Introduction The objective of this systematic review is to reflect on assumptions in relation to codeine use in combination with other analgesics. Methods MEDLINE was searched according to the predetermined keywords and criteria. Only English language studies were taken into consideration and the outcome data of the final studies were extracted by two reviewers independently from each other and were checked by the third reviewer. Additionally, the available codeine-related Individual Case Safety Reports (ICSRs) retrieved from EudraVigilance were reviewed. Results Sixteen placebo-controlled studies that involved 3378 subjects suffering from acute pain were analyzed for the efficacy of low-dose codeine (≤ 30 mg) combination products. Twelve of them found low-dose codeine combinations more efficient in relieving pain than the assigned comparator. According to 20 randomized clinical trials which included at least one dose of codeine (from 30 to 240 mg daily), the vast majority of reported side-effects were mild or moderate in severity. A total of 20 ICSRs for dependence were identified in the EudraVigilance database with codeine as a suspect drug for the 10-year time period for the European region. Conclusions Low-dose codeine combinations are effective after a single application in treating acute pain. Codeine in doses ≤ 30 mg and higher was considered safe since only mild to moderate side-effects were observed. There is no indication in the available sources which clearly links low doses of codeine to substance use disorder in non-dependent subjects.