BackgroundTramadol hydrochloride is a common prescription pain reliever that is structurally similar to morphine and codeine with its analgesic effects identified as a mu-receptor agonist. Due to its opioid-like stimulant effects, the potential for tramadol misuse is a public health concern. As such, the aim of this investigation is to estimate the prevalence of tramadol misuse in a sample of Iranian adolescents and to assess the relationship between tramadol misuse and other substance use. MethodsThis is the first phase of a prospective survey examining the prevalence of adolescent smoking status, substances use and related factors in Ilam city, Iran. Grade 10 male and female students (n=2000) were recruited using multistage sampling. Self-administered multiple-choice questionnaires were conducted with data analysed using cross tabulations and logistic regression models. ResultsThe prevalence of lifetime tramadol misuse was 4.8% (7.6% males; 1.8% females). Adjusted odds ratios and confidence intervals for lifetime tramadol misusers reporting substance use during the past month were 2.2 (1.1–4.4) for alcohol, 5.0 (1.5–21.9) for cannabis, 8.9 (2.7–29.4) for ecstasy, 0.5 (0.03–7.0) for methamphetamine and 2.3 (0.7–7.4) for opium. ConclusionTramadol could be a related factor or co-factor for adolescent alcohol, cannabis and ecstasy use. We recommend future longitudinal studies to investigate the possible role of tramadol as a gateway drug in the development of substance abuse.