Medicines are the substances involved most frequently in paediatric poisoning cases. According to the Working Group on Poisonings of the Sociedad Española de Urgencias de Pediatría (Spanish Society of Paediatric Emergency Medicine) (GTI-SEUP), 59.2% of children aged less than 7 years that seek care in paediatric emergency departments (PEDs) for suspected poisoning do so following exposure to a medicinal drug.1

Since its launch in 2008, the Toxicology Observatory of the GTI-SEUP has not registered any fatal drug poisoning cases in children.2 However, there are descriptions of fatal cases in the international literature, among which we would like to highlight the annual reports of the National Poison Data System (NPDS) of the American Association of Poison Control Centers and studies on paediatric deaths resulting from exposure to toxic substances.3,4 Some of these deaths followed ingestion of very small amounts of the drug (1 or 2 tablets or sips).5–9 These events have led to the coining of the term one-pill killer or the phrase one pill can kill, which refers to drugs the ingestion of a single tablet or teaspoonful of which is enough to reach a lethal dose (LD) to a child with a body weight of 10 kg.10,11

The increased life expectancy and broader therapeutic armamentarium currently available for treatment of chronic diseases entail that a considerable portion of the population consumes medicines habitually. While the pharmaceutical industry has integrated the use of child-resistant packaging, drugs manufactured for the adult population, which have a higher concentration of the active ingredient per unit, may be dangerous to the youngest individuals. The risk is even greater if drugs are stored anywhere other than their original packaging,12 in pill boxes or in novel custom pill dispensing systems, which are very appealing due to their modern design and lack childproof safety mechanisms.

There have been life-threatening and even fatal cases of poisoning following ingestion of various products and drugs sold over the counter, such as ointments containing camphor13,14 or methyl salicylate.9,15 Families do not perceive these products as actual drugs and use even fewer precautions. Thus, we have a long way to go on the prevention of unintentional drug poisonings in the paediatric population.

The aims of our study were:

• 1

  To craft a list of drugs highly toxic to children (DHTCs) currently marketed in Spain.

• 2

  To craft a list of drugs currently marketed in Spain that can reach a LD to a child with a body weight of 10 kg with the ingestion of 1 to 3 units.

Many DHTCs are currently marketed in Spain. Furthermore, many of these drugs belong to the drug groups involved most frequently in cases of suspected unintentional drug poisoning managed in PEDs in Spain. Thus, based on data published by the GTI-SEUP, psychotropic drugs account for 24.5% of visits due to inadvertent drug exposure, cold medicines for 16.2% and analgesics for 15.4%.17

The review of the NPDS annual reports published by the American Association of Poison Control Centers showed that in the United States, the drugs involved most frequently in fatal drug poisonings in children aged less than 8 years are opiates and antihistamines. In the United Kingdom, Anderson et al3 reviewed the data collected by the National Poisons Information Service (NPIS) from 2008 to 2014 and mortality data published by the Office for National Statistics for the 2001–2013 period. The authors identified 28 fatal cases in children aged less than 5 years, of which 16 (57%) resulted from exposure to methadone. Iron also was frequently involved, as it caused 1 death and 13 of the 69 severe cases (PSS grade 3).

In Australia, Pilgrim et al. reviewed data for the 2003–2013 period collected by the National Coronial Information System and found 19 fatal cases of acute drug poisoning in children aged less than 16 years. Prescription opiates were responsible for 10 cases and prescription psychotropic drugs for 6.4

In Spain, reports on mortality trends document 30 cases of fatal unintentional poisoning following exposure to toxic substances in children aged up to 14 years between 2008 and 2016 (12 cases in children aged less than 5 years), although the reports did not specify the drugs involved.18 We ought to highlight that the Toxicology Observatory of the GTI-SEUP did not report any fatal cases. A possible explanation is that the observatory only documents poisoning cases managed at participating PEDs on the 13th, 14th and 15th of each month.

Some of the deaths caused by opiates documented in the NPDS annual reports of the American Association of Poison Control Centers followed ingestion of a single methadone,5,6 buprenorphine-naloxone7 or oxicodon8 tablet. One of the salient reported cases of death due to inappropriate use of a drug corresponds to the administration of a 30 mg oxycodone tablet to a boy aged 7 years with a body weight of 48 kg that had toothache that did not respond to ibuprofen.8 There have also been fatal cases in obese children that were given a prescription for codeine for treatment of postoperative pain or as a cough suppressant.19 Two girls aged 1 and 4 years died after ingesting a used transdermal fentanyl patch.20,21

In Spain, all the opiates in the market reached a LD for children with a weight of 10 kg with a single unit, with the exception of codeine, which would reach a LD with two 30 mg tablets.

