Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information

Abstract

The mechanisms supporting temporal processing of pain remain poorly understood. To determine the involvement of opioid mechanisms in temporal processing of pain, responses to dynamic noxious thermal stimuli and offset analgesia were assessed after administration of naloxone, a μ-opioid antagonist, and on a separate day, during and after intravenous administration of remifentanil, a μ-opioid agonist, in 19 healthy human volunteers. Multiple end points were sampled from real-time computerized visual analog scale ratings (VAS, 1 to 10) to assess thermal sensitivity, magnitude and duration of offset analgesia, and painful after sensations. It was hypothesized that the magnitude of offset analgesia would be reduced by direct opioid antagonism and during states of acute opioid-induced hypersensitivity (OIH), as well as diminished by the presence of exogenous opioids. Surprisingly, the magnitude of offset analgesia was not altered after naloxone administration, during remifentanil infusion, or after the termination of remifentanil infusion. Because thermal hyperalgesia was observed after both drugs, 8 of the original 19 subjects returned for an additional session without drug administration. Thermal hyperalgesia and increased magnitude of offset analgesia were observed across conditions of remifentanil, naloxone, and no drug within this subset analysis, indicating that repeated heat testing induced thermal hyperalgesia, which potentiated the magnitude of offset analgesia. Thus, it is concluded that the mechanisms subserving temporal processing of nociceptive information are largely opioid-independent, but that offset analgesia may be potentiated by heat-induced thermal hyperalgesia in a proportion of individuals.

Conflict of interest statement

Authors have no conflicts of interest to disclose.

Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1. Time course of infusions and thermal testing

A 2 session crossover design was used with separate sessions of naloxone administration (0.01 mg/kg, bolus dose over 5 minutes) and remifentanil administration (individually titrated dose, followed by steady-state infusion for 60 minutes)(see methods for details). Subjects were not told which drug they received, and sessions were scheduled at least 1 week apart. Thermal testing included both short and long-duration stimuli and was administered prior to drug infusions (Pre) and every half-hour for 4 hours after each drug infusion. Two additional sets of thermal testing were performed during the remifentanil infusion. The time between Pre and 0 hr thermal testing sets was approximately 30 minutes during the naloxone session and is displaced in the figure to show matched post-infusion sets of thermal testing across the 2 drug sessions. An additional control session was performed in a subset of 8 subjects out of the original 19 to assess effects of repeated heat testing. The control session involved thermal testing at time points matched to the remifentanil session and did not involve an infusion.

Figure 2. Remifentanil analgesia

(A) Remifentanil produced a mean 56% decrease in VAS pain ratings to 49°C stimuli (5 s) at the end of the titration period (Mean ± SEM). (B) Analgesia at the end of the titration period (percent decreases in VAS ratings) was not significantly related to final steady-state infusion doses (maximum titration rate, ng/ml) per subject (N=19*). *Two subjects showed 100% reductions (VAS=0) at each dose of 2 and 2.5 ng/ml (large dots). VAS, visual analogue scale.

Figure 3. Sensitivity to noxious heat stimuli and offset analgesia during remifentanil infusion (N=19)

Reductions in maximum VAS ratings to constant 49°C stimuli, 40 s (A, Peak VAS) and to 49-50-49°C stimuli (B, MaxT2) occurred at the Inf1 time point, but not at the Inf2 time point. Similarly, Min Offset values from 49-50-49°C stimuli were significantly reduced at the Inf1 time point (C). However, the difference between MaxT2 and Min Offset values was not significantly altered during infusion, resulting in no reductions in Magnitude Offset Analgesia (D). No significant temporal alterations in offset analgesia were observed during remifentanil infusion (E, Min Offset Latency) and after sensations did not occur (F, VAS End Latency). Mean ± SEM; VAS, visual analogue scale.

Figure 4. Sensitivity to noxious heat stimuli and offset analgesia at time points after termination of remifentanil infusion and after administration of naloxone (N=19)

Subjects displayed increased sensitivity over time to constant 49°C, 40 s stimuli (A, Peak VAS) and to 49-50-49°C stimuli (B, MaxT2). However, minimum values during offset analgesia were not significantly altered following naloxone or remifentanil administration (C, Min Offset). Likewise, Magnitude Offset Analgesia (MaxT2 – Min Offset) was also not significantly altered (D). Time to the minimum ratings of offset analgesia was shorter following remifentanil compared to naloxone (E, Min Offset Latency), however, no after sensations were observed (F, VAS End Latency). Mean ± SEM; VAS, visual analogue scale.

Figure 5. Post-stimulus VAS ratings: Evidence for opioid-induced hyperalgesia by remifentanil (N=19)

Post-stimulus VAS ratings to 45°C showed significant increases over time after both infusions of remifentanil and naloxone, with a trend for greater hyperalgesia following remifentanil (A). Post-stimulus VAS ratings to 49°C stimuli also revealed significantly increased sensitivity over time under both conditions, and these effects were enhanced after remifentanil indicating the presence of opioid-induced hyperalgesia (B). Mean ± SEM; VAS, visual analogue scale.

Figure 6. Sensitivity to noxious heat stimuli and offset analgesia after naloxone and remifentanil compared to control condition with no drug infusion (N=8)

Increased sensitivity occurred over time under all conditions for constant 49°C stimuli, 40 s (A, Peak VAS), and for 49-50-49°C stimuli (B, MaxT2). Conversely, Min Offset values remained unaltered under all conditions (C). The Magnitude Offset Analgesia increased over time under all conditions reflecting heat-induced hyperalgesia in this subset analysis (D). The time to minimum values during offset analgesia were significantly longer following naloxone compared to control condition (E, Min Offset Latency) and VAS End Latency values significantly decreased over time, but this was influenced by after sensations at the 0 hr time point in the remifentanil condition (F). Mean ± SEM; VAS, visual analogue scale.

Figure 7. Post-stimulus VAS ratings: Opioid-induced hyperalgesia by remifentanil compared to naloxone and control conditions (N=8)

Post-stimulus VAS ratings to 45°C showed only a trend for increased sensitivity over time across the naloxone, remifentanil and control conditions (A). Post-stimulus VAS ratings to 49°C stimuli revealed significantly increased sensitivity over time for all conditions with a trend for opioid-induced hyperalgesia following remifentanil compared to the control condition (B). Mean ± SEM; VAS, visual analogue scale.

Figure 8. Real-time VAS ratings to short-duration stimuli: Hyperalgesia and increased VAS fall slopes

Maximum ratings to short-duration (4–6 s) stimuli, S.PeakVAS, were increased over time after both naloxone and remifentanil administrations (A, N=19) and under conditions of naloxone, remifentanil and control (B, N=8). VAS fall slopes also became steeper over time under all conditions for both slow stimulus fall rates of 0.5°C/s (C, N=19)(D, N=8) and fast stimulus fall rates of 5.0°C/s (E, N=19)(F, N=8) indicating that temporal sharpening mechanisms were conserved under conditions inducing thermal hyperalgesia.