A 1-year-old boy presented to the emergency department with drowsiness after intoxication from amitriptyline cream. The amitriptyline level in his blood was in the high-therapeutic range for adults. He was admitted for cardiac monitoring. Except for a short episode with irregular heart rate, he recovered completely within 24 hours without adjuvant treatment. Amitriptyline is known as an antidepressant but is also prescribed for neuropathic pain. It is usually prescribed in tablet form; the cream is a novel application. In children, intoxication with amitriptyline may cause drowsiness, seizures, coma, hypotension, tachycardia, and life-threatening cardiac arrhythmias. This is the first case report presenting intoxication in a child with amitriptyline cream. It stresses the importance of keeping children away from the medicine cabinet, even from creams or ointments.
- ECG —
- TCA —
- tricyclic antidepressant
Every year, children are referred to the emergency department with substance intoxication. Many have ingested medication, often present in households. Safety organizations stress the importance of keeping oral medication locked away from children. However, medication that is applied on the skin, such as ointments and creams, is generally not considered as dangerous.
We report a case of intoxication in a young child with amitriptyline cream.
A 1-year-old boy presented to the pediatric emergency department with drowsiness. Some hours earlier, his mother found him playing with a tube of cream. He had cream on his hands, and there were bite holes in the tube, but there was no cream seen in his mouth. He was not sick or drowsy at that time, so his mother did not worry. However, when she tried to wake him some hours later after his nap, he reacted drowsier than normal and was difficult to wake. He was brought to the pediatric emergency department ∼7 hours after the incident with the cream, which was prescribed to his father for neuropathic pain and contained amitriptyline 5% assimilated in cetomacrogol cream. There was no indication that the boy had ingested other medication that could alter the level of consciousness. He was responding but still sleepy. His vital signs and physical examination were normal with a heart rate 110 to 120 beats per minute, arterial blood pressure 91/52 mm Hg, and peripheral oxygen saturation 100%.
We estimated a bite of cream to be 1 g, which then contained ∼50 mg of amitriptyline. Considering his weight (11 kg) and after consulting the Dutch poison center, we assumed this to be a moderate intoxication. We admitted the boy for observation and cardiac monitoring and did additional blood tests. His electrocardiogram (ECG) was normal with regular sinus rhythm 110 beats per minute, PR time 0.12 seconds, QRS 0.06 seconds, QT time 0.28 seconds, and QTc 0.362 seconds. His blood cell counts and liver and kidney functions were normal.
The amitriptyline and metabolite nortriptyline serum concentration were determined in a sample drawn ∼7 hours after possible ingestion. The serum concentration was 239 μg/L (amitriptyline 180 μg/L; nortriptyline 59 μg/L), which is a high therapeutic concentration for adults in the treatment of depression (reference values amitriptyline and nortriptyline: 100–300 μg/L; toxic concentrations >500 μg/L).1,2
During observation, there was a short period of irregular heart rate of 80 to 110 beats per minute 12 hours after ingestion. This disappeared spontaneously within minutes. The boy improved, and in the morning, he was as active as usual. No additional irregularities were observed during cardiac monitoring. Twenty-four hours after ingestion, he was released from the hospital.
Because the first amitriptyline level was within the high-therapeutic range for adults, we repeated an amitriptyline level 24 hours after the first blood test. The amitriptyline and nortriptyline serum concentration in this sample was 93 μg/L (amitriptyline 33 μg/L; nortriptyline 60 μg/L) and just below the lower limit of the therapeutic range for adults.
The father, who was using the cream, also had complaints of drowsiness. These complaints seemed to have started around the same time he began using this cream. Considering his complaints, we also determined the amitriptyline and nortriptyline level in his blood. The levels were below the detection limits of 10 μg/L of both amitriptyline and nortriptyline and therefore did not explain his complaints.
Amitriptyline is registered as a tricyclic antidepressant (TCA). It is also being used off label for additional purposes, such as neuropathic pain, tension headache, and posttraumatic stress. The main side effects of amitriptyline and other TCAs are anticholinergic effects. Patients present with a dry mouth, urine retention, or difficulties in ocular accommodation. In elderly people, orthostatic hypotension, confusion, and sedation are reported.
In high doses, amitriptyline and other TCAs are cardiotoxic, mainly causing cardiac arrhythmia and conduction disorders. Tachycardia, widening of the QRS, and prolonged QT interval are the most reported adverse effects, but ventricular fibrillation and cardiogenic shock also occur. Widening of the QRS complex >100 milliseconds is associated with the development of seizures and arrhythmias. Amitriptyline is contraindicated for patients with long QT syndrome. A high dose of amitriptyline is also associated with central nervous side effects. Depression of the central nervous system is predominant and can present with symptoms such as sleepiness, respiratory distress, and coma. Stimulatory effects displayed by convulsions can also occur. Gastrointestinal effects such as obstipation and in high-dose bowel ischemia and perforation are reported.1–5 TCAs are potentially toxic, especially through their cardiac and neurologic side effects. In a recent case report, this was illustrated by a near-fatal intoxication with dosulepin, another TCA, in a toddler.6
Amitriptyline is generally prescribed orally. In adults, dosages used are 50 to 100 mg daily (maximum dose 300 mg) for the treatment of depression and 10 to 25 mg (maximum 150 mg daily) for the treatment of neuropathic pain. Its availability after ingestion is 53%, with a peak level varying between 1 and 8 hours.3,4
Amitriptyline assimilated in cream is a novel application. The use of amitriptyline cream in neuropathic pain may reduce the chance of adverse effects because of its low systemic concentrations and the gradual sustained delivery of the active compound.7 Amitriptyline is metabolized into its active metabolite nortriptyline by cytochrome P450 enzymes and subsequently eliminated through the kidneys. A small part is eliminated in the bile. The half-life varies from 10 to 25 hours for amitriptyline and 15 to 93 hours for nortriptyline.3,4
On the basis of the 2 measurements of amitriptyline blood levels, the terminal half-life in this child was calculated to be ∼10 hours, which is comparable to that of adults. In our case, nortriptyline levels are not decreased in time, most likely because of additional metabolization of amitriptyline into nortriptyline.
