Intrathecal cyclooxygenase inhibitors in humans: don't throw in the towel!

THE role of spinal cyclooxygenase and prostaglandins in nociceptive processing has been examined, corroborated, and reported in more than 100 publications describing animal and bench studies during the past 3 decades. Relevant observations include the constitutive expression of cyclooxygenase 1 and 2 in the spinal cord, up-regulation of cyclooxygenase 2 (primarily) and cyclooxygenase 1 after peripheral injury, release and production of spinal prostaglandins in response to tonic and often inflammatory nociceptive input, and an association between an increase in spinal prostaglandins and nociceptive behavior. Conversely, intrathecal injection of prostaglandins, most notably prostaglandin E2, causes hyperalgesia and allodynia. Studies in animals further suggest that intrathecal injections of cyclooxygenase inhibitors attenuate both the concentration of spinal prostaglandins and nociceptive behavior, implying that targeted inhibition of spinal cyclooxygenase may be a viable strategy for treating pain in humans. In this issue of ANESTHESIOLOGY, two companion articles by Eisenach et al. report results from studies in human volunteers and patients receiving a single intrathecal bolus dose of the nonsteroidal antiinflammatory drug (NSAID), ketorolac, for alleviating experimental or clinical pain. These studies are significant because they are the first to systematically examine the analgesic effects of an intrathecal NSAID in humans. They represent the culmination of a dogged effort to translate the promising results in animals into clinically useful therapies, including preclinical toxicology, regulatory approval for human use, and a phase I safety study in volunteers. Eisenach et al. documented that intrathecal ketorolac is ineffective against the brief pain evoked in unaltered tissue, which is not unexpected. The studies in patients either undergoing surgery or suffering from chronic nonmalignant pain provided negative results, neither detecting an effect of intrathecal ketorolac on spontaneous pain nor time to rescue analgesia. These results are disappointing and imply that intrathecal NSAIDs are of limited utility for alleviating pain in humans. However, the studies in volunteers paint a more complex picture regarding the effects of intrathecal ketorolac on hyperalgesia and allodynia. These phenomena are associated with tissue injury and chronic pain. In the context of this study, hyperalgesia and allodynia largely reflect the amplification of nociceptive input within the central nervous system. The results suggest modest antihyperalgesic and antiallodynic activities in inflammatory pain states but not in capsaicin-induced pain states. Early proof-of-concept studies in humans are critical for guiding future research efforts, but the limitations must be understood before drawing overly broad conclusions. There are two obvious limitations in this work. First, the drug was given by a single bolus. Second, only 109 volunteers and patients, a relatively small number, were enrolled in seven different protocols. Let us consider each of these. The pharmacokinetics of ketorolac in cerebrospinal fluid and spinal tissue are largely unknown. Data obtained in dogs suggest fast elimination of ketorolac from cerebrospinal fluid with an estimated half-life of 53 min. Ketorolac is also one of the most hydrophilic NSAIDs with limited and delayed tissue uptake. A sophisticated pharmacometric analysis suggested that maximum analgesic effects lag behind peak plasma concentrations by about 1 h after systemic drug administration. Assuming fast elimination and slow-tissue distribution of ketorolac, bolus administration may result in marginally effective concentrations in spinal tissue. A slow uptake of ketorolac into spinal tissue is consistent with the observation that a bolus injection of 5 mg in dogs produced high cerebrospinal fluid concentrations ( 400 g/ml) 30 min after administration that were accompanied by a 48% decrease of prostaglandin E2, whereas continuous administration of 1.2 mg for 24 h produced cerebrospinal fluid concentrations that were 100-fold lower but were accompanied by a 96% decrease of prostaglandin E2. Given these considerations, continuous infusion of intrathecal ketorolac may be a more effective strategy than bolus administration.