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DRUGS-INDUCED/DRUGS CAN WORSEN RLS/PLMD: CAUTION! RLS/PLMD patients taking a medication prescribed by their qualified healthcare provider in this Section should not abruptly stop it. They should consult their qualified healthcare provider first.
DRUGS-INDUCED/DRUGS CAN WORSEN RLS/PLMD: CAUTION! RLS/PLMD patients taking a medication prescribed
by their qualified healthcare provider in this Section should not abruptly stop it. They should
consult their qualified healthcare provider first.
Restless Legs Syndrome: Detection and Management in Primary Care, National Institutes of Health, US
Department of Health and Human Services, March 2000, states: "...Drug-Induced: There is some
evidence from published case reports that RLS symptoms may be worsened or unmasked by medications
such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), lithium, and
dopamine antagonist...." Dopamine antagonists lower dopamine.
Consider this list of medications a partial one. As time goes by, we are discovering new medications
that can make RLS/PLMD symptoms worse or cause a RLS and/or PLMD "Like" Syndrome. All the drugs
listed in this Section do not cause problems for every RLS/PLMD patient.
It is not always possible to avoid all drugs on this list. For those who must take a medication that
has been weighed against what appears to be a worsening of their RLS/PLMD symptoms, they might have
additional treatments considered to quiet those symptoms.
RLS/PLMD is a life-long problem which often progressively gets worse as time passes (unless
secondary to pregnancy, iron deficiency or a low ferritin level, end stage renal disease or
drug-induced). All treatments tried thus far normally stop working given enough time with the
RLS/PLMD patient having to move on to another treatment. A patient might run through the better
treatments sooner, who are on medications causing a worsening of their symptoms, than he/she would
have otherwise. This needs to be considered.
It is important for RLS and/or PLMD patients to check with their qualified healthcare provider
and/or pharmacist on all drugs they are taking and before filling a new prescription, to make sure
they are not dopamine antagonists that cross the brain barrier and/or have dopamine-blocking
activity. It might be easier to check, assuming RLS/PLMD patients' qualified healthcare provider
feels another drug can be safely substituted, than to spend a possible 24 to 48 hours pacing the
floors due to the worsening of RLS/PLMD symptoms while waiting until the drug is out of their
A. ANTIDEPRESSANTS: Any antidepressant can worsen RLS/PLMD symptoms or even cause a RLS "Like"
Syndrome. RLS/PLMD symptoms can worsen shortly or after a more lengthy period of time after starting
on an antidepressant or can unmask it in someone already prone to have RLS/PLMD. Many
antidepressants have an impact on the dopamine system or dopaminergic-blocking action.
Sleep deprivation plus the stress of RLS/PLMD symptoms, might make the patient "appear" depressed.
If I could sleep little night after night because of stressful and excruitating RLS/PLMD symptoms,
and being dead tired the next day, had to try to work, I feel sure I would look and feel depressed!
The answer might be to resolve the RLS/PLMD symptoms first, a judgment call granted, with
appropriate medical care and see once the patient is having restful nights consistently, if the
depression still exists.
SEVERE DEPRESSION, DESPONDENCY, AND RLS, Philip M. Becker, MD, Dallas, TX, NightWalkers, May 2000,
reported: "...Take the case of Mr. G. As he entered my office, he...said, 'You're my last
hope.'...His legs kept him walking 22 hours a day. His family doctor had started him on Prozac in
hopes of helping his depression. It was making his legs worse...he said, 'I'm at the edge of the
cliff, and I'm ready to go over.' Mirapex restored this man to 7 hours sleep each night and the
Prozac could be stopped. 'Doc, I'm a new man'...."
The TRICYCLICS antidepressants, some of which are Anafranil® (Clomipramine), Asendin® (Amoxapine),
Etrafon® (Amitriptyline & Perphenazine), Elavil® (Amitriptyline), Limbitrol®(Chlordiazepoxide &
Librium® and Amitriptyline), Norpramin® (Desipramine), Pamelor® (Nortriptyline), Sinequan®
(Doxepin), Surmonil® (Trimipramine), Tofranil® (Imipramine), Triavil® (Perphenazine [see G of this
Section] and Amitriptyline) and Vivactil® (Protriptyline), might worsen more often than not RLS/PLMD
The SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) might more often than not also worsen RLS/PLMD symptoms.
