Chronic musculoskeletal pain is a major - and growing - burden on today's ageing populations. Professional organisations including the American College of Rheumatology (ACR), American Pain Society (APS) and European League Against Rheumatism (EULAR) have published treatment guidelines within the past 5 years to assist clinicians achieve effective pain management. Safety is a core concern in all these guidelines, especially for chronic conditions such as osteoarthritis that require long-term treatment. Hence, there is a consensus among recommendations that paracetamol should be the first-line analgesic agent due to its favourable side effect and safety profile, despite being somewhat less effective in pain relief than anti-inflammatory drugs. Cyclooxygenase-2 (COX-2)-selective anti-inflammatory drugs were developed with the goal of delivering effective pain relief without the serious gastrointestinal (GI) side effects linked with traditional non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trial evidence supported these benefits, and COX-2 inhibitors were widely adopted, both in clinical practice and in official guidelines. Recently, accumulating data have linked COX-2 inhibitors with serious cardiovascular and/or cardiorenal effects and/or serious cutaneous adverse reactions (SCARs), particularly at anti-inflammatory doses or when used long term. Regulatory authorities in both Europe and the USA have responded to these data with the withdrawal of rofecoxib and valdecoxib, and the strengthening of prescribing advice on all anti-inflammatory drugs. COX-2 inhibitors and non-selective NSAIDs should now be used with increased caution in patients at increased cardiovascular and/or cardiorenal risk, e.g., patients with congestive heart failure, hypertension, etc. Regulatory advice and good clinical practice are to use anti-inflammatory drugs at the lowest effective dose and for the shortest possible time. There are as yet no updated official guidelines that incorporate these new data and regulatory advice. An international multidisciplinary panel, the Working Group on Pain Management, has generated new recommendations for the treatment of moderate-to-severe musculoskeletal pain. These guidelines, formulated in response to recent developments concerning COX-2 inhibitors and other NSAIDs, focus on paracetamol as the baseline drug for chronic pain management; when greater analgesia is desired, the addition of weak opioids is recommended based on a preferable GI and cardiovascular profile, compared with non-steroidal anti-inflammatory drugs.