Committee on Drugs
Use of Codeine-
and Dextromethorphan-Containing
Cough
Syrups
in Pediatrics
In making decisions regarding the use of
centrally acting antitussives, the practitioner
must first consider the indications for the use of
any antitussive agent; then, the efficacy and
safety of the available agents as compared to
those of a nondrug, alternative course of therapy
must be considered. As stated in an editorial in
the British Medical Journal,’ “the fact that a
patient has a cough does not indicate that he
needs treatment for it.” Nevertheless, we
acknowledge the traditional, frequent prescribing
and self-administration of antitussive products
and the almost placebo nature of many of them.
Indications and Contraindications
Coughs may be considered reflex responses to
mechanical or chemical irritation of the
tracheo-bronchial tree that are mediated by a brainstem
“cough center.” Thus, coughing serves the
bene-ficial functions of clearing airways of obstructing
or irritating material and warning against noxious
substances in inspired air.2
In pathologic states (e.g., asthma, chronic
obstructive pulmonary disease, chronic
bronchi-tis, and cystic fibrosis), the cough reflex serves to
maintain airway patency by clearing excessive
secretions. Cough suppression in patients with
these conditions may be not only
counterproduc-tive but also directly harmful. Clearing of
secre-tions filling the tracheobronchial tree of these
patients is essential to management.
In other diseases (e.g., influenza), coughing
simply may be a response to inflammation of the
respiratory epithelium; however, a truly
“nonpro-ductive” cough is unusual in infants and young
children. Rarely, nonproductive coughing may be
severe enough to cause emesis, exhaustion, and
loss of sleep.
A cough is usually a mild symptom of the
common cold, but even in this instance clearing of
secretions is probably beneficial. The most
common problem is defining the cough that is
secondary to an allergic-based inflammation of
the nasopharyngeal mucosa, postnasal drip, and
so forth; but in these instances, therapy directed
at the underlying condition is more likely to
produce a lasting benefit than symptomatic
ther-apy of the cough per Se.
A chronic cough can result from an inhaled
foreign body, and antitussive therapy could delay
diagnosis. An even more subtle etiology for a
cough is as a response to chronic irritation, such as breathing cigarette smoke.
Based on these and other considerations, the
following guidelines for prescribing antitussive
drugs might provide reasonable standards of
care:
1. A cough is a sign of a disorder; as such, it
need not be an indication for specific antitussive
therapy. When a cough results from allergy, a
foreign body, and so forth, treatment must be
aimed at the underlying disorder.
2. A productive cough associated with chronic
pulmonary diseases should not be suppressed;
rather, treatment should be directed toward
mobilizing secretions through appropriate chest
physiotherapy and drug therapy aimed at the
underlying disorder.
3. A productive cough in acute illnesses and a
nonproductive cough (as in influenza, the
conva-lescent phase of pertussis, and so forth) should be
suppressed only when repeated bouts of coughing
result in emesis, exhaustion, or insomnia. In
general, regardless of the etiology or duration, a
productive cough should not be suppressed, and
treatment should be directed toward mobilizing
secretions. Nonmedicinal approaches (e.g.,
phys-iotherapy, hydration, and so forth) are the most
likely to be beneficial.
4. Short-term, symptomatic relief of a mild
cough associated with the usual “cold” or
uncom-plicated upper respiratory tract infection has not
been proven to be safe or to be harmful;
there-fore, treatment for this type of cough is a matter
of individual judgment.
5. Patient and parent education should present
the cough as a protective, beneficial mechanism,
not “something to be stopped” at all costs.
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6. Specific contraindications to centrally act-ing antitussives include the acute phase of
pertus-sis and acute bronchial asthma when inspissation
of mucous plugs can lead to a progressively
downhill course and fatal outcome.
Choice of an Antitussive Agent
If a valid indication exists for recommending an
antitussive agent, the physician has a limited
choice. The two most widely marketed
antitus-sive agents with proven efficacy are codeine and
dextromethorphan. Diphenhydramine
hydrochlo-ride (Benadryl) was considered to be an effective
antitussive by the U.S. Food and Drug
Adminis-tration review panel for over-the-counter cold,
cough, allergy, bronchodilator, and antiasthmatic
products, but documentation of its efficacy has
not been convincing. Recently, clonazepam
(Clonopin) and \-9-tetrahydrocannabinol, an
active component of marijuana, have been
reported to be antitussives. None of the foregoing,
including codeine, has been definitively tested for
efficacy in infants or children.
