Tramadol-induced hiccups: a case–noncase study in the European pharmacovigilance database

Abstract

Background: Hiccups are usually benign and self-limiting, but can sometimes be persistent. If left untreated, they can provoke severe discomfort, and even death. Hiccups can be idiopathic, organic, psychogenic, and caused by drugs. Although some case reports have suggested a possible association between tramadol and hiccups, to our knowledge, no study has analyzed this possible relationship. The aim of this study was to analyze whether a disproportionate number of cases of hiccups are reported for tramadol in the EudraVigilance database. Methods: A case–noncase study was conducted to assess the association between hiccups and tramadol, calculating reporting odds ratios (RORs) from 1 January 1995 to 11 September 2020. Cases were selected using the preferred term ‘Hiccups’. The noncases used as controls were all other adverse drug reaction reports recorded in EudraVigilance during the same period. Exposure was defined as exposure to tramadol among cases and noncases. To reduce the risk of confounding by indication, the RORs for tramadol compared with other opioids were obtained. Additionally, we performed a confirmatory analysis in the World Health Organization pharmacovigilance database, VigiBase®. Results: There were 3089 cases of hiccups in the 7,213,623 reports. Tramadol was involved in 50 cases. The ROR for tramadol exposure was 3.35 [95% confidence interval (CI) 2.53–4.43]. This association persisted when comparing tramadol with other opioids; ROR: 2.13 (95% CI 1.52–2.99). Disproportionality was also observed in VigiBase®: ROR 1.69 (95% CI 1.47–1.93). Conclusion: Our study confirms, for the first time, a possible signal for a tramadol–hiccups association. Nevertheless, observational analytical studies are needed to confirm these results Plain Language Summary Evaluation of the relationship between the tramadol and the risk of hiccups Introduction: Hiccups are sudden involuntary contractions of the diaphragm. This involuntary contraction causes the vocal cords to close very briefly, which produces the characteristic sound of a hiccup. Hiccups are usually benign and self-limiting, but can sometimes be persistent. If left untreated, they can provoke severe discomfort, depression, disability, and in the most extreme cases, even death. Drugs are a rare cause of hiccups. Methods: This study investigated the possible association between tramadol and hiccups (an unmentioned adverse drug reaction in the Summary of Product Characteristics) in the European pharmacovigilance database (EudraVigilance) and a confirming analysis in the World Health Organization pharmacovigilance database (VigiBase). Results: Our analysis shows that hiccups is relatively more frequently reported in association with tramadol than with other medicinal products, with EudraVigilance and VigiBase confirming this association. Conclusion: Tramadol is an opioid analgesic indicated, alone or in combination with dexketoprofen or paracetamol for pain with various causes, so healthcare professionals and patients should be aware of this possible association.

Alkalising agents in urinary tract infections: theoretical contraindications, interactions and synergy

“…Employing methodology published previously, 17 The EUADR database was searched for products containing ciprofloxacin, trimethoprim, sulfamethoxazole (co-trimoxazole), amoxicillin, and nitrofurantoin. Results were screened to those reported by healthcare professionals only and refined by renal.…”

Recurrent Persistent Hiccups on Opioid Treatment: A Case Report and Literature Review

“…In a review of the French Pharmacovigilance Database, Bagheri et al (18) found that opioids accounted for 6% of the 53 cases of drug-induced hiccups reported in France between 1985 and 1997 (three cases in 12 years). In a case-noncase study conducted on the European Pharmacovigilance Database and published in 2021, García et al (19) showed a statistical association between tramadol and hiccups. Their data also suggest that tramadol is more often related to hiccups than other opioids.…”

Risk Factors for Respiratory Depression Associated with Tramadol Based on the Global Pharmacovigilance Database (VigiBase)

“…Globally, the use of tramadol has increased rapidly over the past few decades, resulting in a 22.8% growth between 2012 and 2015 in the United States, making tramadol one of the most prescribed opioids with excessive expectations of safety and low abuse liability [ 5 , 6 ]. However, concomitant use of medications that increase serotonin level, such as fluoxetine, venlafaxine, or overuse of tramadol, has been found to be associated with serious AEs, such as serotonin syndrome or seizures [ 7 , 8 , 9 , 10 ].…”

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