan, Percocet, Roxicodone, Tylox,) 30 mg every 3-4 hours
Oxymorphone (Opana IR or ER) 15-20 mg every 4-6 hours
Fentanyl (Duragesic patches) 50 mcg/hour patch

Some Long-acting Oral Opioids

 

Darvon (Propoxyphene)/Darvocet-N, 50,100 Note: The brand name drug has been withdrawn in the USA (see below).

Darvon is the weakest drug in this class of medication. It comes in several forms. Darvon comes in a plain form with 65 mg of Propoxyphene hydrochloride (this is equal to 100 mg of propoxyphene napsylate) and as a compound (Darvon Compound-65) combined with 389 mg of ASA and 32 mg of caffeine. Darvon-N has 100 mg of propoxyphene napsylate, Darvon-N 50 has 50 mg of propoxyphene napsylate with 325 mg of acetaminophen, Darvocet-N 100 has mg of propoxyphene napsylate with 650 mg of acetaminophen. The drug has a rapid onset of action (less than 30 minutes) and will last hours.

The dose Darvon, Darvon Compound, Darvocet-N 100, or Darvocet-N (all of these have about the same effective amount of propoxyphene) is from 1 to 8 tablets per day taken on an as needed basis of 1-2 tablets every 4-6 hours. The average daily dose for patients with significant RLS is about 3-4 tablets per day. The choice of the various forms of Darvon will depend on trial and error and intolerance of the additives (for example patients with ASA/aspirin intolerance should not take the Darvon Compound). For regular daily usage, the compound with Tylenol or ASA are best avoided to lessen the chance of side effects from a second drug.

This drug may also decrease the arousals from PLMS, but does not seem to decrease the amount of PLMS.

new.gif (980 bytes) Darvon and Darvocet have been withdrawn from the USA drug market due to problems with heart arrhythmia (irregular heart beat) problems. Generic forms of this drug may still be available. Patients should discuss with their doctor whether they should change to another opioid.

Codeine/Tylenol with Codeine No. 2, 3, or 4

This is the next in potency at its lower dose formulation (15 mg). At the higher doses, it may be just as potent as the other narcotic agents. Codeine comes in 15 mg, 30 mg, and 60 mg tablets. Tylenol with Codeine has 3 strengths each in combination with 300 mg of acetaminophen; No. 2 has 15 mg of codeine, No. 3 has 30 mg of codeine, and No. 4 has 60 mg of codeine. It has rapid onset of action (less than 30 minutes) and will last 3-6 hours.

Codeine doses range from 15 mg to 240 mg per day. The medication can be given at 15 mg to 60 mg every 3-6 hours. For regular daily usage, the compound with Tylenol is best avoided to lessen the chance of side effects from a second drug.

Warning:  Some of the SSRI antidepressants (Paxil, Prozac, and Luvox) can cause a decrease in the effectiveness of codeine. These drugs inhibit the O-demethylation of codeine to its active form of morphine. The pain killing effect of codeine can be significantly decreased if you are taking one of the above antidepressants. This problem does not occur with other pain killers on this list.

Talwin/Talacen (Pentazocine)

This medication comes in a 50 mg tablets. This is equivalent to a codeine dose of 60 mg. The dose range is 50 - 200 mg per day, taken at 1 tablet every 3-6 hours as needed. The onset of action is 15-30 minutes and lasts 3-6 hours.

NOTE: There is a new formulation of Talwin called Talwin Nx which contains pentazocine and naloxone which is an opioid antagonist which can worsen RLS.  This drug may help RLS at first but chronic users may need larger doses and develop tolerance to the drug and experience renewed symptoms.

Vicodin/Lorcet/Lortab/Tylox/Zydone/Norco (Hydrocodone)

Vicodin and Lorcet are trade names for the same drugs. Vicodin and Lorcet HD each contain hydrocodone 5 mg and acetaminophen 500 mg. Vicodin ES and Lorcet Plus each contain hydrocodone 7.5 mg and acetaminophen 750 or 650 mg respectively. Lorcet 10/650 contains the highest dose with hydrocodone 10 mg and acetaminophen 650 mg. Lortab comes in 3 strengths, each combined with acetaminophen 500 mg; and hydrocodone 2.5 mg, 5 mg, or 7.5 mg.

A new medication is Zydone which has a lower amount of acetaminophen at only 400 mg   combined with 5, 7.5 or 10 mg of hydrocodone. Another newer preparation of the medication is Norco, which also has lower doses of acetaminophen at 325 mg combined with either 5 or 7.5 mg of hydrocodone.

The daily dose ranges between 5 mg to 40 mg of hydrocodone per day. The drug will last and should be given every 3-6 hours as needed. The onset is rapid with effect noted in less than 30 minutes.

Percodan/Percocet/Percolone/OxyContin (Oxycodone)

This drug is amongst the strongest of this class of medications. It comes in 5 mg tablets combined with ASA 325 mg (Percodan) or with acetaminophen 325 mg (Percocet). It also comes in a smaller dose of 2.5 mg called Percodan-Demy. It also comes in a 7.5 mg tablet with 500 mg of acetominophen and a 10 mg tablet with 650 mg of acetaminophen. You can also get pure oxycodone in the form of Percolone at 5 mg tablets without any additives.

The dose range is 2.5 mg to 20 mg per day divided into doses every 4-6 hours. The average dose was 16 mg per day in one study. This medication works very well for RLS but also may have some benefits for PLMD.  Some studies have shown decreased PLMD, and even decreased arousals from the existing PLMS.

OxyContin is a potent 12 hour duration medication that is used mainly in patients with severe pain (like cancer patients). It come in 10, 20, 40 mg, and 80 mg tablets which can be taken on a twice daily basis. It is a slower acting drug and will not be active for at least one hour. It has potential benefits for RLS patients who are taking other narcotic agents at high doses every 3 to 6 hours (by being in a more convenient 12 hour preparation and it does not contain acetaminophen (Tylenol)), but experience in RLS with this medication is minimal, and for now this drug should be reserved for severe pain patients.

There is also a quick release formula called OxyIR which contains 5 mg of oxycodone and can give immediate relief for pain or RLS discomfort.

