CHEST editorials
VOLUME 98 I NUMBER 1 I JULY, 1990
Is Theophylline Obsolete?
Be not the first by whom the new lire tried, nor yet tht• lllst
to illy the oltlllside. Alexander Pope , 16t'i8-17.J.J .
F orconsidered
almost 50 years, methylxanthines have been
first-line therapy of reversible airflow
obstruction in adults and children, despite their rela-
tively weak bronchodilator effect, narrow therapeutic
window, innumerable drug interactions, and toxic
reactions. 1 The great popularity of this class of drugs,
See pages 3, 5, 44
which yielded sales of about US $1 X 109 worldwide in
1988, probably arose, in part, from the duration of
action of the sustained release formulations at a time
when adrenoceptor-agonist aerosols were relatively
short acting.
In recent years, however, with management of
asthma and chronic obstructive pulmonary disease
(COPD) evolving toward therapy of the underlying
inflammatory component rather than simply treating
the bronchospasm, this class of drugs is gradually
being relegated to the position of third or fourth-line
therapy for patients with reversible airflow obstruction.
Why, then, is theophylline on the threshold of obsoles-
cence after so many years as a first-line medication?~ -'·'-·
The answer is probably that it has been superseded
as a bronchodilator by inhaled adrenoceptor agonists
and anticholinergics for both the maintenance therapy
and treatment of acute exacerbations of asthma and
COPD. 3 Furthermore, with an increased appreciation--""
of the importance of inflammation in the pathogenesis
of asthma, inhaled bronchodilators have been rele-
gated to second-line therapy for controlling asthma by
increasingly potent topical steroids and cromolyn with
an excellent therapeutic ratio. 4 ·5 Thus, the so-called
"step therapy" used in the past that began with a
relatively low dose of inhaled ~ 2 -sympathomimetic to
which was added dose-optimized theophylline, is
being supplanted in the control of asthma by dose-
optimized inhaled steroids and adrenoceptor agonists.
The latter are effective not only for maintenance
therapy but also during acute life-threatening episodes
together with steroids given in relatively large doses
intravenously; or even orally.7 There is now increasing
evidence that the addition of intravenous aminophyl-
line adds side effects to these treatment regimens but
does not increase their efficacy. x
For maintenance therapy of asthma, theophylline
may be obsolete because it is merely a relatively weak
bronchodilator that adds little but side effects to dose-
optimized inhaled ~ 2 -agents ... and does not address
the underlying inflammation, a fundamental charac-
teristic of the disease. 9 In this context, bronchocon-
striction might be considered an epiphenomenon, like
pain in patients with appendicitis. Thus, first-line
therapy for moderate chronic asthma should be dose-
optimized inhaled steroids delivered via a metered
dose inhaler (MDI) add-on device such as the Aero-
Chamber to minimize local and systemic side effects
or for very mild asthma, possibly inhaled cromolyn
sodium (cromoglycate sodium) especially in children.'
Second-line therapy is ~ 2 -agonists. Theophylline is
rarely of additional value except, perhaps, as a steroid-
sparing strategy in the maintenance therapy of patients
with asthma requiring systemic steroids for control
despite maximum tolerated doses of inhaled steroid ,
adrenoceptor agonists, and (rarely) anticholinergic
agents. Where necessary, in individual patients, the
benefit of theophylline should be confirmed by a
properly structured N of one clinical trial 10 to confirm
both efficacy and safety.
Sustained action formulations (such as Theo-Dur or
Uniphyl) previously used to control nocturnal symp-
toms of asthma and early morning "dipping," are
almost never required if inhaled steroids are used in
adequate doses to control the disease. Furthermore,
the new relatively ~ 2 -specific long-acting inhaled
agents such as salmeterol promise to provide effective
bronchodilation (or protection from bronchoconstric-
tion) for a period of 12 hours or more, negating any
remaining advantage of sustained release ingested
theophylline or adrenoceptor agonists. 11
In pediatric practice, ingested theophylline or in-
gested adrenoceptor agonist bronchodilators have in
the past been first-line therapy, probably because
aerosol nebulizer systems are expensive and cumber-
some, while at the same time, many of the more
potent prophylactic anti-inflammatory agents were not
available as nebulizer solutions.
