Endogenous pain control mechanisms have long been known to produce analgesia during "flight or fight" situations and to contribute to cognitively driven pain modulation, such as placebo analgesia. Afferent nociceptive information can also directly activate supraspinal descending modulatory systems, suggesting that these mechanisms may participate in feedback loops that dynamically alter the processing of nociceptive information. The functional significance of these feedback loops, however, remains unclear. The phenomenon of offset analgesia-disproportionately large decreases in pain ratings evoked by small decreases in stimulus intensity-suggests that dynamic activation of endogenous pain inhibition may contribute to the temporal filtering of nociceptive information. The neural mechanisms that mediate this phenomenon remain currently unknown. Using functional magnetic resonance imaging, we show that several regions of the midbrain and brainstem are differentially activated during offset analgesia. These activations are consistent with the location of areas such as the periaqueductal gray (PAG), rostral ventral medulla, and locus ceruleus that have substantial roles in descending inhibition of pain. This transient analgesia contributes to the temporal filtering of nociceptive information by producing a perceptual amplification of the magnitude and duration of decreases in noxious stimulus intensity. Together with the involvement of PAG and associated brainstem mechanisms in cognitively generated analgesia, the present observations suggest that the fundamental role of endogenous pain modulatory mechanisms is to dynamically shape the processing of nociceptive signals to best fit with the ever-changing demands of the environment.

Temporal filtering of afferent information is an intrinsic component of the processing of numerous types of sensory information. To date, no temporal filtering mechanism has been identified for nociceptive information. The phenomenon of offset analgesia, the disproportionately large decrease in perceived pain following slight decreases in noxious thermal intensity, however, suggests the existence of such a mechanism. To test the hypothesis that a temporal filtering mechanism is engaged during noxious stimulus offset, subjects rated heat pain intensity while stimulus fall rates were varied from -0.5 to -5.0 degrees C/s. In the absence of a temporal filtering mechanism, pain intensity would be expected to decrease in direct proportion to the stimulus fall rate. However, psychophysical fall rates were considerably faster than stimulus fall rates, such that subjects reported no pain while stimulus temperatures were clearly within the noxious range (47.2 degrees C). In addition, paired noxious stimuli were presented simultaneously to determine if offset analgesia evoked by one stimulus could inhibit pain arising from a separate population of primary afferent neurons. Pain ratings were significantly lower than those reported from two constant 49 degrees C stimuli when offset analgesia was induced proximal to, but not distal to, a second noxious stimulus. These asymmetric spatial interactions are not readily explained by peripheral mechanisms. Taken together, these findings indicate that offset analgesia is mediated in part by central mechanisms and reflect a temporal filtering of the sensory information that enhances the contrast of dynamic decreases in noxious stimulus intensity.

Background The efficacy of intravenous acetaminophen compared to its oral formulation for postoperative analgesia is unknown. We hypothesized that the addition of acetaminophen to a multimodal analgesia regimen would provide improved pain management in patients following total knee arthroplasty (TKA) and that the effect of acetaminophen would be variable based upon route of delivery. Methods The study was a single center, randomized, double-blinded, placebo-controlled clinical trial on the efficacy of intravenous versus oral acetaminophen in patients undergoing unilateral TKA. One hundred and seventy-four subjects were randomized to one of three groups: intravenous acetaminophen group (IV Group, n=57) received 1-gram intravenous acetaminophen and oral placebo prior to post-anesthesia care unit (PACU) admission; oral acetaminophen group (PO Group, n=58) received 1-gram oral acetaminophen and volume-matched intravenous normal saline; placebo group (Placebo Group, n=59) received oral placebo and volume-matched intravenous normal saline. Pain scores were obtained every 15 minutes during PACU stay. Average pain scores, maximum pain score, and pain scores before physical therapy were compared among the three groups. Secondary outcomes included total opiate consumption, time to PACU discharge, time to rescue analgesia, and time to breakthrough pain. Results The average PACU pain score was similar in the IV Group (0.56 ±0.99 [mean ±SD]) compared to the PO Group (0.67 ±1.20) (P=0.84) and Placebo Group (0.58 ±0.99) (P=0.71). Total opiate consumption at 6 hours (0.47mg hydromorphone equivalents ±0.56 vs 0.54 ±0.53 vs 0.54 ±0.61; P=0.69) and 24 hours (1.25 ±1.30 vs 1.49 ±1.34 vs 1.36 ±1.31; P=0.46) were also similar between the IV, PO, and Placebo Groups. No significant differences were found between all groups for any other outcome. Conclusion Neither intravenous nor oral acetaminophen provides additional analgesia in the immediate postoperative period when administered as an adjunct to multimodal analgesia in patients undergoing TKA in the setting of a spinal anesthetic.