A few of the SSRIs are Celexa® (Citalopram), Luvox® (Fluvoxamine), Paxil® (Paroxetine), Prozac®
(Fluoxetine) and Zoloft® (Sertraline). Effexor® (Venlafaxine) works differently than a tricyclic and
the SSRIs. Many patients have reported that Effexor® worsened their RLS symptoms. However, there are
no studies of Effexor® and its effects on RLS.
Desyrel® (Trazodone), Remeron® (Mirtazapine), Serzone® (Nefazodone) or Wellbutrin® (Bupropion) might
be tried by RLS/PLMD patients suffering from depression. These should be approached with caution,
also. Reports from RLS patients who were prescribed Desyrel®, Remeron® and Wellbutrin®, indicate
they can worsen RLS/PLMD symptoms in many. Serzone® has perhaps the fewest reported problems with
worsening of RLS/PLMD symptoms, although it has not been studied.
A number of studies have linked depression to a folate, B-12, B-1 (thiamin) or other deficiencies.
Thyroid functioning and thyroid stimulating hormone (TSH) tests might also be worth considering in
patients suffering from depression. Folate (folic acid) deficiency has also been linked to bipolar
and other mental disorders.
Paradoxically, some RLS/PLMD patients seem to be helped by tricyclic antidepressants.
REFERENCES: Restless Legs Syndrome and Paxil (Paroxetine), Sanz Fuentenebro FJ, et al. Acta
Psychiatr Scand, Dec. 1996: "This paper describes a case of Restless Legs Syndrome worsened by
Paroxetine...We consider that the reported association between RLS and Paroxetine could be generated
by the antidopaminergic activity of the latter." Mianserin and Restless Legs, Markkula J, et al. Int
Clin Psychopharmacol, Jan. 1997: "...Six cases of Restless Legs Syndrome in association to Mianserin
are presented...." Mianserin is an antidepressant available only outside the US. Fluoxetine (Prozac)
and Restless Legs Syndrome, Bakshi R, J Neurol Sci, Oct. 1996, Complex Movement Disorders Induced by
Fluoxetine (Prozac), Bharucha KJ, et al. Mov Disord, May 1996.
B. ANTIHISTAMINES/DECONGESTANTS: For some RLS/PLMD patients, antihistamines and decongestants, can
aggravate RLS/PLMD symptoms. The most frequent offender seems to be BENADRYL® (Diphenhydramine). A
wide variety of over the counter medications for colds, hay fever, sinus, and sleep remedies, such
as BAYER® PM, EXCEDRIN® PM,and TYLENOL® PM presently contain it. Most other over the counter sleep
aids also contain BENADRYL®.
DIPHENHY® also contains Diphenhydramine, the generic name for Benadryl®. Yet, in other RLS/PLMD
patients, Benadryl® seems to help them sleep. DRAMAMINE® is the trademark name for an antihistamine,
An alternative for some RLS/PLMD patients with rhinitis (nasal congestion, frequently due to
allergies) might be a nasal spray with cortisone (a small amount is absorbed by the body) vs.
antihistamines. Consult your qualified healthcare provider.
For RLS/PLMD patients who find that Benadryl® and/or an antihistamine worsens their symptoms, in the
event of a medical emergency, they might ask their doctor for a letter to carry that explains this.
The letter might request the RLS/PLMD patient be given only cortisone and/or an antihistamine, if
possible, he/she has found to not worsen his/her RLS symptoms.
C. ANTINAUSEA/GASTROINTESTINAL: Most antinausea drugs used in the US cross the blood-brain barrier
and can have dopamine blocking activity or are dopamine antagonist. These drugs, such as
ATIVERT®/BONINE® (MECLIZINE), ATARAX®/VISTARIL® (HYDROXYZINE), COMPAZINE® (PROCHLORPERAZINE),
PHENERGAN® (PROMETHAZINE), THORAZINE® (CHLORPROMAZINE), TIGAN® (TRIMETHOBENZAMIDE) and TRILAFON®
(PERPHENAZINE), can seriously exacerbate RLS/PLMD symptoms.
