Hypersensitivity to Methylphenidate and Dextroamphetamine: A Report of Two Cases

PEDIATRICS Vol. 59 No. 1 January 1977 115

precipitate clinical diabetes in an individual with

latent or “cheniical” diabetes. However, the role

of viral infection as a true etiological factor in

juvemiile diabetes remains to be provemi. Diabetes

mriellitus resulting from acute pancreatic $-cell

destruction by f-tropic virus such as is seen in

experimental animals’ niight coincide with the

seasonal pattern of virus infection in general but,

if slow vinis or post-infectious autoimmiiune

processes are responsible for the induction of the

diabetic state, the patterns of onset of clinical

diabetes niellitus and of comiimiion viral infections

would not be expected to coincide.

CONCLUSIONS

A distinct seasonal incidence pattern in the

onset of detection of diabetes mellitus among

school-age children is apparent. However, the

true picture of seasonal variation in the onset of

symnptonis and detection of juvenile diabetes

mellitus in this coumitry may have to await the

establishniemit of regional or national diabetes

registries similar to those imi Great Britaimi and

Eire. Such data when available must be

inter-preted with caution so that aggravating,

precipi-tating, and true etiological factors underlying

seasonal variation in the onset of juvenile diabetes mellitus are distimiguished.

DUNCAN R. MACMILLAN, M.D., F.R.C.P.(C)

MARCOS KOTOYAN, M.D.

DANIEL ZEIDNER, M.D.

BIJAN HAFEZI, M.D.

Departmiient of Pediatrics, Divisiomi

of Endocrinology,

University of Louisville School of

Medicine Louisvi!!e, Kentucky

ADDRESS FOR REPRINTS: (D.R.M.) Departmemit of Pedi-atrics, University of Louisville School of Medicine, P. 0. Box

1055, Louisville, Kentucky 40201.

REFERENCES

1. Steinke J, Taylor K\’: Viruses and the etiology of

diabetes. Diabetes 23:631, 1974.

2. Adams SF: The seasonal variation in the onset of acute

diabetes. Arch Intern Med 37:861, 1926.

3, Soniersalo 0, Hiekkala H, Rantakallio P, Tuuteri L: Studies in childhood diabetes: Review of 359 cases.

AIlil Paediatr Fenn 6:253, 1960.

4. Bloom A, Hayes TM, Gamble DR: A register of newly

diagnosed diabetic children.

mt

20:20, 1975.

5. Gamble DR. Taylor K\\’: Seasonal incidence of diabetes

mellitus. Br Med J 3:631, 1969.

6. Huang SW, MacLaren NK: Insulin-dependent diabetes:

A disease of autoaggression. Science 192:64, 1976.

Hypersensitivity

to Methylphenidate

and

Dextroamphetamine:

A Report

of

Two

Cases

Among the adverse reactions to

methylpheni-date and dextroamphetaniine are those which

strongly suggest an allergic basis. With regard to

methylphenidate, most reports of allergic

reac-tions in children have involved the skin. Thus,

Rothschild and Nichol’ reported the case of a

5-year-old girl who developed conjunctivitis and

experienced formicatiomi while receiving 5 mug of

methyiphenidate twice daily. Lytton and Knobel2

described a case of urticaria following

methyl-phenidate treatment; and Gross and Wilson1

noted the occurrence of a skin rash in a child. There are also indications that methlyphenidate

allergy may occur amomig adults. For example,

1 reported on a 73-year-old woman who

developed exfoliative dermatitis while on that

medication. Ciba-Geigy Pharniaceuticals has

pro-vided us with unpublished reports of 24 cases,

accumulated since 1956, of suspected adverse

reactions to miiethylphenidate amiiong adults amid

children.3 These include skin rashes-includimig

those due to photosensitivity-urticaria, amid

vasculitis. However, not only do many of these

cases lack important supporting details which

would imiiplicate methylphenidate, but a miumber

of patients concomitantly received other drugs.

