Glucocorticoid withdrawal

Authors
Daniel E Furst, MD
Kenneth G Saag, MD, MSc
Section Editor
Eric L Matteson, MD, MPH
Deputy Editor
Paul L Romain, MD
Disclosures

Last literature review version 19.2: Maio 2011 | This topic last updated:
Dezembro 20, 2006 (More)
INTRODUCTION Chronic glucocorticoid therapy is used in the treatment of a
variety of disorders because of its potent antiinflammatory effects and, occasionally,
because it is thought to have immunosuppressive activity [1]. Among the rheumatic
diseases in which glucocorticoids are often used are rheumatoid arthritis, large- and
small-vessel vasculitis, systemic lupus erythematosus, polymyalgia rheumatica, and,
in some cases, the arthritis associated with inflammatory bowel disease [1].

Despite its efficacy, steroid-induced side effects generally require tapering of the drug
as soon as the disease being treated is under control. Tapering must be done carefully
to avoid both recurrent activity of the underlying disease and possible cortisol
deficiency resulting from hypothalamic-pituitary-adrenal axis (HPA) suppression
during the period of steroid therapy. (See "Pharmacologic use of glucocorticoids",
section on 'HPA axis suppression'.)

This topic discusses the major issues related to tapering, the regimen(s) we use in
most patients, and other glucocorticoid tapering regimens that have been reported
in the literature.

The clinical manifestations, diagnosis, and treatment of adrenal insufficiency are

presented separately. (See "Clinical manifestations of adrenal insufficiency in
adults" and "Treatment of adrenal insufficiency in adults".)

INDICATIONS FOR WITHDRAWING GLUCOCORTICOIDS It is helpful to

briefly review the indications for glucocorticoid withdrawal before discussing the
different glucocorticoid withdrawal regimens. These indications include the following:

When the maximum desired therapeutic benefit has been obtained

When inadequate therapeutic benefit has been obtained after an adequate
trial
When side effects, such as lumbar spine osteoporosis or hypertension,
become serious or uncontrollable with medication
In addition, there are two complications that require immediate cessation, or
reduction to a physiologic dose, of glucocorticoids not tapering:
 Steroid-induced acute psychosis, which is often unresponsive to antipsychotic
medications
Herpesvirus-induced corneal ulceration, which can rapidly lead perforation of
the cornea and possibly permanent blindness
If immediate cessation is not possible, discontinuing steroids as soon as possible is
strongly advised.

GLUCOCORTICOID PREPARATIONS Prednisone will be the agent discussed,

although other glucocorticoid preparations are available (table 1). (See
"Pharmacologic use of glucocorticoids".) These preparations are available in various
strengths (eg, 1, 2, 5, 10, 20 mg for prednisone) and in various formulations (tablet,
intravenous preparations, intramuscular preparations, and rectal suppositories).
Differences in the absorption or metabolism of these various strengths and
formulations could affect the ability to taper steroids. Fortunately, most commercially
available prednisone and prednisolone preparations appear to be bioequivalent.
This can be illustrated by the following observations:

In vivo studies using healthy males in a crossover study revealed no statistical

difference in any pharmacokinetic parameter with five different oral
prednisone preparations [2].
Rectal and oral absorption of methylprednisolone are equivalent, with the
relative bioavailability of oral to rectal administration being 90 percent [3].
The systemic bioavailability of prednisone is equivalent to that of
prednisolone (0.77 to 0.80) [4]. Prednisone itself is biologically inactive, but it is
rapidly converted to the active form prednisolone. However, patients with severe
liver disease may have difficulty converting prednisone to prednisolone; in such
patients, it is possible that one might not get the same effect from prednisone as
from prednisolone. In addition, certain drug interactions can affect the metabolism
and bioavailability of prednisone. As an example, barbiturates, phenytoin, or
rifampin, attenuate the biological effects of glucocorticoids (table 2).
Steroid pharmacokinetics Tapering regimens could potentially be influenced if
drug disposition changed at varying prednisone doses. Although there is a trend
toward dose-dependent kinetics, with larger doses being cleared more rapidly, the
effect is relatively small and usually not of great clinical importance [5-7].

Other factors can influence pharmacokinetics. One interesting study examined 54

patients of varying ages who were given oral and intravenous
methylprednisolone and prednisolone [8]. Eleven patients (20 percent)
demonstrated unusual kinetics. Their drug clearance was approximately twice that of
the rest of the population without an identifiable cause. Other findings included
incomplete absorption of glucocorticoids in four patients and an inverse correlation
(r = -0.88) between prednisolone clearance and age, which means that a given dose
may have a greater effect in older persons. This relation to age has been confirmed
in other studies [9]. In addition, prednisolone clearance is also slower in African-
Americans compared to Caucasians [10].