The use of MDI with valved add-on devices, such
as the AeroChamber and AeroChamber with Mask
has facilitated MDI aerosol delivery of a variety of
bronchodilators, cromolyn, and various inhaled ster-
CHEST I 96 I 1 I JULY, 1990 1
oids in patients ranging in age from a few weeks to the
very elderly, making nebulizers unnecessary. 3 With an
increasing appreciation of the role of airway inflam-
mation in the pathogenesis of asthma by pediatricians,
prophylactic steroid or cromolyn aerosol therapy is
being increasingly applied in the management of
childhood asthma, thus avoiding the common side
effects of hyperexcitability and possibly learning dis-
orders in children when theophylline is used.l 2
The argument for obsolescence is not as readily
made with respect to the use of theophylline for
maintenance therapy in patients with COPD because
the data are still conflicting to a considerable degree.
Furthermore, the available studies, whether pro or
con, suffer from a number of deficiencies, including
small numbers of patients and comparison of theo-
phylline with placebo-treated patients where selection
bias is inevitable due to exclusion of up to 50 percent
of patients due to side effects. 13·14 In studies that have
shown theophylline beneficial when added to adre-
noceptor agonists, the major problem is failure to
optimize the dose of the inhaled adrenoceptor agonist
or anticholinergic agent prior to adding theophyl-
line.15·16 Where adrenoceptor agonist or anticholiner-
gic therapy has been virtually optimized, only modest
additional benefit could be demonstrated when theo-
phylline was added. 17·18 Nevertheless, the number of
patients in these studies is small and it may require a
large (and expensive) multicenter trial to settle the
question. Even when usually modest additional ben-
efit in spirometry has been demonstrated, investiga-
tors have usually been unable to demonstrate benefit
in terms of improved effort tolerance or decreased
dyspnea when such information has been sought. 19
Unlike the highly effective inhaled agents, whose
side effects are minimal, theophylline is a weak and
potentially toxic bronchodilator with a narrow thera-
peutic window and numerous drug interactions that
make its use complicated for the unwary or unin-
formed physician. 20 Its cost of administration is as
great or greater than that of other treatment modalities
because of the need to monitor the serum theophylline
level at regular intervals to assure safety and efficacy.
Thus, theophylline appears to be facing obsoles-
cence because of major advances in the pharmaco-
therapy of the obstructive airway diseases by means
of aerosol therapy and improved aerosol delivery
systems. These aerosol bronchodilators and/or prophy-
lactic anti-inflammatory drugs are generally more
effective than theophylline in the management of
asthma and COPD, enjoy a far superior therapeutic
ratio at lower overall cost, and are thus likely with
rare exceptions to replace theophylline in the treat-
ment of reversible airflow obstruction in adults and
children.
2 Edllollals
Michael T. Newhouse, M.D., F.C.C.P.
Hamilton, Canada
St. Joseph's Hospital, Firestone Regional Chest/Allergy Unit.
REFERENCES
I Furukawa Cf, Shapiro GG, Biennan CW, Kraemer MJ, Ward
OJ, Pierson WE. A double-blind study comparing the effective-
ness of cromolyn sodium and sustained release theophylline in
childhood asthma. Pediatrics 1984; 74:453-59
2 IPPB Clinical Trial Group. Intermittent positive pressure
breathing therapy of chronic obstructive pulmonary disease.
Ann Intern Med 1983; 99:612-20
3 Newhouse MT, Dolovich MB. Control of asthma by aerosols.
N Engl J Med 1986; 315:870..74
4 Selcow JE, Mendelson L, Rosen JP. A comparison of cromolyn
and bronchodilators in patients with mild to moderately severe
asthma in an office practice. Ann Allergy 1983; 50:13-8
5 Adelroth E , Rosenhall L, Glennow C. High dose inhaled
budesonide in the treatment of severe steroid dependent
asthmatics. Allergy 1985; 40:51H>4
6 Fanta CH, Rossing TH, McFadden ER Jr. Glucocorticoids in
acute asthma: a critical controlled trial. Am J Med 1983; 74:845-
51
7 Ratto 0, Alfano C, Sipsey J, Glorsky MM, Sharma 0 . Are
intravenous corticosteroids required in status asthmaticus?