Dilaudid (Hydromorphone)

This drug is a very potent narcotic pain killer.  It is on a par with the strongest narcotic medications and has similar side effects.  It comes in 2 mg, 4 mg, and 8 mg tablets. Its use in RLS has been limited, but it is an option for difficult RLS cases. Some RLS specialists have found this drug to be very effective for severe RLS patients.

Demerol (Meperidine)

This drug is very frequently used by intramuscular injection but can be used orally with a significant decrease in effectiveness.  The amount of this decrease is not well established.  60-80 mg of Demerol (given by intramuscular injection) is roughly equal to 10 mg of Morphine.

Demerol causes less constipation and depression than equal pain killing doses of Morphine. Demerol comes in 50 mg and 100 mg tablets and can be given every 4 to 6 hours for pain/RLS relief.  Its use in RLS is quite rare and really no data is available. 

Duragesic Transdermal Patches (Fentanyl)

This is another potent narcotic, but with a unique delivery system.   Instead of a pill, a patch is placed on the skin which contains the active drug and slowly, but steadily releases it over 3 days.  There are four different patches named by the amount of the drug released per hour; 25 ug, 50 ug, 75 ug, and 100 ug.

These patches are used for patients with chronic pain syndrome such as cancer, arthritis, etc.  We have seen a few patients who have been on Duragesic patches for RLS with some success, but its use in RLS has been quite limited so far.   As with all narcotics, the smallest dose should be tried first, and increased only if necessary.

Dolophine (Methadone)

This drug is actually very effective in RLS. Most physicians will not prescribe Methadone due to its association with drug dependency treatment. Many patients may get relief from this drug when other ones in this class have failed. It should be reserved for when patients fail the other narcotic drugs.

Methadone comes in 5 mg and 10 mg tablets. The dosage range is from 5 mg to 30 mg per day. When given for pain relief, the drug lasts 3-4 hours. In RLS, many patients report much more prolonged duration of effect, often up to 6-12 hours.

Morphine

This is the one of the most potent medication in this class. Because of this, and its reputation as a potent narcotic, Morphine is seldom used in the treatment of RLS.

Morphine comes in 15 mg and 30 mg tablets. These should be used in the smallest dose necessary to achieve relief of about 90% of RLS symptoms on a 3-6 hour basis. There are two 12 hour sustained release forms of Morphine, called Oramorph SR and MS Contin. They comes in 15 mg, 30 mg, 60 mg and 100 mg tablets dosed every 12 hours. This might be a useful medication for severe RLS if used carefully, but we do not yet know of much experience with this sustained release form of Morphine.

Levo-Dromoran (levorphanol tartrate)

Levo-Dromoran is a synthetic analgesic that is as potent as morphine.   It can be used by injection or by tablet and is as potent by either route.   This drug is a narcotic and has an addiction potential equal to morphine.  The drug should thus be given all the precautions of morphine. It is a long acting drug, each dose lasts 6-8 hours by injection or by tablet.

Levo-Dromoran comes in 2 mg tablets with the usual dose being one tablet every 6 to 8 hours.  The dose can be increased to 1 1/2 tablets.

new.gif (980 bytes) Opana (Oxymorphone)

This potent (about twice as potent as oxycodone) narcotic has previously only been available as an injectable or suppository type of drug. It is now available in an immediate release and extended-release formula. There is really no experience with this drug for treating RLS as of yet.

It is available in 5 and 10 mg tablets for immediate release (given every 4-6 hours) and 5, 10, 20 and 40 mg tablets for extended release use (given every 12 hours).

new.gif (980 bytes)  Nucynta (Tapentadol)

It is a centrally-acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor. Its ability to kill pain is more on the order of hydrocodone and oxycodone. Tapentadol is a new molecular entity that is structurally similar to tramadol (Ultram). It has both opioid and nonopioid acitivity in a single compound which may give it more tolerability.

Nucynta comes in 50, 75 and 100 mg tablets which can be taken every 4-6 hours as needed. There are no studies with this drug on patients with RLS (nor is there likely much clinical experience yet) so dose ranges cannot be recommended at this time. However, as with any opioid medications, this drug should be started at the lowest possible dose and increased slowly as needed under the guidance of your personal doctor. The maximum 24 hour dose of this drug when used for pain control is 600 mg per day.

 

Ultram (Tramadol)

Ultram is a new synthetic medication for pain relief and is not chemically related to the opiates unlike all the above medication in this class. It works on the central nervous system by two different mechanisms. First of all, it is a weak opioid inhibitor which only  binds weakly to the opioid mu receptors (which is the opioid pain receptor). It also works by blocking the reuptake of two different neurotransmitters in the brain, norepinephrine and serotonin. Ultram is metabolized to another compound which actually is more potent than the original tramadol in helping to block pain. The drug does not appear to be as addictive as others in this class of RLS medications, but cases of addiction have occurred. Special care should be taken in patients with a history of addiction to opiates, as they may be more susceptible to addiction with Ultram.

This drug can be very effective for treating RLS and many RLS sufferers have gotten excellent relief from the intermittent use of this drug.  Some patients have used Ultram for drug holidays from the other pain killers above (in the narcotic family).  This seems to have been very helpful for many, and no cross tolerance has developed. This information however, is only anecdotal, and is not proven yet in a clinical study or trial.

There have been reports of aggravation of seizures in patients with a prior seizure history, although the incidence appears to be small occurring in 1 out of 100,000 patients. It also may be riskier in patients who are on antidepressants (especially serotonin reuptake inhibitors such as Prozac, Zoloft or Paxil for example) or tricyclic antidepressants such as Elavil. Tramadol may need to be reduced in dosage or eliminated in patients who are on other tranquilizers or sedating medication.

Ultram comes in 50 mg tablets. It has a half life of 5.6 hours after a single dose and 7 hours after multiple doses.  It can be given at 50 - 100 mg every 4-6 hours with a maximum daily dose of 400 mg. Some RLS patients have reported longer duration of action of 6-8 hours, but 4-6 hours is quite common.

new.gif (980 bytes) There is a newer form of Ultram, called Ultram ER.  This is a longer acting form of Ultram and is available only in 100 mg tablets.  It is taken once per day.  Doses start at 100 mg per day and can be increased to 300 mg (3 tablets) per day. There is also a similar long acting new tramadol drug called Ryzolt with the same 3 doses.