With this degree of interpatient variability in kinetics, it is conceivable that some

patients may show greater withdrawal symptoms than others. This may occur despite
the known difference between plasma glucocorticoid kinetics and biologic activity.

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS SUPPRESSION Administration

of exogenous glucocorticoids can suppress the hypothalamic-pituitary-adrenal axis
(HPA). Abrupt cessation, or too rapid withdrawal, of glucocorticoids in such patients
may cause symptoms of adrenal insufficiency. HPA suppression and the clinical
manifestations of adrenal insufficiency are presented separately. (See
"Pharmacologic use of glucocorticoids", section on 'HPA axis suppression' and
"Clinical manifestations of adrenal insufficiency in adults".)

Identifying patients with HPA suppression The potency, dose, and duration
of glucocorticoid use are important but imperfect predictors of the presence of HPA
suppression. A clinical decision about a particular patient's risk of having HPA
suppression guides subsequent decision making about glucocorticoid tapering.
Patients exposed to glucocorticoids can be classified and managed as follows:

Patients suspected of having HPA suppression who are otherwise candidates

for glucocorticoid withdrawal can be cautiously tapered (see 'Tapering
regimens' below).
Patients determined to have a low risk of clinically significant HPA suppression
may have glucocorticoids weaned as dictated by control of disease activity rather
than by concern for adrenal insufficiency.
Patients for whom the likelihood of HPA suppression is uncertain, but for whom
the consequences of developing acute adrenal insufficiency are serious (eg, the
patient who is about to undergo major surgery), may benefit from testing of the
HPA functional reserve to guide further therapy.
Characteristics of patients who are likely to have HPA suppression and those who are
unlikely, or for whom the likelihood of HPA suppression is uncertain, are discussed in
more detail separately. (See "Pharmacologic use of glucocorticoids", section on 'HPA
axis suppression'.) The following is a brief summary:

HPA suppression likely Patients who have received glucocorticoids who meet
the following criteria are presumed to have HPA suppression:

Anyone who has received a glucocorticoid dose comparable to more than 20

mg of prednisone a day for more than three weeks.
Anyone who has received an evening/bedtime dose of prednisone for more
than a few weeks.
 Any patient who has a Cushingoid appearance
Such patients do not need testing to evaluate their HPA function, but should be
treated like any patient with secondary adrenal insufficiency, including the wearing
of a medical alert bracelet or necklace, carrying an emergency medical information
card, and, arguably, a preloaded 1-mL syringe containing 4 mg
dexamethasone phosphate to inject in emergencies (see "Treatment of adrenal
insufficiency in adults").

HPA suppression unlikely Patients who meet one of the following criteria
regarding steroid use are less likely to have a suppressed HPA and therefore may
have glucocorticoids weaned as is appropriate for the underlying disease.

A patient who has received any dose of glucocorticoid for less than three
weeks
Patients treated with alternate-day glucocorticoid therapy
Intermediate/uncertain risk of HPA suppression Patients who have an
intermediate or uncertain risk of HPA suppression include those with the following
characteristics:

Those taking 10 to 20 mg of prednisone per day for more than three weeks
Any patient who has taken less than 10 mg of prednisone or its equivalent per
day, providing that it is not taken as a single bedtime dose for more than a few
weeks
If withdrawal from glucocorticoids is otherwise indicated, gradual reduction in dose
is appropriate for these patients with an intermediate or uncertain risk of HPA
suppression. Such patients do not need to be tested for HPA functional reserve unless
abrupt discontinuation is being considered or the patient is facing an acute stress
such as surgery. In the latter case, one can give stress doses of glucocorticoids (table
3) or, if time permits, test for the responsiveness of the adrenal with an ACTH
(cosyntropin) stimulation test. (See "Evaluation of the response to ACTH in adrenal
insufficiency".)

Estimation of HPA suppression Identifying the degree of HPA suppression is

not simple clinically. Thus, in practice it is unusual to perform any testing of HPA
function prior to beginning the glucocorticoid withdrawal process. However, as noted
above, in certain settings (eg, the patient for whom elective surgery is planned) such
testing may be warranted.

The response to administration of synthetic adrenocorticotropic hormone (ACTH

[cosyntropin]) is the preferred method to assess adrenocortical function. Although
the cosyntropin test does not provide information about hypothalamic function, it has
the advantage that it can be performed in the office or clinic setting over the course
of approximately one-hour. Test results should be available within hours to days
thereafter. (See "Evaluation of the response to ACTH in adrenal insufficiency", section
on 'Standard high-dose ACTH stimulation test' and "Evaluation of the response to
ACTH in adrenal insufficiency", section on 'Biochemical criteria for diagnosis'.)

The standard high-dose ACTH test and the criteria of a normal adrenal response are
summarized as follows:

Standard high-dose ACTH stimulation test

A baseline venous blood sample is taken prior to ACTH injection.