JAMA 1988; 260:527-29
8 Littenberg B. Aminophylline treatment in severe acute asthma:
a meta-analysis. JAMA 1988; 259:1678-84
8a Chieb J, Beecher N, Rees PJ. Maximum achievable bronchodi-
latation in asthma. Respiratory Med 1989; 83:497-502
9 Hargreave FE, O'Byrne PM, Ramsdale EH. Mediators, aiJWay
responsiveness and asthma. J Allergy Clin lmmunol 1985;
76:272-76
10 Guyatt GH, Sackett 0, Thylor OW, ChongJ, Roberts R, Pugsley
SO. Determining optimal therapy: randomized trials in individ-
ual patients. N Engl J Med 1986; 314:889-92
II Ullman A, Svedmyr N. Salmeterol, a new long acting inhaled
P. adrenoceptor agonist: comparison with salbutamol in adult
asthmatic patients. Thorax 1988; 43:674-78
12 Rachelefsky GS, Wo J, Adelson J, Mickey MR, Spector SL, Katz
RM, et al. Behaviour abnormalities and poor school performance
due to oral theophylline use. Pediatrics 1986; 78:ll33-38
13 Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids
reduce the severity of bronchial hyperresponsiveness in asthma
but oral theophylline does not. Am Rev Respir Dis 1987;
136:1174-78
14 Murciano 0 , Auclair M-H, Pariente R, Aubier M. A random-
ized, controlled trial of theophylline in patients with severe
chronic obstructive pulmonary disease. N Engl J Med 1989;
320:1521-25
15 Thylor DR, Buick B, Kinney C, Lowry RC, McDevitt DG. The
efficacy of orally administered theophylline, inhaled salbutamol
and a combination of the two as chronic therapy in the
management of chronic bronchitis with reversible airflow ob-
struction. Am Rev Respir Dis 1985; 131:747-51
16 Guyatt GH, Townsend M, Pugsley SO, Keller JL, Short HD,
Thylor OW, et al. Bronchodilators in chronic air-flow limitation:
effects on airway function, exercise capacity, and quality of life.
Am Rev Respir Dis 1987; 135:1069-74
17 Barclay J, Whiting B, Addis GJ. The influence of theophylline
on maximal response to salbutamol in severe chronic obstructive
pulmonary disease. Eur J Clin Pharmacol1982; 22:389-93
18 Uoberes P, Ram is L, Montserrat JM, Serra J, Campistol J,
 Picado C, et al. Effect of three different bronchodilators during
an exacerbation of chronic obstructive pulmonary disease. Eur
Respir J 1988; 1:536-39
19 Hill NS. The use of theophylline in 'irreversible' chronic
obstructive pulmonary disease: an update. Arch Intern Med
1988; 148:2579-84
20 Mountain RD, NeffTA. Oral theophylline intoxication: aserious
error of patient and physician understanding. Arch Intern Med
1984; 144:724-27
Theophylline Is No More Obsolete
Than "1\vo Puffs qid'' of Current
Beta2 Agonists
fur it so falls out that what we had we prize rwt to the worth
whiles we enjoy it, but being lack'd and lost, why, then we
rack the value, then we find the virtue that possession would
rwt show us whiles it was ours.
Much Ado about Nothing, IV:l
Lam and Newhouse (see pages 1, 44) have summa-
rized the problems and controversies surrounding
theophylline therapy in the US. Writing from the
therapeutically more flexible Canadian environment,
they ask whether theophylline is not on the verge of
becoming obsolete. I submit that the continuing
popularity of theophylline in the US is, in part, due
to the fact that the standard package insert regimen
for a be~ adrenergic metered dose inhaler (MDI) is
inadequate for many patients and is itself obsolete.