Codeine
Codeine has been repeatedly shown in adults to
subjectively and objectively suppress both
artifi-cially induced and disease-related cough.’5
Dosage. A linear relationship has been shown to
exist between codeine dose and a decrease in
frequency of chronic cough, over a dose range of
7.5 to 60 mg. However, a complete suppression
of cough was not achieved, even with the highest
dose of codeine used (60 mg). Thus, the currently
recommended initial dosage for cough
suppres-sion in adults of 20 mg four times a day cannot be
expected to be completely effective, and the dose
may be increased as necessary to a maximum of
60 mg per dose. Doses of this magnitude may
cause significant toxicity when administered to
infants.
Clinical experience and published dosage
recommendations for the administration of
codeine to children lead to an average figure of 1
mg/kg/day, in four divided doses, not to exceed
60 mg/day. However, this dose recommendation
is arbitrary because data from well-controlled
studies are lacking.
Adverse Reactions and Overdosage. The
primary manifestations of codeine toxicity are
respiratory depression and narcosis, which are
dose-related extensions of the pharmacologic
action and therefore are largely predictable. In
adults, doses of 1 mg/kg of codeine have been
shown to cause detectable respiratory
depres-sion,56 and the lethal dose is probably 0.5 to 1 gm
(7
to 14 mg/kg).7A large case study from Berlin of codeine
intoxication in children8 found that single, oral
doses of up to 5 mg/kg produced one or more of
the following conditions: somnolence, ataxia,
miosis, vomiting, rash, swelling, and itching of the
skin; but there were no life-threatening effects. Of
234 children given more than 5 mg/kg, eight
suffered respiratory arrest and two died. Although
extrapolation from this type of data is risky, the
recommended pediatric dose offers only a
four-fold margin of safety with regard to respiratory
depression.
It is even more problematic to extrapolate from
such data to infants. Codeine is seldom
recom-mended in infants who are less than 6 months old,
but it has been used as an antitussive and as an
analgesic. Conjugation to an inactive
glucuron-ide89 is an important inactivation pathway, and
this hepatic enzyme system is not fully developed
in young infants. Therefore, they may be more
susceptible to codeine intoxication. Consistent
with this postulate is that the only reported death
from inadvertent codeine overdosage in pediatric
patients involved a 3-month-old child who was
given 10 mg of codeine orally, four times a day,
for 2#{189}days.9 The Food and Drug Administration
files also contain two case reports of 5-week-old
infants who developed signs of codeine toxicity
(
respiratory depression and coma) after receiving15 mg/day of codeine. The preparation involved
in all three case reports contained an
antihista-mine and a decongestant as well as codeine, and
the relative contribution of the several agents
cannot be determined.
Fortunately, the CNS depression of codeine is
reversed by the specific opiate antagonist
nalox-one hydrochloride (Narcan).
Adverse reactions in nonintoxicated children
include nausea and vomiting, constipation,
dizzi-ness, and palpitations. Non-dose-related and
aller-gic reactions to codeine are rare, but they have
been reported. These reactions may relate to
histamine release, a property shared by
dextro-methorphan. Therefore, allergic reactions may be
more common in atopic or histamine-sensitive
individuals. The high incidence of rash, swelling,
and itching reported in the Berlin series of
intoxicated children8 is consistent with clinically
important histamine release by codeine.
Pharmacokinetics. Despite the widespread use
of codeine-containing pharmaceuticals,
remark-ably little is known regarding the relationship of
serum levels to effects,’#{176} duration of drug in
serum, rate of absorption, and so forth. Only
recently has the Burroughs Wellcome Company
studied codeine kinetics after administration of
with Codeine, to six healthy, young, male
volun-teers.” After oral dosing, peak plasma codeine
concentrations of 102 to 140 ng/ml appeared
within three fourths to one hour; half-life was 3.6
hours. Plasma concentrations of the glucuronide
conjugate far exceeded those of free codeine,
indicating an important “first-pass” effect,
partic-ularly after oral dosing. The presence of this
metabolite may also contribute to the confusion
in reported serum levels of codeine, although the
problem may be simply methodologic.’2 It is
hoped that the radioimmunoassay procedure used
in this study soon will be applied to studies in
infants and children.
