Pain is a leading cause of morbidity worldwide, with published data showing its prevalence as high as 50% for chronic pain in the European population. This prevalence is likely to continue to rise, particularly in elderly people with comorbid conditions and complex aetiologies of pain. There is thus a rapidly growing demand for safe and effective pain management. Management of mild-to-moderate pain has traditionally been based upon the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the synthetic non-opioid analgesic paracetamol (acetaminophen), the latter of which acts centrally, inhibiting brain cyclo-oxygenase (COX) and nitric oxide synthase. Both the NSAIDs and paracetamol are effective for mild-to-moderate pain and are widely recommended and used. However, NSAIDs may not be tolerated due to gastrointestinal (GI) symptoms and can result in potentially fatal peptic ulceration and bleeding. Selective COX-2 inhibitors were developed to reduce the GI side effects and complications, but large-scale studies have highlighted another serious potential effect of anti-inflammatory drugs: cardiovascular events. Both the European Medicines Agency (EMEA) and the Food and Drugs Administration (FDA) in the US have issued advice to apply cautions and restrictions when prescribing COX-2 inhibitors, particularly for patients at increased cardiovascular risk and for long-term use. The FDA also applied cardiovascular warnings with regard to nonselective NSAIDs. Both the EMEA and the FDA have recommended using the lowest effective dose for the shortest duration. These concerns and warnings have left physicians seeking safe alternatives to anti-inflammatory drugs for both short- and long-term uses in many patients. These developments have generated a climate of uncertainty in the absence of official guidance on the selection of alternative analgesic regimens. Amongst the possible strategies, combinations of drugs that provide analgesic efficacy at reduced individual doses may confer the optimal risk-benefit ratio for pain management in the long term or in patients at increased cardiovascular risk. Weak opioids devoid of serious organ-damaging effects combined with paracetamol may well be safer for long-term therapy. Fixed-dose combinations of paracetamol with weak opioids, such as codeine, dextropropoxyphene or tramadol are currently available. Paracetamol plus tramadol is an effective and safe multimodal analgesic regimen for the management of both acute and chronic moderate-to-severe pain. Re-evaluating the role of weak opioids, such as tramadol, and combinations in pain management may prove a valuable option for prescribers seeking alternatives to anti-inflammatory drugs.