 

(4) Anti-Seizure Medications

 

Neurontin (Gabapentin)

This is the most used and possibly the most effective of the anti-convulsant medications used for treating RLS. In one study, all of the 16 patients got 50-100% relief of their RLS symptoms which was sustained. Two patients (with familial RLS) who had previously not responded to any other treatment got significant improvement with Neurontin.  There was no problem with rebound as noted with Sinemet.

Neurontin may work best for RLS sufferers who have pain (painful neuropathy) associated with their symptoms.

The dose of Neurontin varies from 300-2000 mg per day, with the average dose being 800-900 mg. Neurontin should be started one 300 mg capsule at bedtime. Another 300 mg capsule can be added as needed every few days. The usual bedtime dose is between 300-800 mg. For severe RLS, a morning and afternoon dose can be added. Neurontin comes in 100 mg, 300 mg and 400 mg capsules.

In our experience, the response to Neurontin can be quite variable, but many RLS patients have achieved benefit from this drug with minimal side effects. The effectiveness of this medication often diminishes after 1-2 years.  In one study, the average dose of Neurontin needed was about 1800 mg per day.

Side effects are less common and usually transient when treating RLS at low doses of the drug.  With higher doses, sleepiness and dizziness may occur.  The common side effects from the PDR are listed below:

The most commonly observed adverse events associated with the use of Neurontin® in combination with other anti-epileptic drugs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus.

Approximately 7% of the 2074 individuals who received Neurontin® in pre-marketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%).

 

new.gif (980 bytes) Horizant (Gabapentin Enacarbil)

This is a new drug that is now available in the USA. It is a prodrug of gabapentin and only is released as gabapentin when it enters into the body from the bowel. This drug uses the high capacity transporters in the bowel so that a very high percentage of the drug is absorbed into the body which is not the case for regular gabapentin. With gabapentin, the higher doses of drug that you give, the less gets absorbed. Furthermore, Horizant is a time released drug so that it gets into the body more slowly and lasts much longer.

The drug so far is only approved at one dose of 600 mg taken once daily at 5 pm with food. It is very likely that some patients will need a higher dose but this may not be covered by insurance as only the one tablet per day is FDA approved.

Side effects are similar to Neurontin as the drug is converted into the same gabapentin.

Tegretol (Carbamazepine)

This drug has had sporadic results in the treatment of RLS. It is an anti-convulsant drug that is also used to treat trigeminal neuralgia (Tic Douloureux). Common side effects include dizziness, drowsiness, unsteadiness, and nausea. The dosage of the medication should be started as low as possible to avoid getting these side effects. Start with 100 mg and work up to the dose that controls symptoms. Tegretol comes in 100 mg and 200 mg tablets. Blood levels may be helpful in avoiding toxicity with this drug. Regular monitoring of CBC, liver function tests, and urinalysis should be done to check for side effects of Tegretol.

One study found a dose of 100 to 300 mg per day was effective, but side effects occurred in 40% of patients. Younger patients had a better response.

Depakene (Valproic Acid)/Depakote (Divalproex Sodium)

These drugs are used to treat epileptic seizures. Liver disease is a concern and liver blood tests should be monitored regularly. Sporadic success has been noted with these drugs in treating RLS. Low doses should be used to achieve relief of symptoms. Depakene comes in 250 mg capsules and can be given to a maximum of 1250 mg per day. Depakote, the delayed release form of the drug, comes in 125 mg, 250 mg and 500 mg tablets.

Mysoline (Primidone)

This anti-convulsant drug comes in 50 mg and 250 mg tablets. Sporadic improvement of RLS has been documented with Mysoline. The dose should start at 100 mg and can be increased to 750 mg per day in divided doses. Blood levels may be helpful to monitor this drug. Common side effects include vertigo and ataxia (problems with walking/gait).

new.gif (980 bytes) Keppra (Levetiracetam)

This is one of the newest anti-seizure medications.  It may have less sedation than some of the other drugs in this class but so far there is only minimal experience with this drug in RLS.  There have been some reports (not yet published) that this drug may have some positive benefits for RLS sufferers but only time and further testing will tell.

Keppra comes in 250, 500 and 750 mg tablets.  The dose should be started as low as possible (the 250 mg tablet is scored and can be broken in 1/2) with the dose increased by 125 or 250 mg every several days as needed.  The drug can be given 2-3 times per day if needed, but sedation may be a problem as the dose increases, especially daytime doses.  The total daily dose should not exceed 3000 mg but sedation will likely limit reaching this maximum dose.

 Gabitril (Tiagabine)

There are several case reports with Gabitril helping RLS patients.  Sedation may also occur with this medication.

Gabitril comes in 2, 4, 12, 16, and 20 mg tablets.  This drug should be started at the lowest dose and the daily dose can be increased by 2-4 mg each week.  The maximum dose is 32-56 mg per day in 3-4 divided doses.

 Topamax (Topiramate)

This anti-seizure drug is also being used for migraine headaches.  There are many anecdotal cases of this drug helping RLS similar to the other drugs in this class.  Sedation is often the limiting factor in using this drug for RLS.

Topamax comes in 25, 100 and 200 mg tablets.  It should be started at the lowest dose of 25 mg and increased by 25 mg per week if necessary.  The maximum dose is 400 mg per day.

new.gif (980 bytes) Lyrica (Pregabalin)

This is a new anti-seizure drug that also has an indication for treating the pain associated with shingles and diabetic neuropathies.  There are several studies (and 2 more recent ones published in 2014) that demonstrate that Lyrica is a very effective RLS drug. The recent studies found that 300 mg was more effective than Mirapex (pramipexole) at .25 mg and as or more effective than .50 mg.  Sedation may be a significant problem.

This medication comes in 25, 50, 75, 100, 150, 200, 225, and 300 mg tablets.  It is usually dosed at 50-100 mg three times per day or 75-150 mg twice daily.

 

SECONDARY CLASS OF RLS MEDICATIONS

 

(1) Hypertensive (High blood pressure) Medication

NOTE:  There are only a few studies on using blood pressure medication for RLS and most RLS specialists do not treat RLS with these drugs.