As noted here, codeine is inactivated by
glucu-ronide conjugation’#{176}”’3; about 10% of an oral
dose is demethylated to form morphine, which is
believed by some to be the active form of the
drug.’4
Preparations. Current Drug Enforcement
Agency regulations requiring that
over-the-count-er codeine preparations contain a second,
“me-dicinally active,” nonnarcotic agent to prevent
abuse of the preparation are an important
contri-bution to the polypharmacy of today’s antitussive
preparations. Addition of other unproven and/or
dubious agents (expectorants, decongestants,
anti-histamines, and some ingredients dating to folk
medicine) to cough preparations has not been
shown to increase antitussive efficacy and
imposes additional toxicologic and fiscal burdens.
Furthermore, there is some evidence to indicate
that these combination preparations are
attrac-tive to the drug abuser’5 because the addition of
multiple, psychoactive agents (antihistamines,
decongestants) to cough medications may add to,
rather than detract from, their appeal.
Availabil-ity “on-prescription-only” might allow for
mar-keting of a single-ingredient codeine syrup. Also,
formulation in a troche or lozenge might decrease
the abuse potential and the possibility of acciden-tal or intentional overdosage.
Packaging. Marketing of codeine-containing
antitussives with a dispensing system (i.e.,
drop-per, syringe, or spoon) calibrated for age (the dose for a given age to be calculated on the basis of the
50th precentile weight at that age) would
enhance accuracy. For infants 6 months to 2 years
old, calibration could be at two-month intervals;
for children 2 to 14 years old, calibrations could
be at two-year intervals. Such packaging might
also discourage application of the notion that “if a
little is good, a lot is better.”
Other Narcotic Antitussives
Although certain narcotic antitussives have a
greater potency on a “per milligram” basis, their
dependency liability exceeds that of codeine, and
they are classified as Schedule II drugs under the
Controlled Substances Act. Hydrocodone
bitar-trate is the most commonly used of these agents,
and it is marketed in a number of mixtures (e.g.,
Hycodan, Triaminic Expectorant DH, Tussend
Expectorant). No advantage over codeine has
been demonstrated with this drug, and use of it as
well as other potent narcotics, such as
hydromor-phone hydrochloride (Dilaudid) and morphine,
should be restricted to a severe, painful cough
that is resistant to treatment with codeine.
Adverse effects include nausea and vomiting,
dizziness, ventilatory depression, drowsiness, and
constipation.
Dextromethorphan
Because of the small but present addictive
liability of codeine, dextromethorphan has been
widely marketed in a variety of over-the-counter cough and cold preparations. Dextromethorphan
will not substitute for opiates in dependent
mdi-viduals’6; therefore, for legal purposes it is
consid-ered to be nonaddictive. Nonetheless, abuse by
teenagers of over-the-counter preparations
con-taming dextromethorphan plus other ingredients
does occur. Huge doses (300 to 1,500 mg several
times daily) have resulted in intoxication with
bizarre behavior, but no physical dependence. ‘7
Dosage. Doses of dextromethorphan that are
equiantitussive to codeine produce comparable
levels of CNS depression,6 and it is believed that
the site of action is the same as that for codeine.
The usually recommended doses are similar to or
slightly higher than those for codeine in each age
group.’8 However, the safe dose range appears to
be considerably higher than for codeine. The
Food and Drug Administration review panel
found no reports of fatalities, even with doses 100
times greater than the usual adult dose.
Adverse Reactions and Overdose. As noted,
acute overdosage of dextromethorphan can result
in respiratory depression. Presumably this would
be reversible by naloxone, as is true of codeine,
but no clinical data on actual experience were
found. As with codeine, dextromethorphan, at
least in the dog, causes histamine release;
there-fore, it could cause problems in sensitive individ-uals.
Diphenhydramine
Studies in animals support claims for the
anti-tussive activity of diphenhydrammne, a widely
used antihistamine-sedative, but convincing data
chronic bronchitis who were treated with 25 or 50
mg of diphenhydramine every four hours showed
a decrease in frequency, but one half of the
subjects continued to have frequent coughs (ten
per hour) despite drowsiness. The lower dose was
equally effective, but also caused drowsiness and
constipation.
Adverse Effects and Overdosage. The high
frequency of sedation caused by
diphenhydram-me is too familiar to pediatricians to require
comment; in fact, it frequently is the
pharmaco-logic action most desired by the prescriber.
