The Role of Pain Expectations in the Development of Secondary Pinprick Hypersensitivity: Behavioral-Neurophysiological Evidence and the Role of Pain-Related Fear.

Secondary mechanical hypersensitivity, a common symptom of neuropathic pain, reflects increased responsiveness of nociceptive pathways and can be induced temporarily in healthy volunteers using high-frequency electrical stimulation of the skin. Expectations modulate acute pain perception and fear of pain has been shown to attenuate and amplify the placebo and nocebo effects, respectively. However, the role of expectations and fear in the development of mechanical secondary hypersensitivity remains unclear. The modulatory role of fear and expectations in the development of mechanical secondary hypersensitivity remains so far mainly correlational. Here, we randomly assigned healthy participants (women) to a placebo, nocebo, or control group. In the experimental groups, participants' expectations of pain were manipulated using verbal suggestions accompanied by an inert treatment. Fear of pain was evaluated both in terms of fear of pain and via questionnaires. Sensitivity to mechanical stimulation was assessed by self-reported pinprick ratings before and after high-frequency stimulation; pinprick-evoked potentials elicited by the stimulation were recorded. The placebo group developed the least mechanical secondary hypersensitivity (smaller proximal-distal spread), while the nocebo group developed the most, but only when outliers were excluded. Higher expectations of pain predicted a greater development of mechanical secondary hypersensitivity. Anticipatory pain-related fear only mediated the relationship between unpleasantness expectations and perceived pinprick unpleasantness. Dispositional fear of pain moderated the relationship between expectations and the perceived intensity and unpleasantness of pinpricks. No group differences were observed in pinprick-evoked potentials. We provide preliminary evidence that both expectations and fear impact the development of mechanical secondary hypersensitivity. PERSPECTIVE: Expectations of pain may influence the development of secondary mechanical hypersensitivity. This effect is moderated by dispositional fear of pain and partially mediated by situational fear of pain.

No Evidence That Working Memory Modulates the Plasticity of the Nociceptive System, as Measured by Secondary Mechanical Hypersensitivity.

The effect of cognition on the plasticity of the nociceptive system remains controversial. In this study, we examined whether working memory can buffer against the development of secondary hypersensitivity. Thirty-five healthy women participated in 3 experimental conditions. In each condition, they underwent electrical stimulation of the skin for 2 minutes (middle-frequency electrical stimulation [MFS]), which induces secondary hypersensitivity. During MFS, participants executed either an individually tailored and rewarded n-back task (working memory condition), a rewarded reaction-time task (non-working memory condition), or no task at all (control condition). Before and after MFS, participants rated the self-reported intensity and unpleasantness of mechanical pinprick stimuli. Fear of MFS was also assessed. Heart rate variability was measured to examine potential differences between the 3 conditions and steady-state evoked potentials to the electrical stimulation were recorded to investigate differences in cortical responses. We report no significant difference in hypersensitivity between the 3 conditions. Moreover, engaging in the cognitive tasks did not affect the heart rate variability or the steady-state evoked potentials. Interestingly, higher fear of MFS predicted greater hypersensitivity. In conclusion, we found no evidence that working memory affects the plasticity of the nociceptive system, yet pain-related fear plays a role. PERSPECTIVE: This study shows that the execution of a cognitive task, irrespective of cognitive load or working memory, does not significantly modulate the development of secondary hypersensitivity, heart rate variability, or steady-state evoked potentials. However, higher pain-related fear seems to contribute to greater hypersensitivity.

The effect of high versus low cognitive load on the development of nociceptive hypersensitivity: The roles of sympathetic arousal, sex and pain-related fear.