Reports of dextroamphetamine allergy are also

scarce. Weiss et a!. have described one case of

drug-induced urticaria in a child, while both

atopic amid nonspecific dermatitis have been

reported amiiong adult patients.7 III

In this paper we present the cases of two

children who were treated with niethylphenidate

for hyperkinetic behavior disorders and who

showed consequent allergic manifestations. One

child developed angioneurotic edema, amid the

other showed urticaria. \Vhen the first patient

was subsequently placed on dextroamphetam me,

he also developed urticaria.

CASE REPORTS Case 1

Q. V., a 9-year-old 1)lack boy, was referred to the Child

Behavior Research Unit at Downstate Medical Center by his

school because of restlessness, overactivity, and fighting. The

boy’s mother reportedly becanie aware of his l)ehavior

dis-order when he was 6 years of age, but he had received no

prior treatment with either methlphem1idate or

dextroam-phetanTune. Physical and mleurologic examination were

within normal limits. However, Q. V. was reported to have a

history of penicillin allergy.

Upon referral, a diagnosis of hyperkinesis was made and the child was placed on 5 ing of methylphemlidate twice each

day (nloming and noon). After two weeks of therapy, his

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116 METHYLPHEN IDATE AND DEXTROAMPHETAMINE

mother reported some behavioral improvement; however,

his impulsive behavior did mlot diminish. Methylphenidate

was increased to 7.5 mg twice each day. One week following

the increase in dose, the patient’s mother reported an

adverse behavioral reaction (e.g., temper tantrums increased, and crying spells were noted). Medication was subsequently reduced to 5 ITIg twice each day for the next week. At the end

of that time, approximately three to four weeks after the

initiation of methylphenidate therapy, the child’s mother

reported that he developed a swelling of the penis and of the left side of the face. She thereupon stopped giving the medication, and the swelling sul)sided. Under close observa-tion, we then admriinistered approximately 2 mg of methyl-phenidate 111 a single dose. When no allergic response was

noted, we had the mother give him approximately 2 mg the

following morning, and an additional 5 mg dose that

afternoon. Shortly after the afternoon dose, the patient’s upper lip suddenly swelled; however, no involvement of the penis was noted. His mother again stopped the medication, and tile patient was subsequently placed on 5 mg of

dextro-amphetamine twice each day. Within the first week of this

regimen, the patient developed an urticarial reaction

char-acterized by his mother as “itching welts” over his trunk.

Dextroamphetamine was discontinued.

Case 2

P. H. was a6-year-old black boy who was referred to the Minimal Brain Dysfunction Clinic at Kings County Hospital l)ecause of hyperactivity. The patiemlt had no prior history of

exposure to l)5\chostillltilant drugs, and the history revealed

no specific (1mg allergy, although at 4 years of age he had developed an unexplained skill rash, acconipanied by puffing

of the face. P. H. was placed on 5 mg of methylphenidate three times each day (breakfast, noon amld 3 PM). During the

first day of medication on his return from school, he coin-plained to his grandmother of itching legs and arms. She

noted that there were welts on the upper and lower

extremi-ties. Additional adverse side effects reportedly included sleepiness while at school, crying spells, and “shaking as if he

had a chill. On the second day of drug therapy, the boy’s

grandmother noticed that the welts had spread to his neck and face, and they appeared to be “turning into blisters. “ She thereupon withheld nedication, and by the third day all skin manifestations had disappeared. P. H. was then seen by a

pediatrician, and the physical examination revealed no

abnormality. This patient has subsequently been receiving 25 mg of imipramine twice each day without adverse seque-lae.

TESTING SERA FOR

ANTIMETHYLPHENIDATE ANTIBODIES

Subsequent to the above clinical findings, we

sought to identify circulating serum antibodies to

methylphenidate in these children through a

radioimniunoassay procedure. Sera from these

children were kept frozen for four months prior to

the assays; amid the sera from five control children

were assayed along with those of our patients. In

additiomi, assays were done using blank samples.

