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Methylphenidate poisoning

Background on methylphenidate
Methylphenidate is a Schedule II controlled substance approved for the treatment of ADHD and narcolepsy. It also has unlabeled uses in the treatment of depression and to enhance the therapeutic effects of opiates

It is postulated that methylphenidate’s mechanism of action involves increasing dopamine via blockade of dopamine transporters. Modulation of norepinephrine may also play a role.

Effects following overdose
The manifestations of methylphenidate toxicity are consistent with those of typical sympathomimetic agents. Effects include varying degrees of psychiatric or neurological effects (e.g., headache, CNS excitation or depression, abnormal movements or rigidity, changes in mood or behavior, hallucinations, paranoia), cardiovascular effects (e.g., hypertension, tachycardia, chest pain), and occasionally gastrointestinal effects (e.g., vomiting, abdominal pain) or various laboratory abnormalities (e.g., elevated serum transaminases or creatine kinase, thrombocytopenia). In some cases, hyperthermia, dysrhythmias, and seizures have been reported.

Adverse reactions
With therapeutic use, suppressed appetite, insomnia, headaches, abdominal pain, nausea, and irritability are common adverse effects. In a study of 47 children aged 5–16 years, Stein et al. found that insomnia and decreased appetite increased in frequency with increasing dose; other adverse effects were not dose related. Additional adverse events unique to chronic therapeutic dosing include weight loss, growth retardation, and perseveration. In addition, methylphenidate can unmask tics in those with Tourette’s syndrome and has been reported to cause hallucinations. Methylphenidate administration has resulted in an allergic reaction with first-time dosing. It is not clear that methylphenidate increases the seizure risk in patients with ADHD who do not have a seizure disorder, and the drug has been used therapeutically in patients with epilepsy without evidence that it lowers the seizure threshold. New “black-box” warnings address concerns about cardiovascular risk secondary to increases in heart rate and blood pressure documented during chronic use. Any further discussion of the risks associated with therapeutic use is beyond the scope of this guideline.

Formulations for oral methylphenidate include immediate- release (IR), extended-release (ER) and sustainedrelease (SR), controlled-release osmotic pressure delivery system (OROS), controlled delivery (CD), and LA (extended-release Spheroidal Oral Drug Absorption System). Methylphenidate is also available as a transdermal patch. The patch is designed to be worn 9 hours each day. See Table 2 for a pharmacokinetic comparison of the various products. For the modified-release formulations, crushing or chewing of the tablets destroys the products’ modified-release properties. The capsules retain their modified-release properties if opened but not if the beads are crushed.

Methylphenidate demonstrates large pharmacokinetic variability between individuals and in relationships between plasma concentrations and effects (18–21). In one study, the drug displayed nonlinear pharmacokinetics at high doses. Metabolism is predominately by de-esterification with 10–20% being metabolized by the hepatic microsomal oxidase

system. Its major metabolite, ritalinic acid, is inactive Methylphenidate (d,l-threo-methylphenidate) is a racemic mixture of d-methylphenidate and l-methylphenidate. A product approved in November 2001, dexmethylphenidate (Focalin), is the d-threo enantiomer of methylphenidate.

Dexmethylphenidate and methylphenidate have similar therapeutic properties; dexmethylphenidate is absorbed more completely than methylphenidate. Although dexmethylphenidate is described as twice as potent as methylphenidate,

the maximum daily dose is not equal to one-half of the maximal daily dose of methylphenidate (20 mg maximum daily dose compared to 60 mg maximum daily dose for methylphenidate). Due to the lack of toxicity information available for this product, it is not discussed further in this guideline.

Drug interactions
Multiple references state that hypertensive crisis might occur if methylphenidate is given with a monoamine oxidase inhibitor. However, there appears to have been only one published case (in 1964) documenting this reaction. In this case, the reaction (described as “hypertensive crisis and hyperventilation syndrome”) was stated to occur 15 days after methylphenidate was initiated (7 days after hospital discharge) in a patient receiving tranylcypromine. The recorded blood pressure was 140/90 mmHg. It was not documented that food or other drug interactions were ruled out. Feinberg published a literature review documenting the therapeutic use of methylphenidate and monoamine oxidase inhibitors.

This review reported that initial dosages of 5 mg/day of methylphenidate have been utilized in combination with monoamine oxidase inhibitors without adverse effects but suggested that further studies were warranted. The addition of methylphenidate to the regimens of two children taking valproic acid resulted in dyskinesia and bruxism. The reactions occurred after the second dose (10 mg) in a 4-year-old boy and after the first dose (5 mg) in a 6-yearold girl. A pharmacokinetic study in six human volunteers provided evidence that ethanol given with high doses of methylphenidate produces ethylphenidate as a metabolite, which might increase the potential for toxicity.

Abuse potential
Published research and case reports have documented the abuse potential of methylphenidate. Cases of methylphenidate abuse reported to poison centers in the US increased 7-fold between 1993 and 1999. Routes of abuse include oral administration, nasal insufflation of crushed tablets, and parenteral administration of crushed tablets. Because the pharmacokinetics and subsequent pharmacodynamics of the latter two routes of administration differ markedly from oral ingestion, and because nasal insufflation and parenteral administration carry risks not associated with oral administration (e.g., talc emboli), only cases involving oral administration were considered in formulating this guideline. Problems unique to the abuse of the patch formulation have not yet been described in the literature.