224 Journal of Pain and Symptom Management Vol. 33 No.

2 February 2007

Palliative Care Rounds

The Steroid Withdrawal Syndrome: A Review

of the Implications, Etiology, and Treatments
Leon Margolin, MD, PhD, Doris K. Cope, MD, Rachel Bakst-Sisser, MD,
and Joshua Greenspan, MD
University of Pittsburgh Medical Center (L.M., D.K.C.), Pittsburgh, Pennsylvania;
Albert Einstein College of Medicine (R.B.-S.), Bronx, New York; and PainCare Centers, Inc. (J.G.),
Somersworth, New Hampshire, USA

Abstract
Steroid therapy is frequently used for chronic pain, particularly inflammatory pain states.
Steroid withdrawal syndrome can produce a broad array of signs and symptoms, some of
which are not well recognized. High fever is among these. We describe several cases with this
clinical scenario and review the syndrome in broader terms. J Pain Symptom Manage
2007;33:224e228. Ó 2007 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc.
All rights reserved.

Key Words
Steroid withdrawal syndrome, palliative medicine, high fever

Introduction grading, in patients undergoing steroid with-

drawal also in the presence of biochemical
Steroid therapy is frequently used to treat
evidence of hypothalamus-pituitary-adrenal
chronic pain, particularly inflammatory pain
(HPA) system integrity.’’1 Other symptoms
states. Steroid withdrawal may be commonly
mentioned in the literature but occurring
underdiagnosed and untreated, and may cause
less commonly include abdominal pain, vomit-
significant patient morbidity. Withdrawal may
ing, postural hypotension, hyponatremia, and
produce a broad array of symptoms and signs,
hyperkalemia.1
some of which are not well recognized.1e9
An early study reporting this syndrome
High fever is among these.
included 10 patients who had undergone adre-
The most comprehensive and accepted def-
nalectomy due to hyperadrenocorticism.2 A
inition of the steroid withdrawal syndrome is
similar syndrome describing increased fatiga-
‘‘an objective syndrome resembling true adre-
bility, myalgia, arthralgia, and emotional insta-
nal insufficiency and characterized by fever,
bility was found in patients with rheumatic
anorexia, nausea, lethargy, malaise, arthralgias,
diseases during gradual withdrawal of steroid
desquamation of the skin, weakness, and
therapy.3
weight loss occurring, with highly variable

Address reprint requests to: Leon Margolin MD, PhD,
5828 Beacon Street, Apartment #2, Pittsburgh, PA
15217, USA. E-mail: leon3087@gmail.com
Accepted for publication: August 25, 2006.
Cases
Case 1
A 35-year-old woman with ulcerative colitis
for more than a decade was admitted for
colectomy. She had been on prednisone