REGLAN® (METROCLOPRAMIDE) is often prescribed for reflux, nausea, vomiting and for a variety of
gastrointestinal symptoms, and is a dopamine antagonist. There are a variety of other drugs that
might be used instead.
If an RLS/PLMD patient is given any of the antinausea drugs listed, if a narcotic was given
simultaneously, it may (or may not) counteract a worsening of the patient's RLS/PLMD symptoms. I
have had RLS/PLMD patients tell me, "I was given Phenergan® (or Compazine®, etc.) in the hospital
when I had an operation, and it did not worsen my symptoms." That is probably because these patients
were on a narcotic for pain. RLS/PLMD patients should not be misled that they can take these drugs
otherwise without their symptoms possibly worsening.
Two new antinausea medications for those receiving chemotherapy, KYTRIL® (Granisetron) and ZOFRAN®
(Ondansetron), show promise and have little or no affinity for the dopamine receptors. However, they
have not been studied for use by RLS/PLMD patients. They may be considered as alternatives to other
For those who have found that antinausea drugs send their RLS/PLMD symptoms into a tailspin or who
do not wish to risk this, the cost of KYTRIL®, although expensive (approximately $50 for a limited
time of use) and ZOFRAN® (under $100), might be worth considering. HMOs have covered the cost of
ZOFRAN® for RLS/PLMD patients, and I assume they might KYTRIL® also, while others require submission
by the patient's doctor as to why these are "medically necessary." Hopefully, the doctor of RLS/PLMD
patients will be willing to do so once he/she reads this Section and looks into it further.
MOTILIUM® (DOMPERIDONE), an antinausea drug, although a dopamine antagonist, does not cross the
blood-brain barrier and is available in Canada, UK, and some other countries. It is not approved for
sale by the FDA in the US. DOMPERIDONE is only available for clinical trials or perhaps on a
compassionate need basis from the manufacturer in the US. It is much less expensive than Zofran® and
Kytril®. MOTILIUM® (DOMPERIDONE) does not normally worsen RLS and/or PLMD symptoms.
D. CALCIUM-CHANNEL BLOCKING DRUGS: Some calcium-channel blocking drugs, including those for reducing
blood pressure have an impact on the dopamine system. Some in this group of drugs could effect the
availability of dopamine and should be avoided, if possible. The chemical structures of Flunarizine
and Cinnarizine available only outside the US, which are related to neuroleptics, may have a greater
incidence of drug-induced RLS/PLMD symptoms.
E. DOPAMINE ANTAGONISTS: Dopamine antagonists decrease dopamine. RLS/PLMD is thought to be caused by
the depletion of dopamine-producing neuron(s). Dopamine antagonists of which the majority cross the
blood-brain barrier, cannot be avoided in all cases, but at least the RLS/PLMD patient might know
why their RLS/PLMD symptoms have worsened.
F. PRE-MENSTRUAL SYNDROME (PMS): Although not available in the US, VERALIPRIDE, a neuroleptic with
an antidopaminergic effect, might be prescribed for PMS. It can result in the worsening of RLS/PLMD
symptoms. There are other treatments for PMS available which might be considered first.
G. PSYCHIATRIC DRUGS: Neuroleptics and antipsychotic drugs, such as: Compazine® (Prochlorperazine)
Haldol® (Haloperidol), , Loxitane® (Loxapine), Mellaril® (Thioridazine), Moban® (Molindone), Navane®
(Thiothixene), Prolixin® (Fluphenazine), Serentil® (Mesoridazine), Stelazine® (Trifluoperazine),
Thorazine® (Chlorpromazine), Trilafon® (Perphenazine) and Vesprin® (Triflupromazine) can seriously
worsen Restless Leg Syndrome and/or PLMD symptoms. Neuroleptics are dopamine antagonist. These drugs
should not be stopped without medical advice.
