Allergic Reaction to Medication After Years of Taking It: What To Do Next?

Chief Complaint and Presenting Problem

T. was a 10.5-year-old right-handed fifth grade boy in regular education who had been diagnosed with attention-deficit/hyperactivity disorder (ADHD), combined presentation. T. had been referred to the child and adolescent psychiatry outpatient clinic for his extremely hyperactive behavior and inattention in school.

History of Present Illness

T.'s initial referral to the clinic occurred when he was 6 years old because his parents were very concerned about his behavior in school. In kindergarten he had difficulty paying attention and sitting still. He was reported to run out of the classroom without knowing where he was going. He had problems keeping his desk and his backpack organized, always having paper stuffed in every pocket. He did not like putting things away because it took too much time. At school he had to change into gym clothes, and that took so much time that he often missed part of class. He was reported to be very impulsive, touching things that did not belong to him, tapping other kids; at times, he was reported to become very aggressive. T. also experienced difficulty with writing at school and at home with homework assignments, and his parents were concerned about how he would do academically in first grade. In addition, T. was reported to have had longstanding problems falling asleep at night—taking up to 2 hours at times to calm down and relax to fall asleep. Parents reported that there were some kids teasing T. about his behavior, which caused him to become aggressive occasionally during kindergarten.

T. was initially evaluated at age 5 years by a child and adolescent psychiatrist on the west coast and was subsequently diagnosed with ADHD. He was reported to have no signs or symptoms of autism spectrum disorder, anxiety, depression, suicidal behavior, or psychotic symptoms.

T. was subsequently started on dextroamphetamine/amphetamine immediate release (IR) and although he generally tolerated it, mother believed it made him a bit aggressive. Upon referral to the clinic, he was prescribed extended release (XR) mixed amphetamine salts 20 mg daily with a dextroamphetamine/amphetamine IR booster of 5 mg in the afternoon as needed for homework. This was helpful for his behavior in school; however, he was reported to have significant rebound hyperactivity and impulsivity in the afternoon, and became extremely moody and irritable when the medication wore off. Clonidine 0.1 mg was added at bedtime to help with sleep initiation and the irritability as the stimulant's effect was declining.

T. reportedly did well for most of first grade, with some residual behavioral problems, but mother continued to dislike the associated effects on mood. Over time, clonidine was increased to 0.1 mg twice daily to address T.'s impulsivity at school. T. was switched to lisdexamfetamine between the summer of first and second grade; therapeutic effect was modest, but adverse effects improved. However, once school started, the lisdexamfetamine 30 mg did not seem to be helpful for schoolwork. A higher dose caused extreme loss of appetite and weight loss of ∼2 kg.

T. was subsequently switched to 18 mg methylphenidate osmotic release oral system (OROS) XR with a methylphenidate booster IR in the afternoon. T. no longer needed the daytime dose of clonidine, so it was continued only in the evenings for sleep.

In third and fourth grade, T. continued to perform extremely well in school and in after-school sports, excelling in soccer. He became an avid reader, made many friends, and overall was an A student. The methylphenidate OROS XR was gradually increased over the years to a maximum of 45 mg daily. When T. was 9 years old and in fourth grade, he reportedly experienced recurrence of impulsivity in school, and clonidine 0.1 was restored. He continued to thrive and perform well on the methylphenidate XR with minimal adverse effects. At some point, clonidine was replaced with guanfacine.

Over winter break when T. was 10 years old, his stimulant was discontinued for a medication holiday; however, guanfacine was continued. Both parents were reportedly surprised at how much happier and how much less anxious T. was when he was off the stimulant.

T. had reportedly never complained about anxiety before, but he had been taking a stimulant for 4 years and had the methylphenidate OROS XR for >2 years. Upon returning to school for fifth grade, mother restarted the methylphenidate XR and noted that T. appeared more irritable and anxious. Mother reported that during the first week back on the medication after a 3-week break, he developed three significant rashes on his back, which seemed to dissipate over the evening and were gone by morning. On the fourth day on methylphenidate XR, T. reported he felt itchy all over. A maculopapular rash was noted on his back. T. subsequently refused to take the medication, saying it made him feel terrible. Once the medication was discontinued, the rash disappeared, and T. was back to his usual mood and attitude. Mother then tried to introduce a lower dose—27mg—and he reportedly experienced some minor foot swelling (unclear whether related to medication—but never had prior and had not experienced again since stopping the medication)—and this is when mother became concerned about a possible allergy.

