Date Published: April 17, 2019
Publisher: Public Library of Science
Author(s): Hans Järnbert-Pettersson, Marine L. Andersson, Katarina Bilén, Olle Broström, Jonatan D. Lindh, Buster Mannheimer, John Green.
Tramadol, a widely used analgesic drug, inhibits the reuptake of noradrenaline and serotonin impairing the aggregation function of thrombocytes. However, the risk for severe bleeding has previously not been studied. The aim of the present study is to investigate the association between tramadol and bleeding peptic ulcer in the Swedish population.
In this register based case–control study based on the Swedish national patient registry and prescription drug registry, we included 18 306 patients hospitalized with a first-time diagnosis of bleeding peptic ulcer. For every case, 4 matched controls were included. To investigate the temporal aspects of tramadol induced bleeding ulcer, exposure was divided into patients with newly initiated and ongoing treatment. To explore a possible confounding by indication, the effect of codeine, a drug also prescribed for the treatment of moderate pain, but not known to affect thrombocyte function, was investigated. Univariable and multivariable logistic regression was used to analyse the association between tramadol use and bleeding ulcer.
Tramadol was associated with an increased risk of bleeding ulcer (adjusted odds ratio (aOR) 2.1, 95% confidence interval: (2.0–2.3). The association was stronger for newly initiated treatment with tramadol 2.8 (2.5–3.2) and weaker for ongoing treatment 1.7 (1.6–1.9). Codeine was also associated with an increased risk of bleeding ulcer 1.9 (1.7–2.1) and this association was also stronger for newly initiated treatment with codeine 2.3 (2.0–2.6) and weaker for ongoing treatment 1.7 (1.5–1.9).
Treatment with tramadol was associated with an increased risk of bleeding peptic ulcer. Most of this association may be mediated by factors related to the pain condition rather than the pharmacologic effect per se.
About 10% of the Western world population will experience peptic ulcer at some point in their lives [1–4]. Bleeding peptic ulcer is associated with a substantial morbidity in terms of impaired quality of life, and cost for employers and health care systems . The overall mortality rate is approximately 10%  and does not seem to decrease despite the introduction of endoscopic therapy . After infection with Helicobacter pylori, drugs are the most common cause [8, 9], a problem that is likely to have increased during the last decades. According to a Swedish study, investigating drug dispensing from 2005 to 2008, the proportion of the population dispensed ≥5 drugs increased by 8.2%. The proportion of individuals exposed for excessive polypharmacy (≥10 drugs) increased even more . Selective serotonin reuptake inhibitors (SSRIs) have been associated with bleeding peptic ulcer on the basis of thrombocyte inhibition . Tramadol, a widely used analgesic drug also inhibits the reuptake of noradrenaline and serotonin, impairing the aggregation function of thrombocytes in a similar way, which in turn, may increase the risk for gastrointestinal bleeding . However, evidence is lacking. The aim of the present study was to investigate the association between tramadol and bleeding ulcer in the Swedish population.
Over the study period, 18 306 individuals 18 years of age or older were hospitalized due to a first-ever entry of an ICD-10 code of bleeding peptic ulcer in Sweden. For every case, 4 matched controls were included (n = 72 550).
To our knowledge, this is the first study that investigates the associations between tramadol and bleeding peptic ulcer. Tramadol utilization was associated with a two-fold increased risk of bleeding ulcer in the Swedish adult population. The strength of this association among patients with newly initiated tramadol was higher compared with patients with ongoing treatment (aOR 2.8 vs 1.7).