“Taking action” to reduce pain—Has interpretation of the motor adaptation to pain been too simplistic?

Movement adapts during acute pain. This is assumed to reduce nociceptive input, but the interpretation may not be straightforward. We investigated whether movement adaptation during pain reflects a purposeful search for a less painful solution. Three groups of participants performed two blocks (Baseline, Experimental) of wrist movements in the radial-ulnar direction. For the Control group (n = 10) both blocks were painfree. In two groups, painful electrical stimulation was applied at the elbow in Experimental conditions when the wrist crossed radial-ulnar neutral. Different stimulus intensities were given for specific wrist angles in a secondary direction (flexion-extension) as the wrist passed radial-ulnar neutral (Pain 5–1 group:painful stimulation at ~5 or ~1/10—n = 21; Pain 5–0 group:~5 or 0(no stimulation)/10—n = 6)). Participants were not informed about the less painful alternative and could use any strategy. We recorded the percentage of movements using the wrist flexion/extension alignment that evoked the lower intensity noxious stimulus, movement variability, and change in wrist/forearm alignment during pain. Participants adapted their strategy of wrist movement during pain provocation and reported less pain over time. Three adaptations of wrist movement were observed; (i) greater use of the wrist alignment with no/less noxious input (Pain 5–1, n = 8/21; Pain 5–0, n = 2/6); (ii) small (n = 9/21; n = 3/6) or (iii) large (n = 4/21; n = 1/6) change of wrist/forearm alignment to a region that was not allocated to provide an actual reduction in noxious stimulus. Pain reduction was achieved with “taking action” to relieve pain and did not depend on reduced noxious stimulus.

Functional and diffusion MRI reveal the neurophysiological basis of neonates’ noxious-stimulus evoked brain activity

Understanding the neurophysiology underlying neonatal responses to noxious stimulation is central to improving early life pain management. In this neonatal multimodal MRI study, we use resting-state and diffusion MRI to investigate inter-individual variability in noxious-stimulus evoked brain activity. We observe that cerebral haemodynamic responses to experimental noxious stimulation can be predicted from separately acquired resting-state brain activity (n=18). Applying this prediction model to independent Developing Human Connectome Project data (n=215), we identify negative associations between predicted noxious-stimulus evoked responses and white matter mean diffusivity. These associations are subsequently confirmed in the original noxious stimulation paradigm dataset, validating the prediction model. Here, we observe that noxious-stimulus evoked brain activity in healthy neonates is coupled to resting-state activity and white matter microstructure, that neural features can be used to predict responses to noxious stimulation, and that the dHCP dataset could be utilised for future exploratory research of early life pain system neurophysiology.

Functional and diffusion MRI reveal the neurophysiological basis of neonates’ noxious-stimulus evoked brain activity

Understanding the neurophysiology underlying neonatal responses to noxious stimulation is central to improving early life pain management. In this neonatal multimodal MRI study, we use resting-state and diffusion MRI to investigate inter-individual variability in noxious-stimulus evoked brain activity. We observe that cerebral haemodynamic responses to experimental noxious stimulation can be predicted from separately acquired resting-state brain activity (n = 18). Applying this prediction model to independent Developing Human Connectome Project data (n = 215), we identify negative associations between predicted noxious-stimulus evoked responses and white matter mean diffusivity. These associations are subsequently confirmed in the original noxious stimulation paradigm dataset, validating the prediction model. Here, we observe that noxious-stimulus evoked brain activity in healthy neonates is coupled to resting-state activity and white matter microstructure, that neural features can be used to predict responses to noxious stimulation, and that the dHCP dataset could be utilised for future exploratory research of early life pain system neurophysiology.

Functional and diffusion MRI reveal the neurophysiological basis of neonates’ noxious-stimulus evoked brain activity

Understanding the neurophysiology underlying neonatal responses to noxious stimulation is central to improving early life pain management. In this neonatal multimodal MRI study, we use resting-state and diffusion MRI to investigate inter-individual variability in noxious-stimulus evoked brain activity. We observe that cerebral haemodynamic responses to experimental noxious stimulation can be predicted from separately acquired resting-state brain activity (n=18). Applying this prediction model to independent Developing Human Connectome Project data (n=215), we identify negative associations between predicted noxious-stimulus evoked responses and white matter mean diffusivity. These associations are subsequently confirmed in the original noxious stimulation paradigm dataset, validating the prediction model. Here, we observe that noxious-stimulus evoked brain activity in healthy neonates is coupled to resting-state activity and white matter microstructure, that neural features can be used to predict responses to noxious stimulation, and that the dHCP dataset could be utilised for future exploratory research of early life pain system neurophysiology.

Onset hyperalgesia and offset analgesia: Transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.

Why Effective Pain Management Remains a Challenge

Pain is a subjective expression of neural impulses induced by a stimulus with a capacity to potentially damage tissues of the body. Simply put, pain is the reaction of the body to a potentially noxious or noxious stimulus, which threatens the normal homeostasis if unrelieved. Pain can be managed via pharmacological and non-pharmacological means, and pharmacological agents are the most widely accepted means, which have been shown to have variable effectiveness against pain. The barriers to effective pharmacological pain management in clinical practice are discussed in this chapter.

Effects of Standard and Sustained-release Buprenorphine on the Minimum Alveolar Concentration of Isoflurane in C57BL/6 Mice

Both standard and sustained-release injectable formulations of buprenorphine (Bup and BupSR, respectively) are used as preemptive analgesics, potentially affecting gas anesthetic requirements. This study tested the effects of Bup and BupSR on isoflurane requirements and confirmed that buprenorphine could reduce isoflurane requirements during a laparotomy in mice. We hypothesized that both Bup and BupSR would significantly decrease the required minimum alveolar concentration (MAC) of isoflurane. C57BL/6 mice received either isotonic crystalloid fluid (control), Bup (0.1 mg/kg), or BupSR (1.2 mg/kg) subcutaneously 10 min prior to the induction of anesthesia. Each anesthetized mouse was tested at 2 isoflurane concentrations. A 300-g noxious stimulus was applied at each isoflurane concentration, alternating between hindfeet. In addition, a subset of mice underwent terminal laparotomy or 60 min of anesthesia after injection with Bup, BupSR, or saline to ensure an appropriate surgical plane of anesthesia. Mice were maintained at the lowest isoflurane concentration that resulted in 100% of mice at a surgical plane from the aforementioned MAC experiments (control, 2.0%; Bup and BupSR, 1.7%). Analysis showed that both Bup and BupSR significantly decreased isoflurane requirements by 25.5% and 14.4%, respectively. The isoflurane MAC for the control injection was 1.80% ± 0.09%; whereas Bup and BupSR decreased MAC to 1.34% ± 0.08% and 1.54% ± 0.09%, respectively. Sex was not a significantly different between the injection groups during MAC determination. All of the mice that underwent surgery achieved a surgical plane of anesthesia on the prescribed regimen and recovered normally after discontinuation of isoflurane. Lastly, heart and respiratory rates did not differ between mice that underwent surgery and those that were anesthetized only. Bup and BupSR are MAC-sparing in male and female C57BL/6 mice and can be used for effective multimodal anesthesia.