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JOBNAME: 0#0 2010 PAGE: 1 OUTPUT: Sat April 17 02:25:13 2010
Use of Methylphenidate in the Treatment of
Patients Suffering From Refractory Postural
Khalil Kanjwal, MD,1Bilal Saeed, MD,2Beverly Karabin, PhD,1
Yousuf Kanjwal, MD,1and Blair P. Grubb
Methylphenidate has been shown to be an effective therapy in patients with refractory
neurocardiogenic syncope. However, the role of methylphenidate in patients suffering from postural
orthostatic tachycardia (POTS) has not been reported. The study was approved by the institutional
review board. A retrospective nonrandomized analysis was preformed on 24 patients evaluated at
our autonomic center for POTS from 2003 to 2010. The diagnosis of POTS was based on patient
history, physical examination, and response to head up tilt table testing. The mean follow-up period
was 9 6 3 months. The patients were included in the current study if they had a diagnosis of POTS
with severe symptoms of orthostatic intolerance and were refractory to the commonly used
medications. All of these patients were started on methylphenidate and the response to therapy was
considered successful if it provided symptomatic relief. Twenty-four patients (age 28 6 12,
20 women) met inclusion criterion for this study. The response to treatment was assed subjectively in
each patient and was collected in a retrospective fashion from patient charts and physician
communications. Four patients reported side effects in the form of nausea and 2 ultimately had to
discontinue the treatment. Another 4 patients had a follow-up of less than 6 months. Thus,
only 18 patients who received methylphenidate completed the follow-up of 6 months. Out of these
18 patients, 14 (77%) patients reported marked improvement in their symptoms. Nine out of
12 patients who had recurrent episodes of syncope reported no syncope at 6 months of follow-up.
Fourteen (77%) patients reported marked improvement in their symptoms of fatigue and
presyncope. Four patients continue to have symptoms of orthostatic intolerance and 3 continued
to have recurrent episodes of syncope. Methylphenidate may be beneficial in patients with otherwise
refractory postural tachycardia syndrome.
Keywords: methylphenidate, ritalin, postural tachycardia syndrome
Postural orthostatic tachycardia (POTS) is a condition
causing symptoms of orthostatic intolerance (of greater
than 6 months duration) accompanied by a heart rate
increase of at least 30 beats/min (or a rate that exceeds
120 beats/min) that occurs in the first 10 minutes of
upright posture or head up tilt occurring in the absence
of other chronic debilitating disorders.1–4It occurs
principally due to failure of the peripheral vasculature
to maintain adequate resistance during orthostatic
stress, permitting excessive venous pooling to occur.
The resultant increase in heart rate and myocardial
contractility attempts to compensate for the reduced
circulating blood volume. There are roughly 500,000 to
1000,000 people suffering from POTS in United
States.5,6Multiple pharmacotherapeutic agents includ-
ing fludrocortisone, midodrine, bupropion, selective
1Section of Electrophysiology, Division of Cardiology, Department
of Medicine; and2Division of Internal Medicine, Department of
Medicine, University of Toledo
Medical Center, Toledo, OH.
*Address for correspondence: FACC, Professor of Medicine,
Director Electrophysiology Services, Division of Cardiology,
Department of Medicine and Pediatrics, Health Sciences Campus,
The University of Toledo Medical Center, Mail Stop 1118, 3000
Arlington Ave, Toledo, OH 43614. E-mail: blair.grubb@utoledo.
American Journal of Therapeutics 0, 000–000 (2010)
1075–2765 ? 2010 Lippincott Williams & Wilkins
serotonin reuptake inhibitors have been used to
prevent symptoms of orthostatic intolerance in these
patients. However, there are some patients who are
refractory to these pharmaceutical agents. Methylphe-
nidate has been reported to help symptoms of
orthostatic intolerance in patients with refractory
neurocardiogenic syncope.7Methylphenidate (Ritalin),
a piperidine derivative that is structurally related to
amphetamine, has a hemodynamic profile similar to
amphetamine, but with a much lower incidence of side
effects and much favorable safety profile.8–10The aim
of this study was to determine whether methylpheni-
date can be helpful in patients with POTS refractory to
A retrospective nonrandomized analysis was pre-
formed on 24 patients evaluated at our autonomic
center for POTS from 2003 to 2010. The study was
approved by the institutional review board.
Criterion for diagnosis of POTS
POTS is defined as symptoms of orthostatic intolerance
(of greater than 6 months duration) accompanied by
a heart rate increase of at least 30 beats/min (or a rate
that exceeds 120 beats/min) that occurs in the first
10 minutes of upright posture or head up tilt test
(HUTT) occurring in the absence of other chronic
debilitating disorders. Symptoms include fatigue,
orthostatic palpitations, exercise intolerance, light-
headedness, diminished concentration, headache, near
syncope, and syncope. In a retrospective chart review,
we collected data including demographic information,
presenting symptoms, laboratory data, tilt-table re-
sponse, and treatment outcomes.