The method described below has been checked

amid found to be satisfactory with rabbit

antihalo-peridol and antiimnipramiiine antibodies, and with

labeled haloperidol and imipramnine.

The presence of circulating antibodies was

investigated by incubating diluted samiiples with

solutions of amitigen ‘(methylphemiidate) labeled

with carbon 14, in a medium buffered solution of

normal human serum imi salimie (containing

EDTA). After combining the incubation mixtures

with a solution of activated carbomi (Darco 60,

Fisher), the resulting agglutinated complexes of

antigen-antibody should remain iii suspension.

However, free, nonagglutmnated miiolecules of

antigen should bind to activated carbon and formii

a sediment with it durimig centrifugation. The

amoumit of radioactivity remiiaining imi the

supemna-tant is the measure of the amoumit of circulating

antibodies present in assayed serum. The emitire

assay procedure was conducted in a cold roomii.

Serum samples froni the patients and controls

were analyzed in duplicate, and the blanks were

assayed in triplicate. No difference in

nonprecipi-table radioactivity was foumid amomig the patiemit

sera, control sera, and blanks. Readings on the five

control sera ranged from 416 ± 25 to 468 ± 51

counts per minute (cpm), while those on the sera

fromn

Q.

and 465 ± 18 cpm, respectively-well within the

ranges of the controls.

DISCUSSION

The cases reported above contribute to the

very few observations associating

mnethylpheni-date and dextroamphetamiiimie to allergic

manifes-tations. Both children had histories of allergic

reactions, one to pemicillimi amid the other to an

unknown agent-which suggests the possibility of

ami allergic diathesis fri the latter case. However,

mio other allergic condition was presemit in either

child. Since methylphenidate is a structurally

altered aniphetamiiimie it is possible that its

struc-tural simiiilarity to dextroaniphetamine niight be

related to Q.V.’s sensitivity to both drugs.

Inves-tigatiomi by Ciba-Geigy has revealed no reports of

allergic reactions to that particular batch of

niethylphenidate which niight iniplicate

imniu-nogenic imlipurities imi the manufacturing process.

Nor were there other reports of urticaria

asso-ciated with the use of dextroamphetamimie at our

hospital center. Also, according to it is

unlikely that the excipiemits used in miianufactur-ing these drugs are imiiniunogemiic.

Our failure to find amitibodies to

miietIilphemii-date is of note amid may be based on a miumber of

possibilities. For example: (1) the amitibody may

be tissue-bound rather than circulating; (2) the

antigen may be one of methlphenidate’s miiany

miietabolites’’’2; or (3) the response milay be

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PEDIATRICS Vol. 59 No. 1 January 1977 117

secondary to a primiiary drug-tissue reaction.’3 The

latter instance, in which histamine is released

fromii niast cells, seemiis unlikely since if these two

pschostimiiulamits were implicated in that way,

one would anticipate a niuch higher prevalence

of reported allergic miianifestations.

Although this report is not addressed to the

etiology of hyperactive behavior, within the

context of a discussion omi drug allergy a comment

on recent speculations pertaining to food

addi-tives as etiologicall associated with hyperactive

behavior is perhaps of interest. It has been our

current experience that most parents of

hyperac-tive children are concerned about this possibility

and seek imiformation in regard to the possible

treatnient of their children by dietary methods.

The etiology of hyperactivity in children is in

milany instances obscure. Food additives as a

causal factor in Iiyperactivit is a reasonable

hypothesis and worthy of the controlled

investiga-tioii which it is currently receiving. On the other

hamid, such dietary restrictions imlipose a

signifi-cant miionitoring burden on parents imi order to

insure the compliance of their child and may add

to the psychological duress which most families

with behavior disordered children already

experi-emice. In the absence of evidence to support the

effectiveness of dietary treatment it is our view

that it is most prudemit to await the results of the

studies being comiducted before encouraging this

difficult treatmiient approach.

