Pain is one of the main complaints of trauma patients in (pre-hospital) emergency medicine. Significant deficiencies in pain management in emergency medicine have been identified. No evidence-based protocols or guidelines have been developed so far, addressing effectiveness and safety issues, taking the specific circumstances of pain management of trauma patients in the chain of emergency care into account. The aim of this systematic review was to identify effective and safe initial pharmacological pain interventions, available in the Netherlands, for trauma patients with acute pain in the chain of emergency care. Up to December 2011, a systematic search strategy was performed with MeSH terms and free text words, using the bibliographic databases CINAHL, PubMed and Embase. Methodological quality of the articles was assessed using standardized evaluation forms. Of a total of 2328 studies, 25 relevant studies were identified. Paracetamol (both orally and intravenously) and intravenous opioids (morphine and fentanyl) proved to be effective. Non-steroidal anti-inflammatory drugs (NSAIDs) showed mixed results and are not recommended for use in pre-hospital ambulance or (helicopter) emergency medical services [(H)EMS]. These results could be used for the development of recommendations on evidence-based pharmacological pain management and an algorithm to support the provision of adequate (pre-hospital) pain management. Future studies should address analgesic effectiveness and safety of various drugs in (pre-hospital) emergency care. Furthermore, potential innovative routes of administration (e.g., intranasal opioids in adults) need further exploration.