However, infants may exhibit paradoxical
excite-ment and convulsions, and severe overdoses in
children can be fatal or near-fatal. The prominent
anticholinergic (atropine-like) action of most, if
not all, antihistamines frequently causes a drying
sensation of the nose and throat, and it may lead
to a highly undesirable thickening of bronchial
secretions. Because of the latter, many authorities
consider antihistamines to be contraindicated in
asthmatic patients, particularly during the acute
episodes. Moreover, as with codeine and
dextro-methorphan, under certain circumstances
antihis-tamines act to release histamine.
Conclusions and Recommendations
1. Data to establish dosages for the safe and
effective use of codeine, dextromethorphan, and
other antitussives in children-particularly in
infants-are lacking, even though these agents are
widely used and prescribed.
2. Symptomatic treatment may mask serious
underlying disease and may be hazardous,
partic-ularly in infants whose small airways can be easily
plugged with tenacious mucus. Patients with
chronic pulmonary disease (e.g., asthma and
cystic fibrosis) who produce excessive and
thick-ened secretions are at high risk for this potentially fatal effect of antitussives.
3. The few available data suggest a relatively
low therapeutic ratio for codeine in infants.
Centrally active antitussive agents should rarely
be prescribed for children less than 6 to 12
months old.
4. Risk of overdosage is enhanced when
medi-cation is administered by parents for symptomatic relief. Packaging in a container with an integral,
age-specific, calibrated dispenser would diminish
this risk.
5. Physicians caring for children should
evalu-ate the risk/benefit ratio before prescribing or
recommending one of the irrational mixtures such
as the antitussive-expectorant (often plus an
anti-histamine and/or sympathomimetic)
combina-tions currently in vogue. These products cannot
be considered placebos because the ingredients
are pharmacologically active, at least in the
relatively large doses which may be administered to infants and young children.
6. When a valid indication exists for antitussive
therapy, such as a nonproductive cough that
seriously disturbs sleep or school attendance,
either codeine or dextromethorphan, which
appear to be equiactive, should be recommended
in the form of single-ingredient preparations.
When either of these agents is prescribed, instruc-tion should be given to the pharmacist to dispense
the medication in a safety-capped container to
prevent accidental poisoning.
7.
By educating patients and parents, thephysician will aid in diminishing demands to
prescribe antitussive drugs.
COMMITTEE ON DRUGS
Sydney Segal, M.D., Chairman; Sanford N. Cohen, M.D.; John Freeman, M.D.; Reba M. Hill, M.D.; Benjamin M. Kagan, M.D.; Ralph E. Kauffman, M.D.; Albert W. Pruitt, M.D.; Lester F. Soyka, M.D.; Stanley M. Vickers, M.D.
REFERENCES
1. Cough suppressants for children. Br Med I 2:493, 1976.
2. Eddy NB, Friebel H, Hahn KJ, Halbach H: Codeine and its alternates for pain and cough relief. Bull WHO
40:425, 1969.
3. Salem H, Aviado DM (eds): International Encyclopedia of Pharmacology and Therapeutics: Antitussive Agents. Elmsford, NY, Pergamon Press mc, 1970, vol 3 of section 27.
4. Belleville JW, Escarraga LA, Wallenstein SL, Houde RW: The respiratory effects of codeine and morphine in man. Clin Pharmacol Ther 9:435, 1968.
5. Sevelius H, McCoy JF, Colmore JP: Dose response to codeine in patients with chronic cough. Clin Phar-macol Tl,er12:449, 1971.
6. Bellville JW, See JC: A comparison of the respiratory depressant effects of dextropropoxyphene and codeine in man. Clin Pharmacol Ther 9:428, 1968.
7. Winek CL, Collom WD, Wecht CH: Codeine fatality
from cough syrup. Clin Toxicol 3:97, 1970.
8. von Muhlendahl KE, Krienke EG, Scherf-Rahne B, Baukloh G: Codeine intoxication in childhood. Lancet 2:303, 1976.
9. Ivey HH, Kattwinkel J: Danger of Actifed-C. Pediatrics
57:164, 1976.
10. Huffman LH, Ferguson RL: Acute codeine overdose: Correspondence between clinical course and codeine metabolism. Johns Hopkins Med J 136:183, 1975.
11. Findlay JWA, Butz HF, Welch RM: Codeine kinetics as determined by radioimmunoassay. Clin Pharmacol
Ther 22:439, 1977.