Lam and Newhouse would agree on the latter point,
since much of their argument hinges on individualizing
dosing of beta agonists, and the use of high-potency
inhaled corticosteroids-not yet approved in the US.
Dose-response studies show that two puffs of presently
formulated MDis are suboptimal in patients with
constant bronchospasm, both in terms of peak re-
sponse and certainly in terms of the trough , trough
being that recurring state of distress requiring another
two puffs.'~ For example, when properly controlled
by placebo, the FEV1 response to albuterol is nearly
gone at four hours.6 Moreover, the ability of be~
agonists to inhibit bronchoprovocational stress falls off
even more rapidly. 7·8
Must we subject patients to such relentless, periodic
discomfort? Fortunately, patients cheat. They use
more puffs at a time, or more frequent puffs. Others
end up using a nebulized aerosol. We now realize that
the approved dose for liquid nebulization often deliv-
ers a larger effective dose to the airways, but can be
matched by a larger dose from the MDI. 1•9 The reason
that such low doses were specified for the MDI may
have included the only patients with mild asthma for
study (a poor index of reality, but necessary for studies),
a fear of overdosing gained from the asthma deaths in
the UK in the 1960s associated with large doses of
isoproterenol and prior to use of corticosteroids, 10 and
early animal studies examining the cardiac toxicity of
isoproterenol and fluorohydrocarbons under hypoxic
conditions. 11 Concerns linger, especially among phy-
sicians practicing from that era. Recent reports from
New Zealand of an excess of deaths associated with
fenoterol over albuterol, a compound with more beta,
activity, suggest that this concern is not totally irra-
tional.I2.13
But is theophylline obsolete? In their comprehen-
sive study of COPD patients, 14 and that of others in
asthmatic patients, 15 theophylline adds significantly to
the spirometry result both before and after qid dosing
of the beta agonist. Most COPD patients do not
respond to corticosteroids. I am puzzled why the
authors disparage a pre-inhalation FEV1improvement
of 10-15 percent in this population. Patients find
significantly improved performance and quality oflife,
not necessarily reflected in pulmonary function meas-
urements. 14- 16 We do not understand all the reasons.
Improved diaphragmatic performance may be part of
it. 17 When the dose of theophylline is properly ad-
justed to 10-15 J.Lg/ml, most patients tolerate it very
well. It should be no surprise that patients welcome
the comfort and convenience of a cushion of added
pulmonary function and undisturbed sleep 18•19 with a
once- or twice-daily sustained release preparation.
Whether theophylline adds significantly to anticholin-
ergics in the COPD patient must be studied.
Unquestionably, the increased emphasis on antiin-
Oammatory agents is improving care of the asthmatic,
but there are several statements now often seen that
I believe need editorial fine-tuning: I) "Asthma is an
in8ammatory disease . . .with associated broncho-
spasm." Whether in8ammation is accountable for all
asthma remains unproven. Treatment with cromolyn
or even high doses of inhaled corticosteroids usually
produces improvement, but does not eliminate non-
specific airway hyperreactivity and the need for ther-
apy with bronchodilators, particularly in the patient
with more severe asthma. zo.22 2) "Theophylline is a
weak bronchodilator." In one head-to-head compari-
son, 15 J.Lg/ml theophylline was the equivalent of two
puffs of albuterol at their peak effect. 23 When the
FEV 1 response to albuterol is averaged over 4 h,
theophylline is equivalent. 3) "Theophylline causes
behavioral problems in children." Reference should
be made to recent editorial moderation of this contro-
versy.24 In fact, the Furukawa group's most recent
study found that, with proper controls, the majority
of abnormalities were due to the disease itself. 25 4)
"Theophylline is unnecessary in the treatment ofacute
asthma." For most attacks, I agree. The asthma studies
cited were in patients, most of whom were already
receiving some theophylline, and added theophylline
was the issue, with its possibility of overdosing.
CHEST I 98 I 1 I JULY, 1990 3