Ó 2007 U.S. Cancer Pain Relief Committee 0885-3924/07/$esee front matter

Published by Elsevier Inc. All rights reserved. doi:10.1016/j.jpainsymman.2006.08.013
Vol. 33 No. 2 February 2007 Steroid Withdrawal Syndrome
intermittently for 10 years. She was afebrile on
admission to the hospital and had a normal
blood pressure and pulse rate. Physical exam
was unremarkable except for evidence of
weight loss and slight pallor. Adenocortico-
tropic hormone (ACTH) zinc 40 U was admin-
istered intramuscularly every 12 hours for 10
days prior to surgery. After surgery, ACTH
zinc was reduced slowly, and on the fifth post-
operative day, it was reduced to 40 U in 24
hours. This was further reduced gradually
and discontinued 16 days after colectomy.
Upon reduction and discontinuation of
ACTH, the patient’s temperature rose to
104 F. This was accompanied by abdominal
pain and profuse sweating but no rigidity of ab-
dominal muscles and no abnormality of bowel
sounds. A thorough fever workup, including
chest radiography and blood and urine
cultures, was negative. There seemed to be a
localized area of tenderness in the left hypo-
chondrium, and this, along with the chills
and fever, suggested the possibility of a left sub-
phrenic abscess. Laparotomy was again per-
formed, but no abscess was found and the
peritoneal cavity was clean and smooth. On
the day of the surgery, the fever reached
105 F. The patient received 200 mg of hydro-
cortisone intravenously during and immedi-
ately after the surgery, at which point she
became afebrile. Since the only additional
therapy was the administration of hydrocorti-
sone, it was strongly suspected that this drug
caused the remission of fever. No hydrocorti-
sone was given in the next 24 hours and the fe-
ver again rose to 102 F. Oral hydrocortisone
was then given in 200 mg doses daily and the
temperature remained normal. The hydrocor-
tisone was gradually reduced and the patient
remained afebrile.8
Case 2
A 23-year-old man had a total colectomy for
ulcerative colitis. He was on prednisone for
nearly two years prior to surgery. Prednisone
was slowly tapered and discontinued. He devel-
oped severe abdominal pain and fever of
103 F. His blood pressure was 128/82 and
pulse rate 124 bmp. His abdomen was slightly
distended and diffusely tender. The abdominal
muscles were not rigid, but peristaltic sounds
were hypoactive. Due to the fever, abdominal
pain and diffuse abdominal tenderness,
225
possible perforation of ileum was considered
and laparotomy was performed.
The peritoneum was somewhat dull in color
and a small amount of fluid was present, but
no perforation was found and no purulent ex-
udation was seen. Culture of peritoneal fluid
was sterile. The abdominal pain and fever per-
sisted despite intravenous chloramphenicol.
Following administration of intravenous
ACTH aqueous, 20 U given over a 12-hour
period, there was rapid alleviation of the ab-
dominal pain and defervescence. The intrave-
nous ACTH was replaced by intramuscular
ACTH and finally by prednisone, and the
patient remained afebrile and free of pain.
Case 3
This case, previously reported by Margolin
et al.,9 was a 63-year-old woman with breast
cancer metastatic to the brain, who was placed
on a dexamethasone taper after undergoing
a left fronto-parietal craniotomy. Nearly
a month and a half later, upon cessation of
the steroid, the patient developed a fever. Ex-
tensive fever workup was implemented but
did not reveal a source of infection. The fever
reached 102.9 F, at which point the possibility
of steroid withdrawal was considered, and
she was started on prednisone 20 mg daily.
She proceeded to rapidly defervesce and was
started again on a slow prednisone taper.
Comment
These cases exemplify situations in which
fever was a main characteristic of the steroid
withdrawal syndrome. In each, fever workup
was conducted and revealed no source of
infection or explanation for the fever. No
therapy abated the symptoms, aside from
reinstitution of steroids, giving credence to
the concept of steroid withdrawal.
Treatment of the Steroid Withdrawal
Syndrome
High fever in a debilitated patient with mul-
tiple medical problems presents a diagnostic
and therapeutic challenge. There are no clear
evidence-based guidelines on the treatment
approach.
We advocate thorough fever workup first.
If the workup is negative, we advocate
226 Margolin et al.
reinstitution of oral steroids. In case of an
equivocal fever workup, we suggest a combina-
tion of a broad-spectrum antibiotic and the
steroid.
Current literature supports reinstitution of
steroids as the mainstay of treatment in the ste-
roid withdrawal syndrome. However, preven-
tion of untoward sequelae would be a clear
improvement over reactive treatment of with-
drawal complications. To date, no universally
proven or accepted protocol exists for steroid
tapering. Although it is clear that steroids
should never be discontinued abruptly, the
questions still remain about how much and
at what rate steroids should be tapered.
Saracco et al.1 attempted to follow a 9-day
tapering period in children with acute lympho-
blastic leukemia who were either taking
prednisone or dexamethasone. Unfortunately,
this schedule did not adequately avoid a with-
drawal syndrome.
Symptoms of the steroid withdrawal syn-
drome also were clearly described in a study
conducted by Amatruda et al.,5 which included
22 male patients with pulmonary tuberculosis.
Each patient was administered 30 mg daily of
