Investigating the causes, routes of administrations and toxicology of tramadol associated deaths: a systematic review of case studies and case series

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Abstract Purpose: Despite the increased reporting of tramadol poisoning, the nature and toxicology of tramadol associated deaths have not been adequately subjected to systematic evaluation. This review aims to systematically review the causes, characteristics, routes of administration and toxicology of tramadol associated deaths by using the case studies and case series published in peer reviewed journals. Methods: Three databases including Scopus, Embase, and Medline (via Ovid) were searched from inception until 30th May 2020 to identify case studies and case series that reported data tramadol associated deaths. Abstracts, conference proceedings and articles published in non-English language were excluded. In addition to searching the above databases, the first 20 pages of Google Scholar as well as reference lists of eligible papers were screened to make sure that no additional articles were found. A pair of independent reviewers screened the articles for eligibility, firstly at the title and then at the full-text level. A data extraction tool was developed to extract information from the articles reporting the number of deaths, routes of administration, toxicological data and any concomitant drugs usage. The Joanna Briggs Institute’s quality assessment tool was used to assess the quality of included studies. The data was synthesised using a narrative approach. Results: The initial search of the databases identified 451 articles. Of these, 14 (eight case studies and six case series) reporting 19,913 deaths met the inclusion criteria and were included in the review. The data predominantly concentrated on deaths in South Korea (n=19,443) and Iran (n=294). Most of the literatures do not describe clear routes of administration. However, where the route was reported, the most common route that resulted in death was the oral route, rated at 16.9%, followed by parenteral application (15.2%). The majority of people with tramadol intoxication were found to be males (56%). While the exact cause of death has not been reported in most articles, mixed drug toxicity was among the causes reported (n= 227). However, tramadol alone as a cause of death has been reported in 8 cases with the first death being investigated in Germany in 2001. The mean level of blood tramadol for the deaths was 10.6 µg/ml. Conclusions: Although most of the deaths were concentrated in South Korea, many deaths have been reported in the rest of the world. Deaths have increased across both sexes, and the number of deaths in males is substantially higher than in females. Majority of the deaths were attributed to the oral route. Almost all tramadol-associated drugs fatalities have been connected with the use of other CNS depressants, especially benzodiazepines. However, certain evidence has confirmed that deaths also occur as a result of accidental tramadol overdoses. Therefore, healthcare professionals must develop a clear awareness of the potential toxicity of tramadol, and they should take care when using tramadol in combination with other drugs.

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