Mother was extremely hesitant to try T. on another stimulant, concerned about the development of what seemed to be an allergy after >2 years on the medication. Guanfacine XR 2 mg at bedtime was prescribed, but T. became too sedated; when the dose was split into twice daily, he reportedly could not sleep at night and was unable to focus at school. Several weeks later, dexmethylphenidate XR 10 mg daily was prescribed, with a dexmethylphenidate booster of 5 mg IR in the afternoon as needed for homework. He also was continued on the guanfacine at bedtime that had been working well. T. experienced no further rashes or leg swelling and was performing well in school without significant inattention or hyperactivity.

Past Psychiatric History

There was no psychiatric history other than that described previously. T. was evaluated by a child and adolescent psychiatrist on the west coast at age 5 years, and after relocation to the southeast at age 6 years, he was followed in the outpatient clinic at a teaching hospital. There was no history of hospitalization or emergency department visits.

Developmental History

T. was the product of an uncomplicated pregnancy and delivery at 2.7 kg and 12 oz. Motor and language milestones were met on time, with walking and talking at about a year.

Educational History

T. was currently in fifth grade at a public elementary school. He was in regular education classes and continued to read a grade or two above his level. He had received speech therapy in the past year for minor hearing loss after having a bone removed from his ear.

Social History

T. lived with mother and father; father traveled back to the west coast regularly, where he held a job. T. and mother traveled on vacations to be with the father if he was working. There was no history of abuse or exposure to trauma.

T. was reported to have many friends and was extremely close to his grandparents on both sides of the family. There were no siblings.

Family History

Mother reported a history of ADHD that was not treated when she was younger. Maternal grandmother was reportedly diagnosed with anxiety in the past. Several paternal uncles were reported to have had depressive disorders.

There was no known family history of autistic spectrum disorder or other psychiatric disorders.

Medical History

T. was diagnosed with congenital cholesteatoma at age 7 years with moderately severe conductive hearing loss in one ear. He underwent middle ear exploration surgery, tympanoplasty with ossicular chain reconstruction prosthesis, and ear fascia cartilage graft. T. had very mild hearing loss in his one ear, but excellent word understanding in both ears.

T. had no history of any major childhood illnesses and had received all his appropriate vaccinations. He was allergic to cefdinir and possibly methylphenidate OROS XR.

Mental Status Examination

T. was a fairly cooperative boy, with no dysmorphic features, whose response to questions was brief but accurate. T. sat calmly in a chair reading books during the entirety of the visit. No tics or other abnormal movements were apparent during the examination. During the interview, eye contact was appropriate when T. was asked direct questions by the examiner. Prosody, rate, and rhythm of his voice were all normal. Speech was spontaneous in nature and easy to understand.

T. was oriented to time, day, place, and situation. Memory was intact. T. denied auditory or visual hallucinations. His pencil grip and drawing of a person were appropriate to age (6 years when first evaluated). Neurological examination was within normal limits. T's thought process was logical, goal directed, and focused on reading Captain Underpants. There were no obsessions or compulsions, ruminations, or delusions. There was no evidence of suicidality or homicidality.

Brief Formulation

In summary, T. was a 10.5-year-old boy who met diagnostic criteria for ADHD, combined presentation. Notable were hyperactivity, impulsivity, and inattention that caused difficulty both at home and school with onset at age 5 years. These symptoms had persisted over the years although they fluctuated in severity.

From a biopsychosocial perspective, biological factors were contributory. Family history of ADHD and affective illness rendered T. vulnerable to these disorders. Mild hearing loss secondary to the cholesteatoma may have exacerbated his inattention and ADHD symptoms. Father's time spent away from home may have been anxiety producing for the child that could also have exacerbated his symptoms. Fortunately, T. had several strengths in the academic and social domains that were strengthened with treatment.