12. Soyka LF, Neese AL: Comments by Drs. Soyka and Neese. Pediatrics 57:164, 1976.
abstracted. Clin Pharmacol Ther 15:215, 1974. man, abstracted. Pharmacologist 12:231, 1970. 14. Jaffe JH, Martin WR: Narcotic analgesics and antago- 17. Degkwitz R: Dextromethorphan (Romilar) als
Rausch-nists, in Goodman LS, Gilman A (eds): The Pharina- mittel. Nervenarzt 35:412, 1964.
cological Basis of Therapeutics, ed 5. New York, 18. AMA Drug Evaluations, ed 3. Littleton, Mass, Publish-Macmillan Publishing Co, 1975, p 256. ing Sciences Group Inc, 1977, p 667.
15. Younes HP: Exhilarant cough remedies. N Engl I Med 19. Lilienfield LS, Rose JC, Princiotto JV: Antitussive
280:391, 1969. activity of diphenhydramine in chronic cough. Clin
16. Mansky P, Jasinski DR: Effects of dextromethorphan in Pharmacol Ther 19:421, 1976.
A CASE OF CHOLERA INFANTUM CURED BY LUNAR CAUSTIC IN 1829
Cholera infantum was the name Benjamin Rush gave to the so-called
summer diarrhea of infants and children. This disease was also known as “the
vomiting and purging of children” or “the disease of the season” because of its
regularity in appearing during the summer months.1 The mortality from this
malady during the early 19th century was appalling and its treatment
unscientffic as this case history by Dr. Joseph Skinner of North Carolina of his
daughter’s illness will show.
My daughter Cornelia, aged seventeen months, was attacked about the middle of June, 1829, with the usual symptoms of cholera infantum, . . .occasional vomiting, particularly when any
fluid was taken in the stomach; the matter ejected was sometimes tinctured with bile, but more commonly it was merely the fluid taken in the stomach; the bowels were exceedingly irritable, the evacuations copious, frequent, and very offensive; sometimes of a clay colour, at other times resembling coagulated milk; fever of a remittent form; skin hot and dry, &c. . . On examination
of the mouth, I found the gums tumefied and four molares [sic] making their way through, which was believed to be the exciting cause of the train of symptoms which I have described.
In the treatment of the case my first object was to remove all sources of irritation; accordingly the gums were freely scarified, and the bowels were purged with calomel and calcined magnesia and injections of common salt and warm water. This practice was steadily adhered to for several
days, but failing to produce the desired effect, the symptoms of prostration fast approaching, the pulse indicating a great degree of debility, and the fever assuming a more decided remittent type, indicating the influence of miasmata, .. .I gave the patient half a grain of sulphate of
quinine, with three grains of prepared chalk every two hours, and the sixth of a grain of opium every twelve hours, occasionally using an injection of melted fresh butter when the bowels were painful. .. .In a few days . . .the patient seemed nearly convalescent, but owing to the extreme
hot weather and some little error in diet, the disease returned and very shortly assumed a chronic form. The same treatment was pursued with the addition of brandy and port wine, but with little
or no effect. The disease gradually advanced, the patient became more and more emaciated, and
all the symptoms more aggravated, until about the 10th of September, when her situation became exceedingly alarming. The bowels were exceedingly irritable, the skin hot and dry, the tongue thickly incrusted with a whitish fur, the thirst insatiable, eyes thrown back, and apparently insensible, a profound stupor supervened and the mouth kept steadily open. On examining the evacuations from the bowels I discovered small portions of what I believed to be the internal coat of the intestines. In this state of things my hopes all vanished, and was about to give up my little daughter in the hands of its Creator, but recollecting the utility of lunar caustic,
(nitrate of silver,) in severe cases of aphthae, I determined to give it a trial in this case; accordingly I dissolved one grain in a tea-spoonful of the mucilage of gum arabic, and gave her one every four hours; after she had taken three portions I perceived the most happy effects about to take place, which inspired me with confidence in the remedy and a consequent determination
to persevere, gradually increasing the dose and giving it at shorter intervals. The symptoms now began to abate, sensibility began to be restored, and every circumstance of the case seemed to
promise a speedy convalescence. On the third day from the commencement of the caustic I discontinued it, and from that time the patient rapidly recovered upon a plentiful diet of poultry and sweet potatoes, and now she is a healthy and thrifty child.2
Noted by T.E.C., Jr., M.D.
REFERENCES
1. Raclbill SX: The pediatrics of Benjamin Rush. Trans Stud Coll Physicians Phila 40:151, 1973.