BACKGROUND: According to limited-capacity theories of attention, less attentional resources remain available when engaging in a high- versus a low-demanding cognitive task. This may reduce the perceived intensity and the evoked cortical responses of concomitant nociceptive stimuli. Whether and how the competition for limited attentional resources between a cognitive task and pain impacts the development of long-lasting hypersensitivity is unclear. METHODS: Eighty-four healthy participants were randomized into a low or high cognitive load group. Low-frequency electrical stimulation (LFS) of the skin was used to induce secondary hypersensitivity. We hypothesized that performing the high-load task during LFS would reduce the development of hypersensitivity. We examined whether painfulness, nonpain-related sympathetic arousal, or sex related to hypersensitivity, by assessing intensity and unpleasantness of mechanical pinprick stimulation. During task execution, we recorded steady-state evoked potentials evoked by LFS and skin conductance level for sympathetic arousal. Afterwards, participants reported task difficulty and LFS-related fear. For the primary outcomes, we used mixed analysis of variances. RESULTS: The results confirmed the difference in cognitive load. Although LFS successfully induced hypersensitivity, the high-load task did not reduce its development. Next, the steady-state evoked potentials did not differ between groups. Hypersensitivity correlated positively with pain-related fear and negatively with skin conductance level before LFS, despite the lack of group differences in skin conductance level. We did not find any sex differences in hypersensitivity. CONCLUSIONS: These results do not confirm that high cognitive load or sex modulate hypersensitivity, but show associations with pain-related fear and non-pain-related sympathetic arousal. SIGNIFICANCE: Previous research has mainly focused on cognitive load effects on the perception of acute painful stimuli. Yet this study extends our understanding by investigating cognitive load effects on the development of long-lasting secondary hypersensitivity, a common aspect in numerous persistent pain conditions. As cognitive tasks are presented during a painful procedure inducing secondary hypersensitivity, we test the long-lasting effects of cognitive load. Additionally, we used psychophysiological measurements to explored potential underlying mechanisms involving limited attentional resources and sympathetic arousal.

The Effect of Observing High or Low Pain on the Development of Central Sensitization.

It is unknown whether watching other people in high pain increases mechanical hypersensitivity induced by pain. We applied high-frequency electrical stimulation (HFS) on the skin of healthy volunteers to induce pinprick mechanical hypersensitivity. Before HFS participants were randomly allocated to 2 groups: in the low pain group, which was the control condition, they watched a model expressing and reporting lower pain scores, in the high pain group the model expressed and reported higher scores. The 2 videos were selected on the basis of a pilot/observational study that had been conducted before. We tested the differences in perceived intensity of the HFS procedure, in the development of hypersensitivity and the role of fear and empathy. The high pain group reported on average higher pain ratings during HFS. The perceived intensity of hypersensitivity, but not the unpleasantness or the length of the area was higher in the high pain group. Our results suggest that watching a person expressing more pain during HFS increases one's own pain ratings during HFS and may weakly facilitate the development of secondary mechanical hypersensitivity, although this latter result needs replication. PERSPECTIVE: Observing a person in high pain can influence the perceived pain intensity of a procedure leading to secondary mechanical hypersensitivity, and has a weak effect on hypersensitivity itself. The role of fear remains to be elucidated.

Changes in Pain-Related Fear and Pain When Avoidance Behavior is no Longer Effective.

Avoidance is considered key in the development of chronic pain. However, little is known about how avoidance behavior subsequently affects pain-related fear and pain. We investigated this using a robotic arm reaching avoidance task. In a between-subjects design both Experimental Group (n = 30) and Yoked Control Group (n = 30) participants perform either of 3 movement trajectories (T1-T3) to reach a target location. During acquisition, only participants of the Experimental Group could partially or fully avoid a painful electrocutaneous stimulus by choosing the intermediate trajectory (T2; 50% reinforcement) or the longest trajectory (T3; 0% reinforcement) versus the shortest trajectory (T1: 100% reinforcement). After acquisition, contingencies changed (all trajectories 50% reinforced), and the acquired avoidance behavior no longer effectively prevented pain from occurring. The Yoked Control Group received the same reinforcement schedule as the Experimental Group irrespective of their behavior. When avoidance behavior became ineffective for the Experimental Group, pain-related fear increased for the previously safe(r) trajectories (T2 and T3) and remained the same for T1, whereas pain threshold and tolerance declined. For the Yoked Group, pain-related fear increased for all trajectories. The Experimental Group persisted in emitting avoidance behavior following the contingency change, albeit at a lower frequency than during acquisition. PERSPECTIVE: Results indicate participants become more afraid of and sensitive to pain, when previously acquired avoidance is no longer effective. Also, participants continue to show avoidance behavior despite it being not adaptive anymore. These findings suggest that ineffective avoidance may play role in the maintenance and development of chronic pain.