Pharmacological aspects of successful long-term analgesia.

Persistent pain represents a major quality-of-life burden for patients and a challenge for their physician. Chronic pain often arises from multiple tissue sources and involves multiple chemical mediators and pain transmission pathways. Successful long-term pain management requires analgesic regimens that can treat pains of multiple origin and type. Safety and tolerability are also a high priority when prescribing chronic therapy. Recent publications and regulatory developments affecting anti-inflammatory drugs have limited the options available for the management of chronic pain. Major concerns in long-term use of anti-inflammatory drugs include renal toxicity, gastrointestinal ulceration and bleeding and cardiovascular events, which can be of particular concern for elderly patients. Opioid agents avoid the end-organ toxicity seen with anti-inflammatory drugs, but their use may be limited, especially in the long term, by side effects such as constipation or sedation and by concerns about the potential for physical or psychological dependence. Paracetamol (acetaminophen) has a favourable safety and tolerability profile, although exceeding the recommended dose (up to 4 g/day) carries a risk of liver damage. It exerts simultaneous anti-nociception at both spinal and supra-spinal sites, and has shown self-synergy between these two routes of activity. Tramadol, an atypical weak opioid with a multi-modal mechanism of action, inhibits re-uptake of multiple neurotransmitters and has an improved safety and tolerability profile compared with traditional opioids. Rational combinations of analgesic drugs offer a viable approach to managing persistent pain that involves multiple sites or pathways. The combination of paracetamol plus tramadol brings together two well-known analgesics that have different but complementary mechanisms of analgesic action. Laboratory studies have demonstrated that these agents interact to produce synergistic analgesia with a desirable safety/efficacy profile.