Despite the apparently low imicidence of

allergic reactions to either methylphenidate or

dextroamiiphetaniine, we feel it is important to

bring the possibility of such sequelae to the

attention of other clinicians. We would also

welcomiie hearing fromii others who have noted

allergic responses to methylphenidate, so that

their incidence might be specified more

confi-demitlv.

Brooklyn, New York

J

MARIA

J.

OLIVER DAVID, M.D.

BERTRAND G. WINSBERG, M.D.

Child Psychiatric Evaluatiomi

Research Unit,

New York State Departnient of

Mental Hygiene,

Division of Child Psychiatry,

Dowmistate Medical Center

ADDRESS FOR REPRINTS: (J.S.) Child Psychiatric

Eval-uatioii Research Unit, New York State Department of

Mental Hygiene, 524 Clarkson Avenue, Brooklyn, New York

11203.

REFERENCES

1. Rothschild CJ, Nichol H: Allergic reaction to

methyl-. phenidate. Can Med Assoc J 106:1()64, 1972.

2. Lytton GJ, Knobel M: Diagnosis and treatment of

behavior disorders in children. Dis Ners’ Syst 20:334, 1959.

3. Gross MB, Wilson WC: Minimal Brain Dysfunction.

New York, Brunner/ Mazel, 1974.

4. \Veil AJ: Exfoliative derniatitis after medication with

methylphenidate HCL (Ritalfi). Ann Allergy

26:402, 1968.

5. Krause RE: Personal communication, Ma 30, 1975.

6. Weiss G, Minde K, Douglas V, et a!: Comparison of the

effects of chlorpromazine, dextroamphetamine and methylphenidate on the behavior and intellectual

functioning of hyperactive children. Can Med

Assoc J 104:20, 1971.

7. Kauvar 55, Henschel EJ, Ravin A: Toxic eruptions due

to amphetamine sulfate and its analogue

dextroam-phetamine sulfate. JAMA 122:1073, 1943.

8. Caffev EM Jr. Klett CJ: Side effects and laboratory

findings: Combined drug therapy of chronic

schizo-phrenics. Dis Nerv Syst 22:370, 1961.

9. Osserinan KE, Dolger H: Obesity in diabetes: A study of

therapy with anorexigenic drugs. Ann Intern Med

34:72, 1951.

10. Amphetamines in treatment of obesity associated with

diabetes. Nutr Rev 9:198, 1951.

11. Perel JM, Dayton PC, Goldberg LI: Studies with

niethylphenidate: Drug interactions and nletabo-lism. In, Seller EM (ed): Addiction Research

Foun-dation Symposia. Toronto, Canada, Addiction

Research Foundation, 1975, p 182.

12. Faraj BA, Israili ZH, Dayton PC, Perel JM: Metabolism and disposition of methylphenidate- ‘C: Studies in mami and animals. J Pharm Exp Ther 191:535, 1974.

13. Parker CW: Drug allergy. N Engl J Med 292:732,

1975.

Dextromethorphan

Toxicity:

Reversal

by

Naloxone

The use of naloxone hydrochloride (Narcan) as

a specific narcotic antagomiist is well known.’ Its

only denionstrable effect is narcotic antagonism,

and therefore, it is recommended as the antidote

for intoxication by miumerous miarcotic

prepara-tions. These include pentazocine,4

propoxy-phene,3 amid other synthetic narcotics as well as

naturally occurring narcotics. However, to our

knowledge, there have been no reports in the

literature or through the National Poisomi Control

Network documentimig the use of naloxone iii

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1977;59;115

Pediatrics

Jeffrey Sverd, Maria J. Hurwic, Oliver David and Bertrand G. Winsberg

Hypersensitivity to Methylphenidate and Dextroamphetamine: A Report of Two Cases

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Pediatrics

Jeffrey Sverd, Maria J. Hurwic, Oliver David and Bertrand G. Winsberg

Hypersensitivity to Methylphenidate and Dextroamphetamine: A Report of Two Cases

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