The newer "Atypical Neuroleptic" drugs, such as Clozaril® (Clozapine), Risperdal® (Risperidone),
Seroquel® (Quetiapine), and Zyprex® (Olanzapine), might cause less problems with RLS and/or PLMD. At
present, there have been no studies of them for RLS/PLMD patients. There are a few studies involving
Parkinson's (PD) patients, but a different area of the brain is thought to be involved with PD vs.
RLS. The "Atypical Neuroleptic" drugs should also be approached with caution for RLS/PLMD patients.
For those RLS/PLMD patients taking Lithium® (Lithonate®, Lithobid® or Lithotabs®) for bipolar
disorder, it has dopamine-blocking activity, they might look into alternative treatments, one of
which is Neurontin®, to see if their RLS/PLMD symptoms improve once off of it. Neurontin® is also
often an effective treatment for RLS and/or PLMD. An RLS and/or PLMD "Like" Syndrome can develop
shortly or even years after starting any of the drugs listed perhaps in this Section, except
H. SINEMET® (CARBIDOPA/LEVODOPA): Approximately 82% (about 6 out of 7) of all RLS patients on
Sinemet® experience augmentation with increased intensity of their RLS symptoms with onset earlier
in the day than before and can progress to being around the clock and/or rebound in the early
morning hours as the dose wears off. Also, the symptoms can spread to the upper limbs and/or other
parts of the body.
Prior to taking Sinemet®, the majority of RLS patients have their symptoms disappear by 4:00 AM to
6:00 AM and are symptom free throughout the day. The symptoms usually reoccur at 6:00 PM or later,
except occasionally with prolonged rest, such as a long car ride. Not necessarily, if they are on
Sinemet®. This might also hold true for any drug that contains levodopa.
Even on low doses of Sinemet®, if taken every day or almost every day, many doctors who treat large
numbers of RLS patients, have observed that augmentation and/or rebound can take place in 33% to
40%. The higher the dose, such as 300 mg of levodopa or more (25/100 mg; 2nd figure is levodopa),
and the more severe a case of RLS the patient has, augmentation, rebound and/or spreading of the RLS
symptoms can effect almost 100% of patients.
Conversely, a minority of RLS patients, are helped with their symptoms for long-term by Sinemet®.
Those with mild symptoms who need to take only 1/2 of the 25/100 mg Sinemet® pills four times or
less a week might fewer complications than statistics quoted. See Section# 5 on Sinemet®.
I. SURGERY/SEVERE PAIN: For RLS/PLMD patients facing surgery that might involve more than a small
blood loss or autologous blood donations beforehand, the most important planning tool, if time
permits, is to have their ferritin checked and to take measures to bring it up to over 50 to give
them a cushion perhaps. The body must use iron to replace lost blood and make new red blood cells
thus potentially lowering the patient's ferritin level. RLS/PLMD patients should discuss this with
their qualified healthcare provider.
MEPERGAN® (DEMEROL® [MEPERIDINE] combined with PROMETHAZINE [PHENERGAN®]), for nausea; PHENERGAN® is
a dopamine antagonist. Demerol® (Meperidine) alone or as long as it is not combined with one of the
drugs listed that frequently worsen RLS/PLMD symptoms, is usually fine. A narcotic combined with an
antinausea drug or dopamine antagonist, might be sufficient to counteract the worsening of RLS/PLMD
symptoms or it might not be.
As mentioned, most antinausea drugs used in the US are dopamine antagonists and cross the
blood-brain barrier or have dopamine-blocking activity. See C of this Section for more information.
J. TRANQUILIZERS: Major tranquilizers in the Phenothiazine family or referred as the "zines" in the
medical community. They act by blocking dopamine receptors. This is not a complete list; some of the
Phenothiazines are already listed under G of this Section. Phenothiazine or Derivatives:Benperidol,
Cinnarizine, Cyamemazine, Dixyrazine, Flunarizine, Levomepromazine, Levoprome® (Methotrimeprazine),
Metopimazine, Perazine, Promazine, Prothipendyl and Triethylperazine.
"Most people are pantywaists.
Exercise is good for you."
-EMMA 'GRANDMA' GATEWOOD,
at age 67 first woman to thru-hike
the Appalachian Trail (1955), 1887-1973