Clinical pharmacology and rationale of analgesic combinations

Oral fixed drug combination analgesics have potential advantages over monotherapy, but these can only be attained through careful design.

The main reasons for developing combination analgesics are to gain efficacy and to reduce toxicity. Analgesic combinations interact pharmacokinetically, or pharmacodynamically, or both, in positive or negative terms. The t(max) value for both enantiomers of tramadol occur two hours following administration, and that for the active, (+)-M1 metabolite occurs after three hours. Thus, pairing tramadol with acetaminophen, a rapid-onset analgesic, represents a pharmacokinetically rational combination. Analgesic combinations should satisfy two important pharmacodynamic criteria: the components of the combination should display additive or synergistic analgesia; and this interaction should allow lower doses of each substance to be used in combination, resulting in an improved safety profile. Clinical studies of the pharmacodynamic between oral tramadol and acetaminophen in third molar extraction and cold pressor models have provided evidence that this combination provides better efficacy than either individual component of the combination.

In summary, combination analgesics can play a valuable role in pain management. However, dubious combinations (directed against the same targets or with unwanted interactions) and 'old fashioned' fixed-dose multiple analgesic agent combinations should be avoided. Fixed-dose combination analgesics are of value only when they have been developed according to rational pharmacokinetic and pharmacodynamic criteria, and when claims for their benefits have been supported by evidence-based data and well-designed clinical studies.