Methylphenidate is FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults and as a second-line treatment for narcolepsy in adults. Children with a diagnosis of ADHD should be at least six years of age or older before being started on this medication. The treatment of both ADHD and narcolepsy have significantly better outcomes when used concurrently with nonpharmacologic treatments (i.e., social skills training in ADHD or sleep hygiene measures in narcolepsy).
Off-label uses of methylphenidate include as a treatment for fatigue in cancer patients, refractory depression in the geriatric population, apathy in Alzheimer disease, and to enhance cognitive performance (i.e., memory). Since it has the potential of being abused as a cognitive enhancer, it is a Schedule II substance that is federally controlled. The efficacy of methylphenidate for its off-label uses varies from limited to moderate. Most of these relatively newer uses are still being studied and implemented into clinical practice.
Methylphenidate blocks the reuptake of two neurotransmitters, norepinephrine (NE) and dopamine, by presynaptic neurons. More specifically, it inhibits the transporters of these neurotransmitters, increasing the concentration of dopamine and NE in the synaptic cleft. Overall, this creates its classic stimulant effect within the central nervous system (CNS), mainly in the prefrontal cortex. It is chemically derived from phenethylamine and benzylpiperazine. It undergoes metabolism by the liver to ritalinic acid through a process called de-esterification via carboxylesterase CES1A1. Compared to other medications (i.e., amphetamines) that are phenethylamine derivatives, methylphenidate appears to increase the firing rate of neurons. It is also a weak agonist at the 5HT1A receptor, which is an additional mechanism that contributes to the increased levels of dopamine.
With the increase in dopamine levels, methylphenidate can provide neuroprotection in certain conditions like Parkinson disease, which involves loss of dopaminergic neurons, and methamphetamine abuse. This occurs not only through its direct inhibition of the dopamine transporter but also via indirect regulation of the vesicular monoamine transporter 2. The combined interactions methylphenidate has on both of these transporters reduces the amount of dopamine that accumulates within the cytoplasm in patients with these conditions, thereby preventing the formation of reactive oxygen species that would otherwise be dangerously toxic to the brain.
The therapeutic dosages for ADHD or narcolepsy that are prescribed by physicians are not harmful enough to activate the reward system within the CNS, known as the nucleus accumbens. However, excessively higher dosages taken by those who intentionally abuse the drug lead to an overexpression of deltaFosB, a transcriptional activator, in certain neurons within the striatum. This accumulation of deltaFosB in the nucleus accumbens activates a series of signaling cascades that further triggers the addiction.
For medical purposes, methylphenidate is mainly given orally or, less commonly, as a transdermal patch. There are multiple oral formulations available that are divided into how quickly the drug is released: immediate (IR), extended (XR or ER), and sustained. Two of the more unique formulations of methylphenidate is its ER sphenoidal oral drug absorption system that has a bimodal release and the osmotic (controlled) release delivery system. For children, there are chewable tablets (either IR or ER) as well as an IR solution. The dosages range from 5 mg to 60 mg. Doses should not exceed 72 mg, the maximum dose of the ER tablet. If the transdermal patch is given, then it is important that the patient is aware to place the patch on the opposite hip each time to achieve its full effect. Those who abuse methylphenidate for recreational purposes prefer to use either the intravenous (IV) or intranasal route.
Insomnia and nervousness are the most commonly reported adverse effects in patients on methylphenidate. Other frequent side effects mainly involve the CNS (dizziness, headache, tics, restlessness/akathisia), gastrointestinal (nausea/vomiting, dry mouth, decreased appetite, weight loss, abdominal pain) and cardiovascular systems (tachycardia, and palpitations). Dermatologically, patients can complain of excessive sweating and ulceration of their digits. Some patients may even develop blurry vision or decreased libido. Patients are more prone to become easily agitated, irritable, or depressed and go through mood swings/lability). While many of the common side effects can be relieved by adjusting the dosage or avoidance of an afternoon or evening dose, some must be treated emergently to prevent complications. While it rarely occurs, priapism is a medical emergency that requires immediate attention.
It is important to note that there have been reported cases of sudden death in both children and adults with a pre-existing structural cardiac abnormality. Stroke and myocardial infarction also have been noted in adults. Due to the risk of such fatal side effects, it is advised to avoid methylphenidate in patients with a structural cardiac abnormality, cardiomyopathy, or arrhythmias.
Methylphenidate must not be used if a patient is currently on monoamine oxidase inhibitors (MAOIs). There should be a minimum of at least 14 days after discontinuation of MAOIs before methylphenidate can be considered a safe treatment option to begin due to the risk of hypertensive crisis. Medical conditions that are not compatible with methylphenidate include glaucoma, severe hypertension, motor tics, and Tourette syndrome or a family history of Tourette syndrome. If a patient is noticeably anxious, tense, or agitated, then seek alternative treatment options. However, it can be given cautiously in patients with a history of bipolar disorder or psychosis as long as physicians are wary of mania or psychotic episodes induced by the medication. Any patient who develops a hypersensitive reaction to methylphenidate or a certain component of a formulation should have the medication immediately discontinued and be switched to another pharmacologic agent. Children under the age of six years old should not be prescribed this medication as there are limited studies to prove its safety or benefit, and it could possibly cause learning impairments.
A complete blood count with differential should be obtained periodically for those on methylphenidate. At each visit, the main vitals to note are blood pressure and heart rate, especially in patients with underlying hypertension, heart failure, a recent MI, or ventricular arrhythmia as slight elevations can occur with methylphenidate use. If a patient complains of cardiac symptoms, such as chest pain, that worsens with exertion or has a near-syncope episode, then a full cardiac workup should be performed. Physicians should screen for symptoms of depression, agitation, aggressiveness, new-onset or pre-existing psychosis or mania, and suicidality as these can be worsened when initially starting methylphenidate. On physical exam, look for peripheral vasculitis (digital ulceration). Physicians should also monitor for signs of intravenous abuse as frank psychotic episodes can develop. There has been controversial evidence on the potential for methylphenidate to affect seizure threshold. If seizures develop while being treated with methylphenidate, then it should be stopped immediately.
In adults, patients should limit their alcohol use while taking methylphenidate as its stimulant action can mask the actual sedative effect caused by alcohol intoxication, possibly inducing severe respiratory depression. Additionally, a patient who is concurrently on warfarin (Coumadin), phenytoin, tricyclic antidepressants, or SSRIs should have their drug levels monitored and adjust doses as needed to achieve a therapeutic effect. This is mainly because methylphenidate can inhibit the metabolism of these drugs.
In children, it is particularly important to evaluate their growth curve for a stable progression in height and weight since methylphenidate has been shown to suppress growth when used on a daily, long-term basis. The medication should either be readjusted or discontinued if children are not in a healthy percentile on their growth curve.
The first step in a medication overdose is to immediately contact a poison control center for the next appropriate steps in management. Doses that exceed 60 mg of the IR (immediate release) formulation or 120 mg of the ER (extended release) formulation can be considered toxic. If the overdosed quantity is unknown, look for signs and symptoms such as tremors, hyperreflexia, convulsions, euphoria, confusion, hallucinations, delirium, flushing, and fever in addition to the common adverse effects mentioned above. Supportive care with supplemental oxygen, IV fluids, and external cooling methods is the mainstay of treatment. Multiple studies have shown that benzodiazepines can be given, especially if dystonia, agitation, or convulsions are present.