Original Contribution
Tramadol-induced apnea

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Abstract

Background and Objectives

In contrast with other opioids, there are few cases of tramadol-related respiratory depression described in the literature, and renal impairment is a proposed risk factor. The aim of this study is to determine the prevalence of and predisposing factors for tramadol-related apnea in patients referred to our center.

Patients and Methods

All patients referred to Loghman-Hakim Hospital between February 2009 and April 2010 with pure tramadol intoxication were identified retrospectively. Data collected included the patient's age, sex, ingested dose, route of exposure, reason for poisoning (acute overdose or supratherapeutic use), previous history of suicidal attempts, previous history of drug or substance abuse (including tramadol), and clinical features on admission including seizures and apnea.

Results

We identified 525 patients with deliberate self-poisoning (359; 68.4%) or abuse (146; 27.8%), and in 114 (21.7%) of these, there was a history of tramadol abuse. Four hundred twenty-nine (81.7%) of patients had acute poisoning and were referred to hospital within 6 hours of ingestion. Nineteen patients (3.6%) experienced apnea and received respiratory support (16; 84.2%) or naloxone administration (3; 15.8%) within 24 hours of ingestion (mean, 7.7 ± 7 hours; range, 1-24 hours). The mean dose ingested by patients experiencing apnea was 2125 ± 1360 mg (range, 200-4600 mg), which was significantly higher than those who did not experience apnea, 1383 ± 1088 mg (range, 100-6000 mg), P < .001. One death occurred in each group, which was significant (P < .001). Renal impairment was not observed in any of the patients who experienced 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.

References (47)

  • S. Grond et al.

    Clinical pharmacology of tramadol

    Clin Pharmacokinet

    (2004)
  • K.A. Payne et al.

    Tramadol drops in children: analgesic efficacy, lack of respiratory effects, and normal recovery times

    Anesth Prog

    (1999)
  • V. Jovanovic-Cupic et al.

    Seizures tramadol associated with intoxication and abuse of tramadol

    Clin Toxicol

    (2006)
  • R. Pandey et al.

    Prolonged apnea after small single dose of intravenous tramadol

    AANA J

    (2010)
  • T.P. Tantry et al.

    Tramadol-induced respiratory depression in a morbidly obese patient with normal renal function

    Indian J Anaesth

    (2011)
  • B. De Backer et al.

    Quantification in postmortem blood and identification in urine of tramadol and its two main metabolites in two cases of lethal tramadol intoxication

    J Anal Toxicol

    (2010)
  • K.E. Goeringe et al.

    Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers

    J Anal Toxicol

    (1997)
  • K.A. Moore et al.

    Tissue distribution of tramadol andmetabolites in an overdose fatality

    Am J Forensic Med Pathol

    (1999)
  • U.M. Stamer et al.

    Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication

    Anesth Analg

    (2008)
  • C. Mattia et al.

    Respiratory depression following iatrogenic tramadoloveruse in a patient with chronic renal failure

    J Headache Pain

    (2008)
  • K. Gholami et al.

    New guideline for tramadol usage following adverse drug reactions reported to the Iranian Pharmacovigilance Center

    Pharmacoepidemiol Drug Saf

    (2007)
  • H. Hassanian-Moghaddam et al.

    Tramadol intoxication /abuse: a new issue on high-accesspopulation

  • List of narcotic drugs under control

    Secretary for food and drug affairs, Ministry of Health & Medical Education Iran [Persian language]

  • Cited by (0)

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