Catapres (Clonidine)

A few trials have shown that Catapres has been helpful in RLS. It comes in 0.1 mg, 0.2 mg, and 0.3 mg tablets. The dose can be started at 0.1 to 0.3 mg at bedtime (which can often be helpful) and increased to 0.9 mg per day in divided doses. Side effects tend to be few and commonly consist of dry mouth, drowsiness, dizziness and constipation.

Inderal (Propranolol)

This common blood pressure medication comes in 10, 20, 40, 60, and 80 mg tablets. It has been documented to help RLS even at low doses or 5 - 10 mg taken in the evening. Dosage can be increased and is usually well tolerated. Inderal also comes in a sustained release form (Inderal LA), in 60, 80, 120, and 160 mg tablets.

Cardizem (Diltiazem)

This is one of the newer blood pressure medications which is also used for angina (coronary artery disease) patients. It comes in 30, 60, 90, and 120 mg tablets. This is the least well documented hypertensive drug to be used for RLS. Cardizem also comes in 2 sustained release forms, Cardizem SR, a 12 hour drug (60, 90, and 120 mg capsules), and Cardizem CD, a once a day drug (120, 180, 240, and 300 mg capsules). Common side effects include swelling of the legs/ankles, headaches, slowing of the heart rate, weakness and flushing.

(2) Multiple Sclerosis (MS) Medication

NOTE:  There are only a few studies on using MS medication for RLS and most RLS specialists do not treat RLS with these drugs.

Lioresal (Baclofen)

This drug is used as a muscle relaxant and anti-spasm medication. It is used in MS to alleviate muscle spasms and the resultant pain. Lioresal was found in one study to decrease the arousals from PLMD (the intensity of the movements was decreased). Its effect on daytime RLS symptoms is less well understood.

Lioresal comes in 10 and 20 mg tablets. It should be started at the lowest dose (5 mg, 1-3 times per day) and increased every 3 days until symptoms are relieved. The average dose for MS patients for muscle spasticity is 40-80 mg per day. The most common side effect is drowsiness; weakness and fatigue can also be a common problem.

(3) Antidepressant Medication

This class of medications should be used with caution in RLS patients. Antidepressants can worsen RLS symptoms more often than help them. As depression is a common problem, especially in patients with severe and persistent RLS problems, antidepressants are often prescribed for RLS patients. RLS patients who are put on antidepressants and notice worsening of their symptoms should inform their physician of this problem immediately.

There are several different classes of antidepressant medication. If a medication in one class causes problems, then a medication from another class may be of more benefit. As with most RLS medications, much trial and error must take place to see if these medications are helping. Due to the long list of antidepressant medications, we will only list them in their appropriate categories.

There are no specific guidelines for using antidepressants in RLS, and generally they are used for RLS in the same doses as for depression. The oldest antidepressants, the tricyclics, tend to worsen RLS more than they help.  The SSRI's will worsen RLS more often than helping but they seem better tolerated than the tricyclics.  There is only one antidepressant drug, Wellbutrin, which has dopamine like effects, so it may benefit RLS.  This however, has not been looked at systematically yet although there are some case reports of Wellbutrin helping RLS.  Trazadone may not help RLS but it does not seem to worsen the condition.

Tricyclics & Combinations

Ascendin   (Amoxepine)
Elavil   (Amitriptyline)
Etrafon  (Perphenazine and Amitriptyline)
Limbitrol  (Chlordiazepoxide and Amitriptyline)
Norpramin  (Desipramine)
Pamelor  (Nortriptyline)
Sinequan  (Doxepin)
Surmontil  (Trimipramine)
Tofranil  (Imipramine)
Triavil  (Perphenazine and Amitriptyline)
Vivactil  (Protriptyline)

MAO (Monoamine Oxidase) Inhibitors

Nardil (Pheneizine)
Parnate (Tranylcypromine)

Selective Serotonin Reuptake Inhibitors (SSRI's)

Paxil (Paroxetine)
Prozac (Fluoxetine)
Zoloft (Sertraline)
Celexa (Citalopram)
Lexapro (Escitalopram)

Serotonin  and Norepinephrine Reuptake Inhibitors (SNRI's)

Effexor (Venlafaxine)
Cymbalta (Duloxetine)

Tetracyclics

Ludiomil (Maprotiline)

Miscellaneous Antidepressant Medications

Desyrel (Trazadone)
Wellbutrin/Zyban (Bupropion)

Obsessive Compulsive Disorder Medications

Luvox (Flovoxamine Maleate) - This is serotonin uptake inhibitor which is chemically different than the antidepressants above.
Anafranil (Clomipramine) - This is in the class of tricyclic antidepressants.

Noradrenergic and Serotonergic

Remeron (Mirtazapine) - This is the newest class of antidepressants.  It enhances both the noradrenalin and serotonin systems.   Remeron may have less side effects than the serotonin uptake inhibitors and the tricyclics, and it even seems to promote sleep.  There are 2 case reports of Remeron causing worsening of RLS, so it should be used with caution in RLS patients.

(4) Recreational Medication

Marijuana

This illegal drug seems to have very beneficial effects for RLS. There are no known medical studies on this drug for RLS as the drug is not available even for medical research.  There have been many anecdotal reports on the effectiveness of this drug for RLS.

According to the reports from patients who have used marijuana, it often takes only a very small amount of the drug (often as little as 2 inhalations of a marijuana cigarette) to relieve RLS symptoms. The onset of action of this drug can be amazingly fast with complete symptom relief occurring within 2-3 minutes.

This drug should be used with caution as the long term effects of smoking marijuana are not fully known and, of course, since the drug is illegal, legal problems may occur if the user is caught by police.

Currently there is a drug called Marinol (dronabinol) that is FDA approved for the treatment of anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional anti-nausea treatments.  This drug contains delta-9-tetrahydrocannabinol (delta-9-THC) which is the active ingredient of marijuana.

The effect of taking oral Marinol capsules is quite different from smoking marijuana. After oral administration, Marinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours with a duration of action for psychoactive effects of 4 to 6 hours and does not cause the so called "high feeling".  Marijuana, when smoked will onset within seconds to a few minutes with very high peak blood levels compared to the lower steady levels that onset slowly with Marinol.