The protocol used for tilt table testing has been des-
cribed elsewhere, but basically consisted of a 70-degree
baseline upright tilt for a period of 30 minutes, during
which time heart rate and blood pressure were
monitored continually. If no symptoms occurred, the
patient was lowered to the supine position and an
intravenous infusion of isoproterenol started with
a dose sufficient to raise the heart rate to 20%–25%
above the resting value. Upright tilt was then repeated
for a period of 15 minutes. Patients were included
in the study if they had a POTS pattern on HUTT (rise
in heart rate without any change in blood pressure).
The treatment protocols employed were based on our
previous experiences with orthostatic disorders and
are described in detail elsewhere.2–4,11–15We identified
24 patients of POTS who were refractory to other
commonly used medications. Briefly, a sequence of
therapies was employed that included physical counter
maneuvers and aerobic and resistance training and
increased dietary fluids and sodium. If these were
generally consisting of fludrocortisone, midodrine,
selective serotonin reuptake inhibitors, either alone or
in combination. A trial of stimulants including amphe-
tamine or dextroamphetamine failed to provide symp-
tomatic relief in these patients. The patients were
included in the current study if they had a diagnosis of
POTS (described earlier) and were having symptoms
of orthostatic intolerance and were refractory to the
commonly used medications. All of these patients were
subsequently tried on methylphenidate. We did not
employ a formal questionnaire to assess the response to
treatment nor did we assess the response to treatment
with HUTT testing. The information about the sub-
jective symptoms and sense of well being from each
patient were collected from the patient charts, physi-
cian communications, and direct patient inquiry. A
treatment was considered successful if it provided
We screened 100 patients who followed our syncope
and autonomic center clinic. We found 24 patients (age
28 6 12, 20 women) who met inclusion criterion for this
able 1 summarizes the clinical characteristics of
the study population.
Each patient had received methylphenidate 10-mg
po 3 times per day 15–30 minutes before meals, and
the effects were evaluated every month for a mean
of 9 6 3 months.
Clincal profile of POTS patients
Twenty-three patients had the partial dysautonomic
form of POTS and 1 patient had hyperadrenergic form
of POTS. The common precipitating factor noted in this
group was viral infection and the common comorbid-
ities noted were migraine in 10 (41%) and joint
hypermobility in 7 (29%) of patients. The most common
symptom in this group of patients was presyncope
21 (87%), orthostatic palpitations 21 (87%), and fatigue
17 (70%). Syncope was reported by 12 (50%) and
inability to concentrate by 10 (59%) patients.
Response to treatment
The response to treatment was assessed subjectively
in each patient and was collected in a retrospective
American Journal of Therapeutics (2010) 0(0)
2 Kanjwal et al
fashion from patient charts and physician communi-
cations and patient inquiry. A total of 24 patients were
evaluated. Four patients reported side effects in the
form of nausea and 2 ultimately had to discontinue the
treatment. Another 4 patients had a follow-up of less
than 6 months. Thus, only 18 patients who received
methylphenidate completed the follow-up of 6 months.
Out of these 18 patients, 14 (77%) patients reported a
marked improvement in their symptoms. Nine out of
12 patients who had previously experienced recurrent
episodes of syncope reported no syncope at 6 months
of follow-up. Fourteen (77%) patients reported marked
improvement in their symptoms of fatigue and
presyncope. Four patients continued to have symp-
toms of orthostatic intolerance and 3 continued to have
recurrent episodes of syncope (Table 1).