In the reviewed literature, psychoactive drugs and other nervous system and musculoskeletal system drugs were the types of drugs involved most frequently in severe or fatal drug poisoning cases. They also accounted for 9.5% of the deaths documented in the NPDS annual reports of the American Association of Poison Control Centers. Most of these deaths occurred in infancy and early childhood and presented with convulsive seizures and cardiovascular toxicity following accidental ingestion of bupropion or amitriptyline tablets.20,22–24 Three of the cases were homicides, as the caregivers had intentionally administered sertraline or amitriptyline to sedate the child.25,26 Some highly toxic psychotropic drugs and other nervous system and musculoskeletal system drugs are used almost exclusively in adults and paediatricians are not familiar with them. This is the case of rivastigmine or clomethiazole, used for management of Alzheimer disease or dementia. A case has been reported of respiratory failure in the context of cholinergic syndrome in a child aged 3 years that ingested 1 or 2 tablets of rivastigmine.27 Although we did not find any references to clomethiazole in our literature review, 1 of the patients managed at the PED in the retrospective study had severe poisoning and experienced cardiac arrest following ingestion of an unknown number of clomethiazole capsules.

Drugs for symptomatic treatment of the common cold are widely used in the paediatric population despite the lack of scientific evidence in support of this practice, and they are one of the groups of drugs involved most frequently in unintentional poisonings.17 An extensive review of reported fatalities by Dart et al. identified 99 deaths in children aged less than 6 years that were probably related to cough and cold medications, and the most frequently involved drugs were pseudoephedrine, diphenhydramine and dextromethorphan.28 This study found that in most cases the drug was administered by an adult, either with therapeutic intent or in an instance of child abuse. Another aspect worth highlighting is the involvement of products combining several active ingredients with a high toxicity.8,25,29 Dextromethorphan was the agent involved in one of the severe paediatric poisoning cases managed in the PED under study.

Despite the generalised perception that topical dosage forms are harmless, some of them are among the drugs that can be highly toxic to children. This is the case of local anaesthetics such as lidocaine, dibucaine and benzocaine. There have been cases of severe neurotoxicity and deaths associated with the misuse of lidocaine viscous (recurrent administration of doses higher than prescribed to alleviate symptoms of tooth eruption) or ingestion of a single unit of product.30 Dibucaine, marketed in Spain as an ingredient in a haemorrhoid cream, has a high cardiotoxicity.30,31 There are several reports in the literature of severe methaemoglobinaemia following ingestion of topical anaesthetics containing benzocaine.30

Other topical medications that may cause severe toxicity in children aged less than 8 years are products containing camphor or methyl salicylate,13–15 imidazolines,32 apraclonidine,33 benzydamine34 or podophyllotoxin.35

Antiarrhythmics and some antihypertensives (calcium channel blockers, beta blockers and clonidine) can not only cause severe and fatal poisoning in children, but also do so with very small amounts of the drug.32,36,37 In Spain, there are several dosage forms of flecainide, propafenone, clonidine, amlodipine, diltiazem and verapamil in the market that can reach a LD to children with a body weight of 10 kg in a single tablet and thus can be considered one-pill killers.

Due to their ubiquity in homes, we also ought to highlight sulphonylureas, which may cause severe hypoglycaemia leading to convulsive seizures and coma,23,38 and also iron.3,39

There are limitations to our study. Due to the study design, which was based on a literature review, there may have been cases in the period under study that were not reported to the consulted sources or that would not be identified through the key words used in the search. Thus, we may have underestimated the toxicity of some drugs. In some cases, a lack of data (both in the reviewed clinical cases and the cases included in the TOXBASE and POISINDEX databases) made it impossible to calculate the LD. Extrapolating data from the adult population can yield inaccurate results due to pharmacokinetic and pharmacodynamic differences between age groups.

In conclusion, our study showed that drugs highly toxic to children are currently marketed in Spain, some of which are available in dosage forms that can be lethal with ingestion of only a few units. To reduce risk, this information must be disseminated among the health professionals that prescribe and dispense these drugs and those that manage patients exposed to these substances. A strategy that may prove particularly effective would be to implement interventions in the pharmacy setting to educate families at the time of dispensation of DHTCs. In recognition of the importance of health education, educational audiovisual contents have been developed at the regional level with the support of the government to be played in the waiting rooms of health care facilities.40

On the other hand, it would be very useful to establish a national register of severe or fatal cases of unintentional drug poisoning. A close collaboration of this register and the AEMPS would facilitate the generation of alerts, raising awareness on the use of specific drugs and other health products, and the dissemination of safety measures.

The authors have no conflicts of interest to declare.