Patients find that Marinol does not work as dramatically as smoking marijuana.  Based on anecdotal clinical patient reports it appears that a minority of RLS sufferers may experience a modest benefit for their RLS symptoms with Marinol.  This drug comes in 2.5, 5 and 10 mg tablets that can be taken up to 2-3 times per day with a maximum daily dose of 20 mg.


(5) Other New Experimental Medications

Botulinum Toxin (Botox)

There is one recent article that details the use of Botox injections for RLS.  They report on three patients with RLS who improved with these injections.  These results are very preliminary and the study does not have a control group (who gets placebo) to compare with so it is too early to say whether this is a promising treatment.  We are looking forward to more studies to verify this very interesting result. However, we have seen some patients who have tried this treatment with either no success or worsening of their RLS.

 

OTHER RLS/PLMD TREATMENTS

This section will include therapies that will work on only certain patients with RLS. Treatment of underlying conditions associated with RLS will be discussed in this section. You should not attempt to treat yourself with these therapies for underlying conditions that can cause RLS without the guidance of a medical doctor.

Included in this section will be vitamin therapy and other nonconventional therapies that can be tried with minimal physician guidance.

(1) Medication to Treat Deficiency States

Iron Therapy

Iron therapy in patients with no iron deficiency has not been demonstrated to be of benefit. However, in patients with significant (and often even minor) iron deficiency states, adding iron may be of very profound help in alleviating RLS symptoms. Iron deficiency has been found in a high percentage (20-25% in some studies) of RLS patients. All patients with RLS should have their iron levels checked as detailed below.

Iron deficiency is usually diagnosed by the resulting anemia (decreased amount of red blood cells/smaller red blood cells), with hemoglobin levels of below 14 for men and 12 for women measured with a CBC (Complete Blood Count). However, in mild iron deficiency states, the hemoglobin may be within normal limits and therefore not indicate the patient's iron deficiency problem. Therefore, more sensitive tests such as direct iron levels (with iron binding capacity) is suggested. An even more sensitive test is the serum ferritin level. For patients with severe iron deficiency (serum ferritin levels below 18 mcg/L) or mild iron deficiency (serum ferritin levels between 18-45 mcg/L), therapy with iron was very beneficial for relieving RLS symptoms. Patients with serum ferritin levels of between 45-100 mcg/L may have some response to iron therapy, but generally not as significant as with lower serum ferritin levels.

Treatment of this iron deficiency should be with oral iron tablets (ferrous sulfate) of 325 mg (5 grain), three times a day. Iron is better absorbed on an empty stomach, but this may cause some stomach upset. If so, then take the iron tablets with food. The other common side effect of iron therapy is constipation (and it also turns the stool black). Metamucil (1-2 teaspoons per day) is recommended to counteract this problem (and the fiber itself has been reported to help RLS). It takes 6 months to replace iron stores, at which point the serum ferritin should be rechecked and iron therapy stopped if appropriate levels have been reached.

Please do not start iron therapy without the consent of your doctor. Taking iron inappropriately can cause serious problems! Therefore, do this only with proper physician guidance.

Folic Acid (Folate)

Deficiencies of folic acid cause anemia with decreased hemoglobin levels similar to iron deficiency above, except that the red blood cells are larger than normal rather than smaller as in iron deficiency. A CBC test will reveal the anemia, then a folic acid level blood test will diagnose the anemia as due to folic acid deficiency.

Folic acid can be replaced easily with folic acid supplements. These can be obtained in multivitamins over the counter (usually about 0.4 mg of folic acid) or in prescription strength preparations with up to 1 or 2 mg of folic acid. It can be given in higher doses intramuscularly, if necessary.

Vitamin B12

Deficiencies of vitamin B12 cause anemia with larger than normal red blood cells similar to folic acid deficiency noted above.  The diagnosis is made on finding a low hemoglobin on a CBC, then checking a vitamin B12 level which should be low.  A Schilling test (special blood and urine testing) is then performed to see if the problem is with absorbing B12 into the body from the stomach (called Pernicious Anemia)

If the problem is with absorption of vitamin B12, then monthly intramuscular injections of B12 are needed.  If the problem is lack of intake of vitamin B12 (much less common as this requires a very restrictive diet devoid of any animal related products), then vitamin B12 oral supplementation or change in diet is advised.

Magnesium

Magnesium has long been used to treat toxemia of pregnancy.  It was found to relieve RLS in these patients.  A recent study (SLEEP, August 1, 1998, Vol 21, No.5, pages 501-505) showed that magnesium oxide (approximately 400 mg) helped RLS and PLMD about as much as some Parkinson's disease medications (bromocriptine). The reason why magnesium works is not known. There was no decrease in blood magnesium levels in these RLS patients.

There were few if any significant side effects from magnesium therapy. Few studies have used magnesium for long term therapy, so the long term safety is not known.   So far no serious side effects were noted in the few studies done with up to two years of magnesium therapy.

We do not recommend this treatment yet, until others reproduce this good result and the long term safety of this therapy is resolved.

(2) Disease states associated with RLS

Kidney Failure (Uremia)

Patients with kidney failure cannot clear toxins from their blood. When the kidney failure is severe and the toxins build up in the blood (as measured by elevated blood urea), the chance of getting RLS/PLMD increases very significantly. In one study, 1/3 of the patients in a dialysis unit had RLS complaints. In kidney patients with uremia (high levels of blood urea), as many as 60-80% will have RLS and PLMD.

Treatment of the kidney failure (usually with dialysis) may result in improvement of the RLS symptoms. Sedative medication such as Klonopin and Xanax have been used to treat the RLS/PLMD with kidney failure. Sinemet has also been used safely in some studies (Sleep 1996 April;19(3):214-8) in uremic patients. A recent study (SLEEP Vol. 21, No. 6, Pages 617-622) should mixed results with Permax in renal patients. Opiates have also been recommended.

Renal failure patients are often anemic and it has been found that treatment with erythropoietin (a drug that stimulates red blood cell formation) also reduces the RLS symptoms of these patients.

Amyloid Neuropathy

Amyloid is an uncommon disease in which an abnormal protein, Amyloid is deposited in various tissues in the body. When the Amyloid protein is deposited in nerves, it can cause abnormalities called polyneuropathy.

