Opioid-Independent and Opioid-Mediated Modes of Pain Modulation

Abstract

Pain is regulated endogenously through both opioid and non-opioid mechanisms. We hypothesized that two novel pain modulation tasks, one drawing on context/expectations and one using voluntary reappraisal, would show differing levels of opioid dependence. Specifically, we expected that naloxone would block context-related analgesia, whereas mental imagery-based pain reappraisal would be opioid-independent.A double-blind, placebo-controlled intravenous naloxone versus saline crossover design was used. Twenty healthy volunteers completed the two modulation tasks with acute heat stimuli calibrated to induce moderate pain. In the mental imagery task, participants imagined either a "pleasant" or a "comparison" scenario during painful heat. In the relative relief task, moderate heat stimuli coincided with visual cues eliciting relief from the expectation of intense pain, and were compared with moderate heat stimuli delivered under the expectation of non-painful warmth. Both "pleasant imagery" and "relative relief" conditions significantly improved ratings of pain intensity and pleasantness during saline treatment. Indeed, the target stimuli in both tasks, which had been calibrated to induce moderate pain, were rated as mildly pleasant. Furthermore, consistently with the main hypothesis, blocking endogenous opioid signaling with naloxone did not significantly affect imagery-induced regulation of pain intensity or pleasantness. In contrast, the relative relief-induced pain regulation (i.e., context/expectation) was blocked by naloxone. We conclude that endogenous opioid signaling is necessary for expectation-related relative relief analgesia, but not for pain reappraisal through mental imagery. These results support mental imagery as a powerful and clinically relevant strategy for regulating pain affect also in patients where endogenous opioid mechanisms might be compromised.SIGNIFICANCE STATEMENT Neurotransmitter systems in the human brain can be probed through antagonist drugs. Studies using the opioid antagonist naloxone have demonstrated that the brain relies on both opioid and non-opioid mechanisms to downregulate pain. This holds clinical relevance given altered endogenous opioid processes in many chronic pain conditions. The present study used a double-blinded, placebo-controlled naloxone blockage of endogenous opioids in healthy humans to show differential opioid involvement in two pain modulation tasks. Context/expectation-driven (relative relief-related) analgesia was blocked by naloxone. In contrast, pain reappraisal through mental imagery was intact despite opioid receptor blockade, suggesting opioid independence. These results support mental imagery as a powerful, clinically relevant strategy for regulating pain as it does not rely on a functioning opioidergic system.

Keywords: descending pain modulation; expectation; mental imagery; naloxone; pain modulation; pain relief.

Figure 1.

Overview of study design. Participants were pseudorandomized into starting either with the naloxone or saline (placebo) session. After a brief standardized instruction, participants practiced the mental imagery tasks. Following that, the two sessions contained the same sequence: a heat pain calibration preceded the start of the infusion, which was followed by the three task runs presented in counterbalanced order. At the end of the second session, a debriefing took place.

Figure 2.

Overview of the two pain modulation tasks. The temperature, number and duration of moderately painful stimuli, as well as the timing of cues, stimuli and VASs were kept the same across tasks to facilitate comparison. To avoid skin sensitization while keeping experiments brief, two thermodes were used to deliver stimuli. A, In the mental imagery task, participants imagined scenarios in which the moderate heat-pain stimuli would either be pleasant (i.e., useful to alleviate hypothermia) or noxious (i.e., a standard, potentially harmful source of heat such as a pain device or a clothes iron). Visual cues displaying the words “different” (target: pleasant imagery) or “device” (comparison imagery) were presented 9 s before the onset of each heat stimulus, instructing participants to start imagining. B, In the relative relief task, visual cues displaying the word “Wait” were presented 9 s before each heat stimulus to induce expectation of intense pain (Intense run, text on red background) or non-painful warm stimuli (Warm run, text displayed on a blue background). Before task onset, participants were informed that the heat stimulus following the initial visual cue would “most likely” be the cued stimulus, the onset of which was then indicated by a cue reading “Feel” (same color background). However, when the second cue was an arrow pointing downward or upward, it indicated the delivery of a modified stimulus. Unbeknownst to participants, the temperature used then was always the one calibrated to induce moderate pain. In the Intense run, the downward pointing arrow indicated a lower temperature stimulus than expected, thus constituting a relative relief cue. In the comparison run, the upward pointing arrow indicated a higher temperature stimulus. The target and comparison stimuli were thus matched for expected and actual likelihood as well as for temperature, duration, and order of appearance.

Figure 3.

Overview of pleasantness and pain intensity ratings for moderate heat stimuli in the two pain modulation tasks. A, As hypothesized, we observed a significant three-way interaction between Drug, Task type, and Stimulus type for pleasantness ratings. This reflected a significant reduction in pain pleasantness for the target stimulus in the relative relief task during naloxone. In contrast, participants' ability to use mental imagery to upregulate pain pleasantness was not reduced in the naloxone condition. We also observed significant two-way interactions between Drug, Task type and Stimulus type, as well as significant main effects of Drug and Stimulus type. B, Individual mean difference scores (comparison − target VAS pleasantness) for each task and each drug condition are included for illustration purposes. C, A similar pattern of results was found for ratings of pain intensity ratings. Although the three-way interaction did not reach significance, naloxone completely blocked the analgesic effect of the relative relief manipulation, yet did not significantly alter the analgesia induced by pleasant mental imagery. We also observed a significant two-way interaction between Task and Stimulus type, and a significant main effect of stimulus type. D, Individual mean difference scores (comparison − target VAS pain intensity) for each task and each drug condition are included for illustration purposes. Error bars are within-subject SEM. *p < 0.05, ***p < 0.001.

Figure 4.

Overview of secondary outcomes. A, VAS ratings of pleasantness and intensity for the intense heat and warm stimuli. A trend toward higher pain intensity ratings of the intense stimulus in the naloxone condition led to the inclusion of these ratings as a confound regressor in the analysis of the ratings of the target and comparison stimuli. B, Ratings of other relevant aspects of the tasks were collected via verbal, 11-point NRSs after each run. Post-run ratings of cue-related anxiety for moderate pain stimuli (target and comparison) in both tasks revealed a significant interaction between Task and Stimulus type, but no significant differences between Drug conditions. Post-run ratings of the effort that was exerted during mental imagery similarly did not reveal any effects of naloxone nor of type of imagery. Post-run ratings of relief (0–10 NRS scale after Intense run) or disappointment (0–10 NRS scale after Warm run) elicited by the delivery of the moderate stimulus revealed no significant effect of naloxone. Error bars are SEM.