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Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas
Address correspondence and reprint requests to Paul F. White, PhD, MD, FANZA, Department of Anesthesiology and Pain Management, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9068. Address e-mail to paul.white{at}utsouthwestern.edu
Many commonly used anesthetic drugs exist as racemic mixtures of two optically active isomers (1). Analogous to previous findings with the ketamine isomers (2), Bonabello et al. (3) have reported that the S(+) isomer of ibuprofen provides improved analgesic (and antiinflammatory) activity when compared with the racemic mixture of this popular oral nonsteroidal antiinflammatory drug (NSAID).
The NSAIDs have become increasingly popular for the perioperative period because of their opioid-sparing effects and potential for reducing opioid-related side effects and improving the recovery process (4). Unfortunately, nonselective NSAIDs such as ketorolac and ibuprofen also have the ability to interfere with platelet function, as well as the potential for producing adverse effects on gastric mucosal and renal tubular function (5). Interestingly, the report by Bonabello et al. (3) also suggested that S(+) ibuprofen may be associated with less gastric mucosal toxicity than racemic ibuprofen in their rat model. The current findings of Bonabello et al. (3) support an earlier clinical investigation by Dionne and McCullagh (6), which suggested that the S(+) isomer of ibuprofen improved pain control and reduced side effects after oral surgery compared with the racemic mixture. However, it will also be important to determine whether the apparent differential effects of the ibuprofen isomers extend to the drug’s effect on platelet and renal tubular function.
Although S(+) ibuprofen could prove to be a useful analgesic adjuvant during the perioperative period, it may actually offer greater clinical advantages over the currently used racemic mixture when administered to patients requiring long-term NSAID therapy for chronic pain syndromes. In a recent report in the Lancet, MacDonald and Wei (7) reported that racemic ibuprofen appeared to antagonize the cardioprotective effects of small-dose aspirin in patients with established cardiovascular disease. Compared with patients with known cardiovascular disease who were taking aspirin alone, chronic use of ibuprofen in combination with small-dose aspirin increased their risk of cardiovascular mortality (7). In contrast to the irreversible cyclooxygenase (COX) inhibition provided by aspirin, ibuprofen produces reversible inhibition of COX. It remains to be determined whether the S(+) isomer of ibuprofen can provide effective analgesia without interfering with aspirin’s cardioprotective effects. Therefore, the effects of S(+) ibuprofen on platelet function could have important implications with respect to both short-term (i.e., perioperative) and long-term (i.e., for treatment of chronic pain) use of this drug in the future. Of interest, Geisslinger et al. (8) reported that S(+) ibuprofen was a more effective analgesic than the R(-) isomer or the racemic mixture in a small pilot study involving patients with chronic pain associated with rheumatoid arthritis.
Given the increasing popularity of the more highly selective COX-2 NSAIDs (e.g., celecoxib, rofecoxib, valdecoxib, and parecoxib) in the perioperative period (9–12), it would be of interest to compare the safety and efficacy of S(+) ibuprofen with these COX-2 inhibitors when they are used before and/or after surgery as part of a multimodal pain management regimen. Concerns regarding the side effects of the traditional nonselective NSAIDs and the higher cost of the COX-2 selective NSAIDs have led many practitioners to use acetaminophen (13). However, recent comparative analgesic studies suggest that acetaminophen may be less effective than the newer COX-2 inhibitors in adults (9,10). Therefore, the availability of a potentially more effective NSAID such as S(+) ibuprofen, which also produces fewer adverse effects, could have a major effect on the use of NSAIDs in the perioperative period.
Finally, it is of interest that the S(+) isomer of anesthetic and analgesic drugs appears to be more potent than the R(-) antipode with respect to their effects on the central nervous system. S(+) ketamine was found to be two to three times more potent than the R(-) isomer with respect to both its anesthetic (hypnotic) and analgesic properties (2,14,15). The S(+) isomer of another NSAID, S(+)-flurbiprofen, has also been found to be more potent than the R(-) isomer in reducing inflammation-induced nociceptive activity in rat spinal neurons (16,17). The primary clinical benefit of using more potent isomers of drugs is that smaller dosages are required to control pain, thereby decreasing the incidence of adverse side effects. Because the pharmacodynamic profiles of optical isomers are generally similar (2,14), the same type of adverse side effects would be produced if large enough doses of the more potent isomer were administered.
Given the growing interest in the use of non-opioid analgesic drugs for preventing pain after surgery (18), the availability of a more potent NSAID that is devoid of adverse gastrointestinal, platelet, and renal effects would be of great interest to all anesthesia practitioners. Further investigations involving the isomers of NSAIDs and other analgesic drugs represent a potentially important area for analgesic research in the future.
Acknowledgments
Supported by endowment funds from the Margaret Milam McDermott Distinguished Chair in Anesthesiology.
References
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