Because one of the cardinal features of the POTS is
a failure to maintain vascular resistance during ortho-
static stress, many therapies are aimed at increasing
vascular tone.1–5Midodrine hydrochloride is an exam-
ple of a peripheral alpha-1 receptor stimulant that is
marketed for the treatment of orthostatic disorders.16–20
Although effective in some patients, its use is limited by
patient complaints of nausea and sensation of ‘‘goose
bumps’’ and scalp tingling.16–20The search for an
effective alternative agent for patients in whom mido-
drine was either ineffective or not tolerated led us to
explore the use of chemically similar ephedra alkaloid
Methylphenidate (Ritalin) is a peperdine derivative
that is structurally similar to amphetamine.9It appears
to act by releasing stored catecholamine from the
reserpine sensitive presynaptic vesicular pool, decreas-
ing their reuptake, inhibiting monomine oxidase, and
has a direct postsynaptic alpha receptor stimulating
amphetamine, methylphenidate is poorly bound to
plasma proteins. It undergoes relatively rapid metabo-
lism to an inactive metabolite, ritalinic acid. Although
its peripheral vascular effects are quite similar to
amphetamine, the side-effect profile of methylphenidate
is felt to be significantly less, and its addictive potential
is also considered much less.11This difference in side-
effect profile has led it to become the treatment of choice
in children with ADD
Dextroamphetamine has been reported to be benefi-
cialin thetreatmentof vasodepressor syncope.Susmano
et al21reported use of dextroamphetamine for the pre-
vention of vasodepressor syncope in 3 patients with
vasodepressor syncope. A repeat HUTT after adminis-
tration of dextro-amphetamine failed to reproduce
hypotension or symptoms of syncope or presyncope
in these 3 patients. Grubb et al reported on the use of
methylphenidate in patients with refractory neurocar-
diogenic syncope.8In this report, 7 patients (all women
mean age 31 6 15 years) with recurrent syncope and
positive head upright tilt induced hypotension/brady-
cardia (refractory to normal therapy) were placed on
methylphenidate 10 mg orally 3 times per day. Six of
the 7 patients became both tilt negative and clinically
asymptomatic over a 7-month follow-up period. It was
concluded that methylphenidate may be an effective
therapy in patients with recurrent neurocardiogenic
syncope refractory to other forms of therapy.8
In the current study, we found that methylphenidate
may be potentially helpful in POTS patients in whom
other therapies are ineffective, not tolerated or are
Table 1. Clinical characteristics of patients suffering
from drug refractory postural tachycardia syndrome.
Total number of patients screened
Number of patients who
met inclusion criterion
Total number of patients who
Number of patients who discontinued
Methylphenidate(due to intolerance)
Number of patients with incomplete
Type of POTS
Clinical features in patients included for analysis
Females (N, %)
Comorbidities (N, %)
Clinical symptoms of POTS
Inability to concentrate
Response to methylphenidate
Number of patients reporting
response to methylphenidate
28 6 12
American Journal of Therapeutics (2010) 0(0)
Refractory Postural Tachycardia Syndrome3
contraindicated. Initial therapies in the patients of
POTS usually consist of an increase in salt and fluid
intake and aerobic reconditioning with resistance
training to increase lower extremity strength. Pharma-
cotherapy can be used alone or in combination in the
following order: fludrocortisone 0.1 mg po bid, mido-
drine 5–10 mg po tid, propanolol 10 mg po tid,
pyrodostigmine 60 mg po bid, serotonin reuptake
inhibitor, modafinil 100 mg po qam, or dextroamphet-
amine. Not every patient receives every medication.
Although majority of POTS patients will respond to the
above mentioned therapies, however, there is a group
of patients in whom these medications are either
ineffective or poorly tolerated. In the current analysis,
we found that methylphenidate can be effective in
ameliorating symptoms of POTS in patients who failed
other medications. There are also published reports
that methylphenidate is safe when used for a long
periods of time in the treatment of patients with ortho-
static hypotension.22As was alluded to earlier, in
patients with POTS, the main mechanism is the con-
sistent failure of the peripheral vascular system to
increase resistance during upright posture. A number
of peripheral vascular constrictive agents have been
used as therapeutic modalities in an attempt to aug-
ment peripheral vascular resistance in face of ortho-
static stress.2–5,8,12–16Methylphenidate seems to be an
effective vasoconstrictive agent with a reasonable
safety profile that can be used as a chronic therapy
for patients with symptomatic POTS. Although meth-
ylphenidate has a favorable safety profile it has
a potential to exacerbate angina or cardiac arrythmias.
Other side effects may be anorexia, nausea, euphoria,
dry mouth, and occasional anxiety.10In the current
study, nausea was reported in 4 patients and it was
severe enough to warrant discontinuation of this
medication in 2 patients. Although the potential for
addiction is considered to be much less than for
amphetamines, very close supervision of the drug is
required.11For these reasons, methylphenidate should
be reserved only for otherwise refractory cases of POTS.
Limitation of activities of daily living
POTS in our study population has resulted in sub-
stantial limitation of daily activities. POTS can have
tremendous effect on the quality of life often resulting
in a severe limitation of daily activities. In addition, an
often neglected but nonetheless important aspect of
this disorder is the tremendous social, economical, and
emotional toll it takes on the patients and their families.
Although we did not employ a formal quality of life
questionnaire, following treatment with methylpheni-
date 14 patients reported marked improvement in their
activities of daily living.
There are several important limitations to our study.
The study group itself was small, and it was not
a randomized-controlled trial. Rather, each patient was
used as their own control. In addition, patients with
POTS may exhibit spontaneous variations in symptom
severity. Hence, we cannot be absolutely sure that the
beneficial effects noted can be wholly attributed to the
actions of the drug. However, this group of patients
was highly symptomatic who had not responded to
any other therapeutic modality. Thus, it seems reason-
able to conclude that methylphenidate contributed to
the beneficial effects noted. Finally, the patients
presented here all tended to have unusually severe
forms of the disorder, and therefore may not be
representative of the majority of patients with POTS.