RLS has been linked to Amyloid polyneuropathy and can even be the first presenting problem noticed from the disease. It generally responds well to Klonopin.

Fibrositis Syndrome/Fibromyalgia Syndrome/Rheumatic Pain Modulation Disorder (RPMD)

The above names are all for the same disorder which is characterized by localized areas of tenderness, widespread musculoskeletal pain, chronic fatigue, and mood changes.  There has been an association of this disorder with RLS and PLMD, in that they occur more frequently in patients with Fibrositis (Sleep Related Myoclonus in Rheumatic Pain Modulation Disorder [Fibrositic Syndrome], Moldofsky et al, Journal of Rheumatology 1986;  13:614-617). Patients with Fibrositis who have leg cramps, also have a higher incidence of RLS and PLMD.  Rheumatoid Arthritis is a separate disorder, but that too has been linked to increased RLS (Restless Legs Syndrome and leg cramps in Fibromyalgia Syndrome: A controlled study, Muhammad, B Yunus, Aldag, Jean C.,  BMJ  1996;312:1339).

There is as yet no special treatment for RLS/PLMD associated with the Fibrositic Syndrome.  Sedative night time medications (Klonopin) have been tried with variable success.

Hypertension (High Blood Pressure)

A recent study (Espenarsierra J., et al, in psychiatry & Clinical Neurosciences 1997;51(3):103-107) found that PLMD was much more common in people with high blood pressure. The PLM's were worse in the people with higher blood pressure.  The PLM's in these subjects did not cause a lot of arousals, however.   The study did not address the effect of treatment on PLMD.

Spine/Back Trauma causing RLS

There have been many anecdotal reports of patients developing RLS (or having very significant worsening of their pre-existing mild RLS) after surgery or trauma to their back.  The most common link seems to be with lumbar laminectomy surgery (possibly due to the fact that this is one of the most common back surgeries), but even cervical (neck) surgery seems to be a not uncommon trigger of this type of RLS.

There is no understanding yet of the cause of this link to RLS (just as there is no understanding of the cause of RLS in general).  We hope that research in the future will uncover the cause and treatment of both RLS in general and the link between spine injury triggering this disease.

Other conditions associated with an increased incidence of RLS

Neurological disorders                       Incidence of RLS

Parkinson’s Disease                                20%
Charcot-Marie-Tooth type 2                     35%
Spinocerebellar ataxia type 3                  30%

Diabetes mellitus

Rheumatoid arthritis

(3) Surgical treatment for RLS

Sclerotherapy of Varicose Veins

Sclerotherapy is a treatment for varicose veins in which a chemical (sodium tetradecyl sulphate) is injected into the varicose vein. In a recent study (Dermatol Surg 1995 April;21(4):328-32), 111 of the 113 treated patients(98%) reported initial relief from RLS symptoms. Follow up showed a recurrence rate of 8% at 1 year and 28% at 2 years.

This is an interesting study which shows surprising results. The improvement of RLS symptoms from sclerotherapy is not understood. Patients who have both RLS and significant varicose veins may want to consider sclerotherapy before starting chronic drug therapy.

NOTE:  Most RLS specialists do not recommend sclerotherapy for treating RLS.

 

(4) Non-drug treatment for RLS

Neuromuscular Stimulation

An electrical neuromuscular stimulation device (the EMS-250) was used in one study (Arch Phys Med Rehabil 1991 May;72(6):385-9) to treat PLMS. 8 patients were treated with 30 minutes of electrical stimulation to the lower leg muscles and showed significant improvement in their PLMS. Leg movements during sleep decreased from an average of 45 per hour to 14 per hour after treatment. The overall sleep quality however, showed only minimal improvement (as measured during a sleep study) despite the improvement in the PLMS.

Mental Activity

Mental activity, especially those using mathematical calculations, can calm RLS. Using a computer and video games have been very helpful for many RLS patients while traveling long distances in cars and airplanes when they must sit still for prolonged times.

Physical Measures/Activity

(1) Stretching exercises:

Many RLS sufferers have noted that various stretching exercises can help their symptoms. This can be especially helpful when done just before bedtime.  There are many different types of stretching exercises that have helped RLS patients, and only trial and error can help you decide which type is suitable for you.

(2) Leg wrapping:

This is a technique employed by several RLS sufferers to help relieve their symptoms.  There are many different ways to wrap the affected limbs, but click this link to get a detailed description of how to do it.

(3) Foot tickling:

We have a few reports of this technique of RLS treatment.  For one report, click this link.

 

(5) Non-conventional treatment for RLS

This section will include treatments that have not been tested by the standard, accepted scientific method. These treatments have not undergone the rigorous clinical trials and statistical analysis that the treatments in the above sections have all passed. Because of this lack of proper testing, we can neither recommend or condemn the treatments detailed below.

These treatments may be great for some or all patients, but they could be totally ineffective therapies. Many so called "wonder treatments" have only a placebo effect (sugar pill effect - if you think a pill or treatment should work, it often will work despite no real medication), and until a treatment or medication has been properly tested, we can not say if it really works. For those of you who have tried the treatments below and have gotten improvement of your RLS symptoms, we suggest you should continue the treatment, as long as there are no significant side effects.

Click here to go to a discussion of Enzyme Therapy.

Click here to go to a discussion of Colloidal vitamins/supplements Therapy

Click here to go to a discussion of Calcium Therapy

Click here to go to a discussion of St. John's Wort for RLS.

Click here to go to a discussion of Urine Therapy (yes, you read this correctly).

Click here for a discussion of Water Therapy (different than topic above) or click here for a another similar discussion of Water Therapy with a web link.

Click here for a discussion of Brewers Yeast Therapy.

Click here for a discussion of avoiding foods grown with Pesticides to help your RLS.

Click here for a discussion of avoiding sugar to help your RLS.

Click here for a discussion of avoiding Mono and Diglycerides to help RLS.

Click here for information and a link to Herbal Therapy.

Click here for information on a Herbal treatment called Butcher's Broom

Click here for information on Hydergine (ergoloid mesylate),  DPLA ( dextro,levo-phenylalanine), and Kava kava for RLS.

Click here for a discussion of Relfexology for treating RLS.

