Investigation of drug–drug interactions and pain—From volunteer studies to randomized controlled trials in patients with chronic pain

There is little information on the prevalence of clinically significant adverse drug reactions in patients suffering from chronic pain. However, it has been estimated that for instance in the USA alone the number of deaths attributed to adverse drug reactions may be as high as 200000 deaths per year (Chyka, 2000). Many patients with chronic pain have also other medical problems which require drug therapy. The incidence of adverse reactions increases exponentially as the number of drugs prescribed rises and this is most likely at least in part due to drug interactions (Pirmohamed et al., 2004). Thus, patients with the most complicated pain problems have also the greatest risk of clinically significant drug–drug interactions.

Drug interactions are often studied in healthy volunteers under tightly controlled conditions. Despite their shortcomings, volunteer studies have, for instance, revealed that azole antimycotics and calcium antagonists forcefully increase the systemic absorption and/or decrease the elimination of many benzodiazepines and the opioid analgesic alfentanil thereby increasing and prolonging their effects (Olkkola et al., 1994, Palkama et al., 1998, Varhe et al., 1996). Ahonen et al. (Ahonen et al., 1996) nicely confirmed that the information from drug interaction studies in volunteers may be translated to clinical practice by studying the effect of diltiazem on midazolam-alfentanil anaesthesia in patients undergoing coronary artery bypass grafting.

Recent studies in healthy volunteers have demonstrated that cytochrome P450 (CYP) 3A4/5 isoenzyme is of vital significance for the elimination of oxycodone (Hagelberg et al., 2009, Grönlund et al., in press, Nieminen et al., 2009). CYP2D6 has only a minor effect on oxycodone pharmacokinetics but it has a clear-cut effect on the production of oxymorphone, an active metabolite of oxycodone (Heiskanen et al., 1998). Although studies in volunteers are useful, it is important to study the effects of different CYP inhibitors in patients with chronic pain outside the laboratory in normal clinical setting. In the current issue of the Scandinavian Journal of Pain Lemberg et al. (Lemberg et al., 2010) report the effect of paroxetine, a selective serotonin re-uptake inhibitor and inhibitor of CYP2D6 on oxycodone pharmacokinetics and analgesia. The study was done in patients with stable chronic malignant or non-malignant pain. The authors used a randomized cross-over study design which increases the reliability and validity of the results. The results demonstrated that although the inhibition of CYP2D6 caused a 67% decrease of oxymorphine concentrations associated with a 19% increase of oxycodone concentrations, there were no alterations in the analgesic efficacy of oxycodone. The present results are in line with previous studies suggesting that it is the parent oxycodone which is responsible for its effects (Heiskanen et al., 1998, Lalovic et al., 2006). They also remind the clinicians that as far as the clinical significance of an intervention is concerned, there are no alternatives to clinical studies in the target population.