Amitriptyline is rarely prescribed to children. In the Netherlands, it is not registered for use as an antidepressant in children <12 years. In children >6 years, amitriptyline can be used in the treatment of nocturnal enuresis at a dosage of 1 to 1.5 mg/Kg.8 In experimental settings, it is used for treatment of functional gastrointestinal disorders.9
Because of its minimal use in children, little is known about adverse effects and toxic dosages in this population. In one study on functional gastrointestinal disorders, all subjects, aged between 3 and 17 years, were prescribed 10 mg of amitriptyline, regardless of weight. Patients who did not respond to the initial dosage were offered an increased dose. Only anticholinergic effects were reported. In this study, there were no reported cardiac symptoms. However, no ECGs were conducted, so theoretically prolonged QT time could not be ruled out.9
Most literature available on adverse effects of amitriptyline ingestion in children originates from amitriptyline poisoning. Lethargy, tachycardia, and even coma have been described. Seizures and cardiac arrhythmias, requiring resuscitation and antiarrhythmic therapy, are also noted. Eventually, most children return to normal within several days and improve without remaining complaints.10,11
In a review of 44 children with acute amitriptyline poisoning, 2 children died. One had ingested 36 mg/kg and died of cardiopulmonary arrest, another child had ingested 97.5 mg/kg and died of status epilepticus.12
Management of amitriptyline poisoning consists of securing the airway because many patients present with depressed consciousness. Subsequent observation of vital functions, especially ECG monitoring, is necessary. Sodium bicarbonate is recommended if the QRS width is more than 100 milliseconds. Inhibition of absorption by gastric lavage should be considered if ingestion was recent (∼1–2 hours) and activated charcoal (with or without laxatives) can be administered because amitriptyline delays gastric emptying due to its anticholinergic effects. Repeated doses of charcoal may be necessary to interrupt the enterohepatic cycle. In some studies, charcoal hemoperfusion was performed with good results.13,14 In another review of amitriptyline poisoning in 52 children, most children presented with tachycardia and lethargy, and almost half presented with coma. Almost a quarter of the children presented with QT prolongation, of which 8.2% was significant.15
The relationship between potential toxic doses and symptoms in children is hard to determine, and literature on this topic is scarce. Steel et al16 described several cases of amitriptyline poisoning in children. Strikingly, the data from their article demonstrate that the dosage (milligrams of amitriptyline per kilogram body weight) does not in itself predict symptoms and outcome. Furthermore, there is no clear correlation between amitriptyline drug serum concentrations and the severity of the intoxication. In general, amitriptyline levels in the range of 1000 μg/L or higher are considered to be severe intoxication.3,4
In our case report, the high-therapeutic levels of amitriptyline and nortriptyline can explain the observed drowsiness. Whether amitriptyline has entered the systemic circulation by oral or dermal absorption remains unclear. It is known that other medications such as opioids and nicotine can enter the blood by the cutaneous pathway and cause intoxication.17,18
In our patient, it is most likely that the systemic amitriptyline levels were caused by oral absorption instead of a cutaneous pathway. This is supported by the fact that amitriptyline was not detected in the father’s blood. In trials on the use of topical amitriptyline, most patients had no detectable blood levels.19
In conclusion, this case report is the first to present intoxication from amitriptyline cream in a young child. Clinically significant amitriptyline and nortriptyline levels were measured, and drowsiness with a short period of irregular pulse was observed. This case report stresses the importance of keeping children away from medicines, including creams and ointments. Furthermore, it illustrates the potential toxicity from TCAs.
- Accepted April 30, 2012.
- Address correspondence to Paul H.G. Hogeman, MD, PhD, Meander Medical Centre, Ringweg Randenbroek 110, 3816 CP Amersfoort, the Netherlands. E-mail address:
Dr Lak’s current affiliation is Wilhelmina Pediatric Hospital, Utrecht, the Netherlands.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
- ↵Toney GB, Ereshefsky L. Cyclic antidepressants. In Schumacher G, ed. Therapeutic Drug Monitoring. Norwalk, CT: Appleton & Lange; 1995: 411–448
- ↵NVZA (Dutch Association of Hospital Pharmacists). Commission of Analysis and Toxicology, The Netherlands. Therapeutic Drug Monitoring Monography: Tricyclic Antidepressants [in Dutch]. 2005(December 17)
- ↵Merck Sharp & Dohme BV, Haarlem, The Netherlands. Summary of Product Characteristics Tryptizol (amitriptyline) [in Dutch], 2010, November 9th. Online source.
- KNMP (Royal Dutch Association for the Advancement of Pharmacy)
- ↵Hendron D, Menagh G, Sandilands EA, Scullion D. Tricyclic antidepressant overdose in a toddler treated with intravenous lipid emulsion. Pediatrics. 2011;128(6). Available at: www.pediatrics.org/cgi/content/full/128/6/e1628
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- Copyright © 2012 by the American Academy of Pediatrics