Original ContributionTramadol-induced apnea
Introduction
Tramadol is a widely used analgesic with a dual mechanism of action: weak agonist at the μ-opioid receptor and inhibition of serotonin and norepinephrine reuptake [1]. It is generally considered to lack the serious adverse effects of pure opioid receptor agonists, such as respiratory depression and drug dependence [2]. Although it appears be a safe and effective analgesic, adverse effects are reported particularly from abuse and intoxication [3]. Intravenous exposure to tramadol has caused apnea [4], [5] and death due to nonrespiratory etiology [6], [7]. In some autopsied cases associated with tramadol, the route of exposure was not clear [8], [9], [10]. In studies involving oral administration of tramadol, death was attributed to coingestion of other central nervous system depressants particularly benzodiazepines, barbiturates, and/or drugs with serotonergic effects [11], [12], [13], [14]. Impaired clearance of the metabolite in patients with renal impairment has also been thought to contribute to deaths [15], [16].
Tramadol was marketed in Iran in 2002 [17], and since then, its use has increased. The Iranian Ministry of Health reported that 24 million tramadol tablets (100 mg) were sold from March 21, 2004, through March 20, 2005, during an Iranian year. In the next year, sales increased to 162 million and then 350 million the following year (2006-2007), consistent with a 14.6-fold increase over 2 years [18]. Because of increasing misuse among adolescents, tramadol was classified as a controlled drug in Iran in April 2007 [19]. However, undocumented supply (eg, without a prescription) appears to be common, so these data most likely underestimate the true usage of tramadol in Iran [20].
The incidence of tramadol poisoning has also increased during this time. Interestingly, there were no reports of acute poisoning noted 2003 to 2005 [21], [22], [23]. The Iranian Pharmacovigilance Center reported 337 cases of tramadol-induced adverse drug reaction with therapeutic use, including 3 deaths from April 2002 to February 2005 [17]. A retrospective study in Tehran noted that tramadol exposure was present in more than 15% of hospitalized poisoned patients who were older than 12 years (2006 to 2007) [24]. Forensic data from Tehran show an increasing incidence of death due to tramadol, from 4 cases in 2005 to 62, 98, and 130 cases in 2006, 2007, and 2008, respectively, a 32.5 times increase in deaths [25].
Opioid agonist activity appears to be an important contributor to death from tramadol poisoning, including respiratory depression and apnea. The aim of this study was to determine the prevalence of and predisposing factors for tramadol-related apnea in poisoned patients referred to our center.
Section snippets
Patients and methods
In this retrospective study, all patients referred to Loghman-Hakim Hospital (February 2009 to April 2010) due to pure tramadol poisoning were identified via coding by medical records; patients with coingestants were excluded. Data recorded in the medical records include patient demographics, details of the exposure, clinical observations, and important complications, which include respiratory arrest and seizures. Extracted data included the patient's age, sex, number and strength of tramadol
Results
During the 14 months encompassed by this study, nearly 32 000 patients presented to our institution, and 14 000 of these were hospitalized. We identified 732 patients (~ 5.4% of hospitalized patients) with a history of tramadol exposure, of which 525 reported poisoning with tramadol as the sole agent so were included in the study; see Fig. The mean age was 22.8 ± 6.9 years (range, 3-72 years), and they were predominately males (70.1%). The reason for presentation was intentional self-poisoning in
Discussion
This is the first large cohort study describing an incidence of apnea in 3.6% of patients with isolated tramadol overdose. No definite risk factors for the development of apnea were identified. Although the mean dose ingested was statistically larger in those who developed apnea, a wide range of doses (as low as 200 mg) were reported. The mortality from tramadol poisoning appeared to be increased in those patients with apnea; although overall numbers were low so further studies are required to
Conclusions
Tramadol abuse and intoxication are social and health concerns in Iran, in particular to the younger population. We observed that apnea occurs in 3.6% of cases when tramadol was the sole poison, and this may occur up to 24 hours postingestion and is not preceded by prominent central nervous system depression or seizures. The cases of apnea presented here are a fraction of the number of patients with lesser degrees of respiratory depression due to tramadol; these cases also need prompt diagnosis
Acknowledgment
The authors wish to thank Dr Darren Roberts for his comments on the manuscript and English linguistic assistance.
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