Click here for a discussion of vegetable oil massage therapy, avoiding food with pesticides and the possible relationship of ELF's (extremely low frequency fields) and RLS.

Click here for information on  the Enermed pulsed electromagnetic field generator.

Click here for information on Foot Zoning (form of reflexology).

Click here for information on a device worn on your foot called Cramp Busters.

Click here for discussion of marijuana use for RLS. or click here.

Click here for discussion of Bonnie Pruden's Myotherapy for RLS.

Click here of a discussion of Silent Night by Nature's Way, a valerian root product or additional information here.

Click here for information on Gingko Biloba (Memory Mate) for RLS.

Click here for info on Magnet Therapy

Click here for info on Chiropractic Therapy for RLS.

Click here for info on Vitamin E for RLS.

Click here for info on L-tyrosine for RLS.

Click here for info on Super Blue or Blue Stuff (Emu oil, Aloe Vera and other stuff).

Click here for info on Peanut butter for RLS. or click here.

Click here for info on AtoB Calm, a Freeze Dried Instant Calcium Magnesium Drink.

Click here for info on sleeping with Soap to help RLS. or here for additional info.

Click here for info on Coenzyme Q-10 for RLS.

Click here for info on Spring Valley's Calcium, Magnesium, and Zinc for RLS.

Click here for info on Chinese Energy Therapy for RLS. or go to www.chineseenergytherapy.co.nz.

Click here for info on Myoflex for RLS.

Click here for info on Pantyhose for RLS.

Click here for more info on Niacin.

Click here for more info on bananas for RLS and Gonstead chiropractic method to help RLS.

Click here for info on Lite Salt for treating RLS.

Click here for info on using Vinegar for treating RLS.

Click here for info on using Marie Goodwin's low salt diet for RLS

Click here for info on using the vitamin combination called Empower Plus.

(6) Drugs and Foods to avoid to improve RLS

This section will discuss various drugs and foods that may worsen RLS. Things that cause worsening of RLS in some patients may not bother others in the same way; in fact, others may even be helped by these same medications or foods that worsen others. Please free to email us with any foods or drugs that worsen your RLS problems. Keeping a diary or log of foods, medications taken and worsening of RLS may also be helpful to determine what might be affecting you.

Ice Cream

Some patients have found that ice cream (all flavors) cause worsening of RLS. Avoiding this food eliminates significant RLS worsening, especially in patients who eat a lot of ice cream. The cause of this relationship is unknown. For a possible explanation of why ice cream may exacerbate RLS, click here for a discussion of avoiding Mono and Diglycerides to help RLS.

Caffeine

Drugs and foods containing caffeine are very common. Coffee, tea, and colas are all commonly known beverages which contain significant amounts of caffeine and can cause worsening of RLS symptoms. Chocolate can also contains caffeine.

Many medications use caffeine in their formulation, especially pain pills, so you much check them out one by one. Some common medications with caffeine include: Cafergot, Darvon, Esgic, Exedrin, Fioricet, Fiorinal, Migralam, Norgesic, Wigraine, Anolaor, Butalbital, Femcet, Medigesic, Pacaps, Repan, and Synalgos-DC.

Antihistamines

These include the common allergy and cold remedies, most of which are available over the counter. Examples are Actifed, Benadryl, Chlortrimeton, Comtrex, Contact, Corcidin, Dimetapp, Drixoral, PediaCare, Sinutab, Tavist, TheraFlu, Triaminic, Tylenol (flu, cold, PM, allergy), Vicks.  Note that many cough syrups may contain antihistamines, especially if they are recommended for cold or flu symptoms.

The newer, non-sedating antihistamines, Allegra, Zyrtec and Claritin are generally better (and some RLS patients can take these without problems), but can be just as bad as the over the counter medications.

Antidepressants

The tricyclic and serotonin uptake inhibitors (see Antidepressant Medication section above) can cause significant worsening of RLS problems. Paradoxically, some patients have noted marked improvement while on these medications, making it harder to understand why some patients worsen and others improve.

Antinauseants

Medications to treat nausea can worsen RLS symptoms. This class of drugs includes: Anitvert, Atarax, Benadryl, Bonine, Compazine, Phenergan, Thorazine, Tigan, Trilafon and Vistaril.

There is an antinausea medication only available in Canada and Mexico called Domperidone (available over the counter as Motilium 10 in Mexico) , which does not cause worsening of RLS symptoms. This can be obtained by Americans over the internet from Canadian pharmacies (example is canadameds.com or www.canadapharmacy.com or www.thecanadianpharmacy.com) with a valid prescription from an American medical doctor. 

Reglan (metoclopramide) is an anti-nausea agent that is also used to prevent reflux and has significant anti-dopamine activity, so it should be avoided.

There are two newer anti-nausea  medications available in t he USA, Kytril (granisetron hydrochloride) and Zofran (ondansetron hydrochloride) which do not affect the dopamine system and thus should be safe for RLS. The only problem with these medications are that they are very expensive.

Cough syrups

Most OTC cough syrups are fine to use for RLS patients if they are just simple cough medications (like regular Robitussin which contains guaifenesin and the DM version that also contains dextromethorphan).  When they are combination preparations (also good for colds, flu, etc.) they likely contain antihistamines which as noted above, worsens RLS.  So, check the ingredients carefully before you buy any cough medication (OTC) as they may contain harmful ingredients.

The prescription cough syrups usually contain a narcotic (codeine or hydrocodone).  The most common one prescribed is Phenergan with codeine,  which contains the anti-nausea agent phenergan which usually worsens RLS.  It is countered by the presence of a small dose of codeine, but this may not be enough to cover the RLS worsening effects of the phenergan.  Tussionex is an example of the hydrocodone containing syrups.  It is combined with chlorpheniramine, a potent RLS worsening antihistamine, but the hydrocodone is at a high dose of 10 mg which usually will overcome any worsening effects of the chlorpheniramine.  Hycomine is similar to Tussionex but Hycotuss does not contain any RLS worsening medications so it may be a better choice.