Synthetic ACTH (cosyntropin 250 g [85 nmol, or 40 IU]) is injected
intravenously or intramuscularly.
Venous blood is obtained 30 and 60 minutes after the injection and serum
cortisol concentrations are measured on these and the baseline sample.
If ACTH is given intravenously a serum cortisol value of 20 g/dL (550 nmol/L)
or more at any time during the test, including before injection, is indicative of a
normal adrenal response. After intramuscular injection, a serum cortisol value of
16 g/dL (440 nmol/L) or more at any time indicates normal adrenal function.
Corticotropin releasing hormone (CRH) test

The corticotropin releasing hormone (CRH) test can assess both the ACTH and cortisol
responses and may be used instead of the cosyntropin test if there is concern about
pituitary function. (See "Corticotropin-releasing hormone stimulation test".)

Other tests either do not address the adrenal response to stress (eg, plasma cortisol
or urinary cortisol excretion) or are more time-consuming than is practical for most
practice settings (eg, metyrapone stimulation and insulin-induced hypoglycemia
tests).

Recommendation Testing for HPA-axis function is appropriate when patients are

using 5 mg/day of prednisone and there is difficulty reducing the dose further
because of non-disease related symptoms. We prefer the low dose ACTH stimulation
test.

If ACTH stimulation testing indicates normal adrenal responsiveness but a patient

continues to have non-disease related symptoms with further attempts to reduce
glucocorticoid dosing, then CRH stimulation testing may be used. In our experience,
CRH testing is needed on very rare occasions.

OTHER FORMS OF GLUCOCORTICOID DEPENDENCE Other forms of steroid

dependence (beyond symptomatic and biochemical evidence of HPA suppression)
have been identified which can hinder steroid tapering. These include [11,12]:

Psychologic dependence on steroids

Recrudescence of the disease for which the drug was prescribed
 Symptoms of apparent adrenal insufficiency despite normal HPA function and
lack of disease recrudescence
TAPERING REGIMENS There is a paucity of clinical evidence to support any
particular regimen of glucocorticoid tapering. Published controlled trial-derived data
do not specifically address the issue of weaning patients from long-term moderate or
high-dose glucocorticoids in chronic rheumatic or other inflammatory disorders. The
following illustrative reviews and selected studies have principally addressed the
effect of tapering regimens of different durations have had on the activity of the
underlying disease:

A year 2002 systematic review found nine controlled trials with random
patient assignment that compared different glucocorticoid tapering regimens [13].
The published reports reviewed dealt almost exclusively (seven of nine trials) with
the treatment of asthma or chronic obstructive pulmonary disease (COPD)
exacerbations and generally assessed relapse-rates and/or physiologic measures
(such as peak expiratory flow rates, forced expiratory volumes, or oxygen
saturation) as patients were weaned from systemic to inhaled glucocorticoids.
The authors of the review concluded that there was no significant difference between
abrupt, rapid, or slow glucocorticoid tapering regimens for these outcomes in asthma
or COPD. The other two trials reviewed were 7 week versus 15 week tapering
regimens in Crohn disease and 10 versus 21 week tapering in bone marrow transplant
patients with graft versus host disease [14,15]. Again, In these latter two studies
there were no clinically significant differences in outcomes between the shorter and
longer tapers.

A trial evaluated 46 children with nephrotic syndrome who were treated with
high doses of prednisolone (60 mg/m2 per day) [16]. Tapering was performed over
eight weeks or five months. Twenty-nine children in the short taper group received
60 mg/m2 per day for four weeks, followed by 40 mg/m2 per day on three days a
week for four weeks. Prednisolone was then discontinued. Seventeen children in
the long taper group received 60 mg/m2 per day for four weeks, 60 mg/m2 per
day on alternate days for four weeks, followed by tapering by 10 mg/m2 every
other day every four weeks over five months. The number of patients who relapsed
with the nephrotic syndrome within six months after initial taper was significantly
higher in the rapid taper group.
RECOMMENDED TAPERING REGIMEN Short-term glucocorticoid therapy (up to
three weeks), even if at a fairly high dose, can simply be stopped and need not be
tapered. HPA suppression due to glucocorticoid use of this duration will not persist
and is highly unlikely to have any clinical consequence. However, in a frail or
dangerously ill patient, the clinician may elect to proceed more cautiously as noted
below.
In patients who have taken a glucocorticoid for a longer time, we suggest a regimen
which is largely based upon experience and rests upon the following assumptions:

Factors of age, frailty, concomitant illnesses, dangerousness and likelihood of

flare of underlying illness, psychological factors, and duration of previous use of
glucocorticoids are taken into account.
The disease is sufficiently stable so that tapering of the dose is appropriate.
The patient has received long-term steroid therapy, not recurrent "pulses" as
might be used in asthma.
The observation, based upon physiologic data, that HPA suppression is
uncommon at prednisone doses below 5 mg/day means that most patients on a
daily dose of 5 mg/day do not have to be tapered [17].
The regimen we recommend also assumes that repeated morning cortisol
determinations are too expensive for routine use (see 'Other published tapering
regimens' below) and that the appropriate end-points are the patient's signs and
symptoms.