Interestingly, T. had been maintained on methylphenidate OROS XR for ∼3 years with good clinical response. He apparently began to develop sensitivity to the medication after taking his first 3-week break off it in the past year. After restarting the medication, T. developed a significant rash and foot edema that seemed directly related to medication use. Rash and swelling seemed to resolve after discontinuation.

Multi-Axial Diagnoses

Discussion

This case represents an interesting and fairly uncommon occurrence of cutaneous reaction after the use of a stimulant for the treatment of ADHD. ADHD is one of the most common neurodevelopmental disorders of children between the ages of 3 and 17. Up to 8% of children are diagnosed with this disorder with as many as 50%–60% having persistent symptoms into adulthood. Psychopharmacological intervention is considered the primary treatment of ADHD for most children and adolescents, and for several decades, methylphenidate has been a first-line therapy (Warshaw et al. 2008, 2010). Stimulant treatment is characterized by 70%–80% response rate in affected children. The most common adverse effects have historically been decreased appetite, weight loss, sleep disturbances, and nausea. There have been case reports, but very few studies, demonstrating cutaneous eruptions caused by XR methylphenidate (not including the transdermal formulation) (Kaya and Coskun 2016).

Not surprisingly, there are many reports of transdermal methylphenidate (Daytrana) causing skin irritation or rash, but very few of skin eruptions after oral medication and almost none after 2+ years of treatment. Interestingly there were no reports of a similar rash related to amphetamine usage, only methylphenidate (Kaya and Coskun 2016).

As might be expected, there are many reports and studies looking at allergic reactions through contact with the skin with transdermal application of methylphenidate. But neither allergic contact dermatitis nor allergic contact urticaria, which have been reported with transdermal use, characterized T's rash that was likely secondary to oral methylphenidate (Warshaw et al. 2008). Heinzerling et al. (2011) reported a case of a 9-year-old who developed pustules on his skin after 6 weeks of treatment with methylphenidate. After discontinuation and 3 days of prednisone, skin erythema and pustules resolved.

Allergy to methylphenidate seems to be extremely rare, especially dermatologic reactions (Heinzerling et al. 2011). There was another report of an 8-year-old child who only experienced a skin reaction with the XR methylphenidate, but not with the IR formulation. This reaction did occur directly after starting the XR formulation, but the child had been stable on the IR formulation for the previous 2 months. The question this case report raised was whether the reaction was from the methylphenidate itself or from a substance in the vehicle in the OROS formulation. Methylphenidate OROS does contain several substances in the capsule—including butylated hydroxytoluene, carnauba wax, cellulose acetate, hypromellose, phosphoric acid, poloxamer, polyethylene oxides, povidone, propylene glycol, sodium chloride stearic acid, succinic acid, synthetic iron oxides, titanium dioxide, and triacetin; it is possible that any of these or a combination may have been the inducing agent (Coskun et al. 2009).

One concern about T.'s rash is that he was also taking guanfacine during this time. He did not have skin reactions while he was taking guanfacine alone, which suggests that the reaction was more likely associated with methylphenidate. But it is unclear whether there was a potential drug–drug interaction with the two medications, even though T was stable on both of them for years before the rash occurred (Coskun et al. 2009).

Interestingly, there is a case report of desensitization of a methylphenidate-induced rash, where this was the only medication that was effective in treatment of the patient's symptoms. In this case, methylphenidate was given in increasing dosages, 30 minutes apart, for a 10-day period. Once the child reached 10 mg daily without developing a rash, she was continued on this dose for 3 months with no subsequent rash (Confino-Cohen and Goldberg 2005).

In summary, this case illustrates a temporal correlation between rechallenge with methylphenidate OROS XR and development of a skin rash and feet swelling. Although T. was taking this medication without adverse effects for >2 years, it seems that the several week break from medication potentially rendered T. vulnerable to the allergic reaction upon rechallenge. Increased vigilance regarding adverse dermatological reactions that may develop after long-term exposure to stimulants is recommended,