Effects of intrathecal ketorolac on human experimental pain

Abstract

Background: Nonsteroidal antiinflammatory drugs, the most commonly used analgesics, reduce pain not only by inhibiting cyclooxygenase at peripheral sites of inflammation but also by potentially inhibiting cyclooxygenase in the central nervous system, especially the spinal cord. Animal studies suggest that products of cyclooxygenase in the spinal cord do not alter pain responses to acute noxious stimuli but reduce pain and sensitization after peripheral inflammation. We used a spinal injection of small doses of the cyclooxygenase inhibitor ketorolac to survey the role of spinal cyclooxygenase in human experimental pain and hypersensitivity states.

Methods: After regulatory agency approval and informed consent, we examined the effect of 2.0 mg intrathecal ketorolac in 41 healthy volunteers to acute noxious thermal stimuli in normal skin and to mechanical stimuli in skin sensitized by topical capsaicin or ultraviolet burn. We also examined the effect of intravenous ketorolac.

Results: Intrathecal ketorolac reduced hypersensitivity when it was induced by a combination of ultraviolet burn plus intermittent heat and, according to one of the two analytical strategies, when it was induced by ultraviolet burn alone.

Conclusions: These data suggest a more limited role for spinal cord cyclooxygenase in human pain states than predicted by studies in animals.

Figure 1

Areas of hyperalgesia (upper row) and allodynia (lower row) after intrathecal injection of saline or ketorolac in volunteers with hypersensitivity induced by capsaicin plus intermittent heat (A), ultraviolet-B (UV-B) burn (B), or UV-B burn plus intermittent heat (C). Symbols represent the median [plusmn] 25th and 75th percentiles of 7 subjects in panels A and B and 14 subjects in C. * P [lt] 0.05 compared with intrathecal saline.

Figure 2

Areas of hyperalgesia and allodynia in volunteers with ultraviolet-B burn plus intermittent heat. Heat was applied for 5 min before each measurement. Intravenous saline was administered immediately after the measurements at 45 min and 30 mg intravenous ketorolac was administered immediately after the measurements at 85 min. Values are mean [plusmn] SEM of 10 subjects. * P [lt] 0.05 compared with time 0. # P [lt] 0.05 compared with time 85 min.

Figure 3

Intensity (upper row) and unpleasantness (lower row) visual analog scale (VAS) measurements after intrathecal injection of ketorolac (left column) or saline (right column) immediately after time 0. Values are mean of 7 subjects. No significant effect at any temperature over time in either group.

Figure 4

Cerebrospinal fluid (CSF) concentrations of 2 mg ketorolac after intrathecal injection, at time 0. CSF was only sampled once in each subject, and each symbol represents the time and CSF concentration of ketorolac in one subject.