The goal of tapering is to use a rate of change that will prevent both recurrent activity
of the underlying disease and symptoms of cortisol deficiency due to persistent HPA
suppression. We generally aim for a relatively stable decrement of 10 to 20 percent,
while accommodating convenience and individual patient response. The dose is
tapered by:

10 mg/day every one to two weeks at an initial dose above 60 mg of

prednisone or equivalent per day.
5 mg/day every one to two weeks at prednisone doses between 60 and 20
mg/day.
2.5 mg/day every one to two weeks at prednisone doses between 19 and 10
mg/day.
1 mg/day every one to two weeks at prednisone doses between 9 and 5
mg/day.
0.5 mg/day every one to two weeks at prednisone doses below 5 mg/day. This
can be achieved by alternating daily doses, eg, 5 mg on day 1 and 4 mg on day 2.
This regimen will generally prevent symptoms of cortisol deficiency. At some point,
however, many patients with rheumatic diseases complain of recurrent symptoms of
the underlying disease. In this setting it may be difficult to distinguish between mild
symptoms of glucocorticoid withdrawal (ie, arthralgia and myalgia or
"pseudorheumatism") or recrudescence of the underlying rheumatic disease.

If the symptoms are not major, we try to wait 7 to 10 days, and use a nonsteroidal
antiinflammatory drug or other analgesic. Resolution of symptoms during this period
of time suggests pseudorheumatism. If the symptoms do not subside within this time
frame, we increase the prednisone dose by 10 to 15 percent (to the next convenient
mg tablet regimen) and maintain that dose for two to four weeks. If the symptoms
resolve, the above tapering regimen can be resumed, using two to four weeks
between decrements rather than one to two weeks.

Should this modest increase in dose not be sufficient to alleviate symptoms, we

double the prednisone dose. The disease flare is allowed to subside and the taper is
reinstituted at a slower rate (eg, once monthly) or at smaller decrements (eg, one-
half of the original decrement).

It should also be appreciated that incremental change is inappropriate if life-

threatening flares occur (as in acute recurrence of lupus nephritis, severe hemolysis,
acute polymyositis, or vasculitis). In these settings, a return to the original, highest
dose of steroids should be instituted. Tapering which is slowed in rate or decrement
can be undertaken after the flare subsides, but specific guidelines become both
convoluted and impractical in the latter situations.

Alternate-day regimen We are not aware of any evidence-based data relating

to steroid tapering on an alternate-day regimen. We do, however, use the following
alternate-day approach (in which the entire dose is given on the alternate days) in
some patients. After the daily regimen has reached 20 to 30 mg of prednisone per
day, we decrease the alternate day dose by 5 mg every one to two weeks until the
dose is 20 to 30 mg alternating with 10 mg. We then reduce the alternate day dose
by 2.5 mg every one to two weeks until the prednisone dose on the alternate day
has fallen to zero. At that point we decrease the remaining drug in the same manner
as was suggested for the daily dosing regimen.

Although this regimen is generally effective in most rheumatic diseases, patients with
rheumatoid arthritis often do not tolerate alternate-day dosing.

OTHER PUBLISHED TAPERING REGIMENS Other published glucocorticoid

tapering regimens include the following:

A report in 1976 used plasma cortisol measurements to gauge withdrawal

[18]. Patients returned to the clinic at two to four week intervals for morning
plasma cortisol measurement. Tapering was done at a rate of 2.5 mg of
hydrocortisone/week down to a single morning dose of 10 mg of hydrocortisone
(equivalent to 2 mg of prednisone). Steroid therapy could be discontinued when
the morning plasma cortisol concentration rose to greater than 10 g/dL. Stress
doses of steroids might be needed for infections. This approach, however, has not
gained much popularity and is generally not used.
Another report in patients with rheumatic disease suggested either switching
to alternate-day therapy or gradually lowering the daily dose [19]. To switch to an
alternate-day regimen, the dose was doubled on alternate days and then tapered
 as described below. This regimen, however, might result in synovial and serosal
flare and symptoms on the alternate days.
To reduce the dosage without switching to an alternate-day regimen, the authors
suggested decrements of 5 to 10 mg every one to two weeks when the
prednisone dose was above 40 mg/day, 5 mg decrements every one to two weeks at
a dose between 40 and 20 mg/day, and 1 to 2.5 mg/day decrements every two to
three weeks at a prednisone dose below 20 mg/day. The rate of reduction was
dependent upon the clinical response.

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