prednisone and 40 U of ACTH zinc every
other day for three months. Despite a tapering
period of over three weeks, the symptoms still
prevailed, with 20 of the 22 patients develop-
ing symptoms after withdrawal of steroid-
ACTH therapy. In some cases, symptoms be-
gan during the final days of prednisone taper
and/or ACTH therapy. Withdrawal symptoms
included moderate anorexia in 20/22 patients,
lasting for a few days. Nausea, seen in 11/22
patients, was common and occurred at differ-
ent times of the day, usually without any vomit-
ing. Emesis also occurred in 5/22 of the
subjects. Lethargy, found in 15/22 patients,
was often profound, and a diffuse headache,
found in 9/22 of the patients, was sometimes
the most distressing symptom, often lasting
for many days. Fever was low grade and of brief
duration and developed in 8/22 of the pa-
tients. A fine desquamation occurred in 10 pa-
tients, which usually started on the face and
often involved other areas of skin. The desqua-
mation was at times so intense that shed skin
was found on the patient’s clothing. Arthral-
gia, seen in 6/22 patients, and myalgia in 4/
22 patients were usually mild but for some
briefly disabling. Two patients developed
Vol. 33 No. 2 February 2007
temporary arthritis and a third an acute olecra-
non bursitis. Marked weight loss was observed
in 11/22 patients, and three patients devel-
oped postural hypotension, with one of the
three developing symptomatic hypotension
whenever he stood. Only 2/22 patients re-
mained completely asymptomatic after predni-
sone-ACTH withdrawal.5
In a study conducted by Henneman et al.,6
19 chronic asthma patients who had been on
cortisone therapy from 11 to 38 months devel-
oped symptoms lasting from one to four days
within 24e48 hours after the cortisone was dis-
continued. In nine patients, the symptoms were
either mild or did not occur; in four patients,
the symptoms were moderate, and in the re-
maining six patients, the symptoms were severe.
Children, too, experience symptoms of with-
drawal upon cessation of steroid, as was dem-
onstrated in the study conducted by Saracco
et al.1 Most children reported subjective signs
and symptoms including malaise, hyposthenia,
arthralgias/myalgias, lethargy, and anorexia.
Objective signs including weight loss, hypoten-
sion, and skin desquamation were mainly
observed in the dexamethasone group.1
These reports indicate that symptoms re-
lated to steroid withdrawal can occur after sin-
gle or multiple doses of steroid and can occur
in otherwise normal individuals with no under-
lying disease.
Etiology of the Steroid Withdrawal
Syndrome
Although progress is being made in under-
standing the etiology of steroid withdrawal syn-
drome, the exact mechanism still remains
obscure. At one time, it was believed that the
withdrawal syndrome was related to adrenal in-
sufficiency because prolonged administration
of glucocorticoids leads to a reduction in the
secretion and synthesis of ACTH by the pitui-
tary,10 leading to adrenal atrophy and im-
paired responsiveness to ACTH.11 Similarly,
prolonged hypersecretion of hydrocortisone
by an adrenal tumor produces atrophy of the
contralateral adrenal gland due to suppression
of ACTH.12
Another theory attempting to explain
the withdrawal syndrome is that during the
period of elevated steroid levels, the tissue
Vol. 33 No. 2 February 2007 Steroid Withdrawal Syndrome
requirement for adrenocortical steroids may
be increased as an adaptation. This theory
has not been confirmed, as infused cortisol re-
sulted in a normal rate of disappearance from
the plasma of patients with induced hyperadre-
nocorticism.13 Other theories attempting to
explain the withdrawal syndrome include
hypervitaminosis A, hypercalcemia, and acute
pancreatitis, but they have all been disproven.5
As the search for the etiology of the syn-
drome continued, another plausible theory
has been suggested. Glucocorticoids act to sup-
press inflammation by reducing the amount of
fatty acid precursor for synthesis of prostaglan-
dins.14 Evidence indicates that this precursor is
phospholipase A2.15 Prostaglandins are known
to cause headaches,16 inflammation,17 nausea,
vomiting,18 and fever,19 which are all symp-
toms that have been experienced upon with-
drawal of steroids.
Recent data have focused on the inflamma-
tory cytokines tumor necrosis factor a, inter-
leukin-1, and interleukin-6. These cytokines
are secreted at inflammatory sites in tandem
and play a crucial role in the inflammatory
and wound-healing processes by causing in-
creased concentrations of glucocorticoids in
the plasma.20 These cytokines are known to ac-
tivate the hypothalamus-pituitary-adrenal axis
via stimulation of the CRH neuron. Interest-
ingly, studies have shown that glucocorticoids
inhibit the release of these cytokines.20 It has
been postulated that the fall in cortisol levels
upon withdrawal leads to increased interleu-
kin-6 and, to a lesser extent, those of tumor
necrosis factor a and interleukin-1b,20 which
may lead to steroid withdrawal symptoms.
As further research is conducted on this syn-
drome, perhaps a better understanding of the
withdrawal mechanism will be established,
leading to improved treatment protocols.
Clearly, it would be best to prevent the syn-
drome rather than treat it. Currently recom-
mended treatment remains reinstitution of
steroid therapy with a slower taper, but clinical
parameters are, at present, ill defined.
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