Antipsychotic medications

Many of these drugs are similar chemically to the anti-nauseants (in fact many are used as anti-nauseants). They can worsen RLS just like the antinausea drugs. This class of drugs includes: Clozaril, Compazine, Haldol, Loxitane, Mellaril, Moban, Navane, Prolixin, Risperdal, Zyprexa, Serentil, Stelazine, Thorazine, and Trilafon. Also, lithium, a drug which is very helpful in the manic-depressive disorders, can worsen RLS.

Bladder Control drugs

We have gotten some case reports of worsening RLS with drugs such as Ditropan.  These drugs should thus be used with caution in RLS sufferers.

Alcohol

Alcohol had been found by many RLS sufferers to cause worsening of their RLS.  The amount that does this can be very small in some cases.  Individual tolerance can vary considerably (many may not be bothered at all).

(7) Pregnancy and RLS

Pregnancy can cause a worsening of RLS (in at least 50% of patients who have RLS and become pregnant) or be the first time that a patient experiences RLS symptoms. It usually occurs in the third trimester and has been reported in up to 12% of all pregnancies.   10% of women will have their first experience with RLS during pregnancy.  The RLS symptoms will usually go away after the pregnancy, then often come back later in life.   Various problems such as iron or folate deficiency have been postulated as causes, but the real reason why RLS worsens with pregnancy is unknown.

If the symptoms are severe enough to warrant drug therapy, then the sedative category of medication has been used for treatment (with the approval of the patient's obstetrician).   Many RLS specialists will prescribe the opioid category of medication during pregnancy, due to their safety in pregnancy.

The risk of RLS medication in pregnancy is as follows (Category A,B,C,D,X, where A is the best and X is the worst and should never be taken during pregnancy; Category A drugs are quite safe and have a proven track record in pregnancy, Category B drugs have limited data and experience and should be used only if clearly needed, Category C drugs generally have no adequate or well controlled studies in pregnant women and should be used only if the potential benefit justifies the potential risk to the fetus):

Pregnancy Risk Category

Drug Name

A

None

B

Pergolide (but limited data), Ambien, Percodan (short term use), Dostinex, Ambien, methadone (low dose), Percocet, Percodan, OxyContin

C

Mirapex, Requip, Sinemet, Ultram, Darvon (short term use), codeine (short term use), Vicodin or Lortab (for short term use), Sonata, Lunesta, Tegretol, Neurontin, Catapress

D

Xanax, Klonopin (and most benzodiazepine sedatives),
Darvon, codeine, Vicodin, Percodan, all for long term use, methadone (higher doses)

X

Restoril

 

 

Pregnant women should be checked for anemia and proper iron supplementation as indicated.  Magnesium (used for treatment of toxemia of pregnancy) has recently been looked at for treating RLS, but this is only in the preliminary stages.

Nursing mothers can be treated with Darvocet (Darvon).  Small levels of this drug will get into the breast milk, but no adverse effects have been noted in the infants getting the breast milk. Sedatives do get into the breast milk and can cause lethargy in the infants, so this class of medication should be avoided in nursing mothers. Dopamine agents may decrease lactation (milk production).

For more information on the risks of drugs in pregnancy or with breast feeding check out Motherisk Program or the Organization of Teratology.

(8) Quinine

This drug rarely (less than 5% and that is being generous) helps RLS and is only included on this page to help avoid RLS sufferers from receiving this drug for their disorder.  It is probably one of the most common drugs prescribed by doctors unfamiliar with RLS when they hear the RLS complaints of their patients.  This inappropriate treatment occurs because the RLS symptoms are confused with leg cramps for which quinine is the correct treatment.

We have received several reports from RLS sufferers that quinine has helped them, but we cannot be sure whether they have RLS and leg cramps, or in fact only leg cramps. I have treated several patients who definitely had RLS and found that quinine helped (sometimes very significantly) their RLS, but this is still a very small minority of RLS sufferers. As with many of the treatments above, some remedies seem to help only a few RLS patients and therefore cannot be recommended to the majority.

However, the safety of quinine has been a major concern of the FDA and below is a recent communication from the FDA.

Qualaquin, the only formulation of quinine sulfate available in the US, is approved only for treatment of uncomplicated malaria, but most prescriptions for its use are written for treatment or prevention of nocturnal leg cramps. The FDA recently issued a warning about its safety.

Between April 2005 and October 2008, 38 cases of serious or life-threatening adverse effects of quinine were reported to the FDA. Twenty-one of these patients had thrombocytopenia and required hospitalization. Two deaths were reported: one from hemolytic and the other from thrombotic thrombocytopenic purpura (TTP). Some patients developed mucosal bleeding (gingival, gastrointestinal, epistaxis), hemoptysis, petechiae or ecchymosis. The median time to onset of adverse effects after starting quinine was about 13 days. Most patients with thrombocytopenia recovered when quinine was stopped.1 In addition to hematologic toxicity, quinine can cause cinchonism (tinnitus, headache, disturbed vision and nausea) and QT prolongation.

1. FDA drug safety communication: new risk management plan and patient medication guide for Qualaquin (quinine sulfate). Available at www.fda.gov/Drugs/DrugSafety/PostmarketDrug
 

(9) Other RLS Information and Associations

Summer RLS

Many patients have found that there is a seasonal variation in their RLS.   They do fairly well for most of the year, then start to have worsening of their RLS symptoms in the late spring or early summer.  This generally will occur with a change in the weather to hotter and more humid.  There is of course, no understanding of why this phenomenon occurs.

The treatment of this increased RLS in the summer is to increase the dose of current medication.  If that does not suffice, then addition of other classes of medications may be necessary until the fall months.

Menstrual Cycle RLS

There is a subset of female RLS sufferers who find that their RLS symptoms wax and wane with their menstrual cycles.  Generally the RLS will worsen before menstrual flow and abate several days after.  This seems to follow the pattern of PMS.  This association is not understood at all and brings up the question if RLS is associated or related to PMS or other hormonal conditions (such as RLS in pregnancy).  

We have also seen changes during the onset of menopause and after menopause.  This can vary quite a bit amongst female patients with RLS.  Some RLS sufferers will have their RLS complaints get better with menopause, and some have even noted worsening if placed on estrogen replacement therapy.

more to come



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Source: Southern California RLS Support Group, Comprehensive Review of Medications used in Treating RLS and PLMD.
http://www.rlshelp.org/rlsrx.htm
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