Based on our observations in this study we conclude
that methylphenidate may be a beneficial therapy in
POTS patients who fail or are intolerant to first line
therapy. A prospectively designed randomized study
in future may better define the role this therapy in
patients with POTS.
1. Sandroni P, Opfer-Gehrking TL, McPhee BR, et al.
Postural tachycardia syndrome: clinical features and
follow-up study. Mayo Clin Proc. 1999;74:1106–1110.
2. Grubb BP, Kanjwal Y, Kosinski DJ. The postural
orthostatic tachycardia syndrome: current concepts in
pathophysiology, diagnosis, and management. J Interv
Card Electrophysiol. 2001;5:9–16.
3. Grubb BP, Kosinkski DJ. Syncope resulting form auto-
nomic insufficiency syndromes associated with ortho-
static intolerance. Med Clin North Am. 2001;85:457–472.
4. Kanjwal Y, Kosinski D, Grubb BP. The postural orthostatic
tachycardia syndrome: definitions, diagnosis, and man-
agement. Pacing Clin Electrophysiol. 2003;26:1747–1757.
5. Robertson D. The epidemic of orthostatic tachycardia and
orthostatic intolerance. Am J Med Sci. 1999;317:75–77.
6. Goldstein DS, Robertson D, Esler M, et al. Dysautono-
mias: clinical disorders of the autonomic nervous system.
Ann Intern Med. 2002;137:753–763.
7. Grubb BP, Kosinski D, Mouhaffel A, et al. The use of
methylphenidate in the treatment of refractory neurocardio-
genic syncope. Pacing Clin Electrophysiol. 1996;19:836–840.
8. Birmaher B, Greenhill L, Cooper T, et al. Sustained release
methylphenidate: pharmacokinetic studies. J Am Acad
Child Adolesc Psychiatry. 1989;28:768–772.
9. Duncan MK. Attention deficit disorders: evaluation
treatment. Ped Ann. 1985;14:383–398.
American Journal of Therapeutics (2010) 0(0)
4 Kanjwal et al
10. Pelham W, Greenslade K, Vodde-Hamilton M, et al. Download full-text
Relative efficacy of long acting stimulants on children
with attention deficit-hyperactivity disorder: a compari-
son of standard methylphenidate, sustained-release
methylphenidate, sustained release dextro-amphetamine
and pemoline. Pediatrics. 1990;86:226–237.
11. Grubb BP, Kanjwal Y, Kosinski DJ. The postural
tachycardia syndrome: a concise guide to diagnosis and
management. J Interv Card Electrophysiol. 2006;17:108–112.
Olshansky B, eds. Syncope: Mechanisms and Management.
Malden, MA: Blackwell Publishing; 2005:72–91.
13. Grubb BP. Neurocardiogenic syncope. In: Grubb BP,
Olshansky B, eds. Syncope: Mechanisms and Management.
Malden, MA: Blackwell Publishing; 2005:47–71.
14. Grubb BP. Neurocardiogenic syncope and related dis-
orders of orthostatic intolerance. Circulation. 2005;111:
15. Grubb BP. Postural orthostatic tachycardia. Circulation.
16. Lai CC, Fischer PR, Brands CK, et al. Outcomes in
adolescents with postural orthostatic tachycardia syn-
drome treated with midodrine and beta-blockers. Pacing
Clin Electrophysiol. 2009;32:234–238.
17. Kuchinskaia EA, Pevzner AV, Vershuta EV, et al. [Com-
parative efficacy and tolerance of atenolol and midodrine
in patients with vasovagal syncopes]. Ter Arkh. 2006;78:
18. Stewart JM. Midodrine for the treatment of vasovagal
syncope (simple faint). J Pediatr. 2006;149:740–742.
19. Hoeldtke RD, Bryner KD, Hoeldtke ME, et al. Treatment
of postural tachycardia syndrome: a comparison of
octreotide and midodrine. Clin Auton Res. 2006;16:
20. Chen LY, Shen WK. Neurocardiogenic syncope: latest
pharmacological therapies. Expert Opin Pharmacother.
21. Susmano A, Volgman AS, Buckingham TA. Beneficial
effects of dextro-amphetamine in the treatment of vaso-
depressor syncope. Pacing Clin Electrophysiol. 1993;16:
22. Fealey R, Robertson D. Management of orthostatic
hypotension. In: Low P, ed. Clinical Autonomic Disorders.
Boston, MA: Little, Brown & Co.; 1993:731–743.
American Journal of Therapeutics (2010) 0(0)
Refractory Postural Tachycardia Syndrome5