Methylphenidate and the Paradox of Sedation: A Case Report

Dear Editor,

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children and adolescents. It typically runs a chronic course and is associated with high rates of psychiatric co-morbidities, which necessitates treatment to prevent long-term functional impairment. ¹ Pharmacological treatment options predominantly consist of two types of medications: stimulants and non-stimulants. Though the exact mechanism of action is not understood, stimulants like methylphenidate are believed to increase the concentration of neurotransmitter dopamine in the synaptic cleft by blocking the Dopamine transporter (DAT 1) and Norepinephrine transporter (NET). ² As the name suggests, stimulants lead to a heightened level of awareness, with common side effects being insomnia, appetite disturbance, stomach ache, headache, and dizziness. ³ However, rarely, stimulant medications like methylphenidate may cause paradoxical sedation as an adverse reaction challenges the conventional understanding of their pharmacological action.^4,5 This case summary details a patient who had sedation following the administration of methylphenidate.

Case Report

A 10-year-old adolescent boy, born out of a non-consanguineous marriage with no perinatal complications and normal development till the age of around five years and belonging to a lower socio-economic status, ⁵ presented to us with complaints of difficulty in concentrating on tasks. He had a family history of hypertension and thyroid disorder in two of his third-degree and one first-degree relatives but no history of any psychiatric or neurological illness in any of the family members. The informants reported no history of any drug or food allergies. It was noted that his notebooks would be shabby, and most of his assignments would be left incomplete despite his parents making him sit and do his homework, but he would keep squirming around and ignoring details. He could grasp concepts quickly, but his grades began to fall, and he barely managed to pass the examinations apart from having difficulty organizing things and waiting for his turn. The falling grades and frequent reprimands at school worsened in one year for which the patient was brought for evaluation. A general physical examination revealed a prominent upper jaw, which was deemed to be constitutional without any airway obstructing pathology after pediatric consultation, and a detailed neurological examination ruled out any focal neurological deficits. No abnormality was detected in routine blood investigations, including thyroid function tests, but no further investigation could be done due to logistical issues.

The child was diagnosed with “F90.0 Hyperkinetic disorder with disturbance of activity and

attention” according to ICD 10 (Clinical Descriptions and Diagnostic Guidelines) criteria. ⁶ Treatment was initiated with Tab Methylphenidate 5 mg sustained release formulation once in the morning daily along with behavioral interventions. ³ The compliance to medications was ensured by the patient’s mother, who did not observe improvement in medications. However, she observed that the child would get drowsy within 20–30 minutes before sleeping for the next two to three hours. He would be agitated 10–15 minutes after waking up but would become like his usual self with no sequelae. No complaints of sudden staring spells, unresponsiveness, jerky movements, unusual motor activity, and urinary or fecal incontinence were reported. He used to sleep for seven to eight hours daily, only at night. Caregivers reported that this phenomenon did not occur when the medications were skipped, but reappeared upon resuming them and persisted until the follow-up visit two weeks later, when the medication was changed due to these concerns. The patient was then started on tablet Atomoxetine at the dose of 5 mg/day (patient’s weight was 26 kg), and improvement was noted without sedation; however, the child was lost to follow-up.

Discussion

Methylphenidate is a US FDA-approved first-line drug for the treatment of ADHD in children as well as adults and a second-line treatment for narcolepsy to promote wakefulness and manage excessive daytime sleepiness. ⁷ The common CNS side effects of this medication are insomnia, nervousness, dizziness, headaches, and growth retardation.^8–10 Patients with ADHD have been known to have sleep disturbances, and it has been found that they are drowsier during the day as compared to healthy people, though it is helped by stimulant treatment rather than exacerbated by it.^4,11,12 One review compared the effects of non-stimulant atomoxetine with stimulant Methylphenidate and concluded that the latter had more statistically significant treatment-emergent side effects for insomnia and decreased appetite as compared to Atomoxetine.^13,14

The Naranjo Adverse Drug Reaction (ADR) Probability Scale, which is equally reliable to detailed algorithms, had a score of seven in our case, indicating that the drug might be a probable cause of this reaction.^15,16 The responses suggest that the adverse event appeared after the suspected drug was administered, improved upon discontinuation, and reappeared when re-administered. Additionally, alternative causes that could explain the reaction were considered but all relevant investigations to rule them out could not be done. However, there was no objective confirmation or evidence related to dose-response relationships.

A similar case had been described of a six-year-old child with ADHD and co-morbid autism spectrum disorder after using immediate-release mixed amphetamine salts, which resolved after switching to atomoxetine. The authors had concluded that it was a definite adverse reaction based on a Naranjo scale score of 9.^15–17 Sedation after taking an immediate-release formulation of methylphenidate may lead to drowsiness as the drug’s effect wears off, like a rebound phenomenon. However, it usually occurs after around five to six hours. ¹⁸ Rapid metabolism of the drug has also been postulated in a minority of the patients who develop drowsiness as the drug’s effect wears off. ¹⁹ A low dose of stimulant leading to transient sedation and lethargy was demonstrated where 13 out of 20 normal adults in an experimental study exhibited lowered electrical brain activity along with dysphoric mood immediately after taking the stimulant drug Dextroamphetamine, though later had heightened alertness. ²⁰ The authors used contingent negative variation, an event-related electrical brain wave, to indicate alertness. ²¹ Concerning our case, the agitation might be the expression of a dysphoric mood state as it was transient, and the patient did not have any other symptoms of affective disorder.

A few important limitations should be acknowledged as being a case report, its findings are not generalizable, and its descriptive nature makes it challenging to establish a direct causal relationship between methylphenidate and paradoxical sedation. Also, the diagnosis was made by a single clinician, which impacts the inter-rater reliability and higher investigations, such as polysomnography, EEG, and neuroimaging, which could have helped to rule out differential diagnosis but could not be performed due to logistical and financial constraints. The observed association between methylphenidate and paradoxical sedation may have been incidental rather than causal.

Conclusion

This case highlights an unusual adverse effect of sedation associated with methylphenidate methylphenidate in a child with ADHD, as determined by a probable causality score on the Naranjo Adverse Drug Reaction Probability Scale. While methylphenidate is widely recognized for its efficacy in managing ADHD symptoms, sedation remains a rarely reported side effect. The resolution of symptoms upon switching to atomoxetine underscores the importance of individualized treatment approaches and careful monitoring of adverse effects. Clinicians should remain vigilant for atypical reactions to stimulant medications and consider alternative treatment options when necessary to optimize patient outcomes.

Supplemental Material

Supplemental material for this article available online.