Acute Pain Induction Research Articles

Automatic detection of pain using machine learning.

Pain is one of the most common symptoms reported by individuals presenting to hospitals and clinics and is associated with significant disability and economic impacts; however, the ability to quantify and monitor pain is modest and typically accomplished through subjective self-report. Since pain is associated with stereotypical physiological alterations, there is potential for non-invasive, objective pain measurements through biosensors coupled with machine learning algorithms. In the current study, a physiological dataset associated with acute pain induction in healthy adults was leveraged to develop an algorithm capable of detecting pain in real-time and in natural field environments. Forty-one human subjects were exposed to acute pain through the cold pressor test while being monitored using electrocardiography. A series of respiratory and heart rate variability features in the time, frequency, and nonlinear domains were calculated and used to develop logistic regression classifiers of pain for two scenarios: (1) laboratory/clinical use with an F1 score of 81.9% and (2) field/ambulatory use with an F1 score of 79.4%. The resulting pain algorithms could be leveraged to quantify acute pain using data from a range of sources, such as ECG data in clinical settings or pulse plethysmography data in a growing number of consumer wearables. Given the high prevalence of pain worldwide and the lack of objective methods to quantify it, this approach has the potential to identify and better mitigate individual pain.

Characterization of rat ultrasonic vocalization in the orofacial formalin test: Influence of the social context

Rats emit ultrasonic vocalizations (USVs) about 22 kHz and 50 kHz sound frequency to communicate the presence of negative or positive emotional states, respectively. The calling behavior may be influenced by several factors, including environmental factors. Likewise, pain behavior can be modulated according to the social context, and also can be transferred to conspecifics through direct observation and/or social interaction. Herein we investigated if acute pain induction was related to changes in emission of aversive and appetitive calls and how different social contexts affected the nociceptive behavior and USVs. Our results demonstrated that orofacial formalin injection in rats induced aversive calls in addition to the nociceptive behavior, and both are reduced by systemic treatment with morphine (2.5 mg/kg). Exposure of formalin-injected rats to cagemates had no effect on the nociceptive behavior or calls emitted by the demonstrator, but the observer showed emotional contagion of pain. In contrast, exposure of formalin-injected rats to non-cagemates decreased the nociceptive behavior of the demonstrator, without affecting the calls emission. The emotional contagion was not detected in non-cagemates or in cagemates separated by a visual barrier. In conclusion, we suggest that familiarity and the visual contact contributes to emotional contagion of pain. USV analysis may represent an additional measure in the evaluation of the emotional aspect of orofacial pain, and for the study of pain modulation.

Tactile Precision Remains Intact When Acute Neck Pain Is Induced

A growing body of evidence suggests that chronic pain is associated with perceptual changes, such as impaired tactile acuity and laterality judgements. A recent study on low back pain showed that tactile acuity was decreased immediately after acute pain induction. Biologically, acute pain should lead to enhanced rather than disruptive changes in tactile acuity to meaningfully respond to potentially damaging nociceptive stimuli. In this double-blinded experiment, 30 healthy volunteers attended 3 experimental sessions (injection, sham injection, and control condition) separated by 1 week each, to investigate the effect of acute nociception on tactile precision and laterality judgements. In the real injection condition, acute pain was induced by hypertonic saline solution injected into the mid portion of the trapezius muscle. Tactile acuity (2-point discrimination and an estimation task) and laterality judgements were measured before and during pain perception. In the sham condition, the injection was mimicked by a sham procedure (without piercing the skin), and in the control condition no intervention took place. Results showed that tactile acuity remained intact (P = .92), indicating that experimentally induced neck pain did not affect tactile precision. The time needed to complete the laterality judgement task improved over time in all conditions, reflecting a learning effect (P = .05). We conclude that acute neck pain does not result in perceptual distortions, possibly reflecting a higher protection demand for the neck, a body region in close anatomic proximity to neural centers responsible for vital functions. These data—in the context of existing evidence—indicates that tactile acuity may respond differently to noxious stimulation in different anatomic regions. PerspectiveIn this study, a sensory adaptation to acute neck pain was investigated. It was found that experimental neck pain did not elicit changes in the sensory axis, leaving tactile acuity intact in otherwise healthy participants. These data support site-specific sensory adaptation to pain.

Cognitive and Affective Benefits of a Mindful State in Response to and in Anticipation of Pain

The present study aimed to extend the existing literature of mindfulness as a stress protective factor by (1) exploring the role of mindfulness state, not only in response to but also in anticipation of acute pain and (2) investigating an explanatory pathway, decreased rumination, between anticipation of acute pain and cognitive performance, with mindfulness moderating this indirect effect. One-hundred-and-four undergraduates were assessed for state mindfulness and then underwent an acute pain induction using the cold pressor task (CPT). Pain measures included pain threshold, pain tolerance, pain intensity, short-form McGill Pain questionnaire, and pain catastrophizing. Next, half of the participants were told that they would be repeating the CPT after some intervening tasks; half were not told to expect a second CPT. Participants completed a Cognitive Estimation Task (CET) that involved problem-solving, followed by a measure of rumination during CET. Results showed no meaningful associations between mindfulness state and sensory measures of pain (e.g., pain tolerance, pain threshold), but higher mindfulness state was related to lower pain catastrophizing and lower McGill affective subscale scores. There was also evidence of a moderated indirect effect: the indirect effect of condition through rumination on CET performance was moderated by mindfulness. That is, those in the anticipation condition with higher mindfulness state later reported ruminating less during CET and performed better at CET. Mindfulness thus appeared to have a protective role in maladaptive emotional responses when one anticipates acute pain, shielding self-regulatory resources needed to think flexibly when expecting a stressor.

Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels.

There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells. This indicates that MCF7 cells not only express functional TRPV1 channels, but also produce endogenous TRPV1 agonists. We investigated the effects of MRS1477 and capsaicin on cell viability, caspase-3 and -9 activities and reactive oxygen species production in MCF7 cells. The fraction of apoptotic cells was increased after 3 days incubation with capsaicin (10 μM) paralleled by increased reactive oxygen species production and caspase activity. These effects were even more pronounced, when cells were incubated with MRS1477 (2 μM) either alone or together with CAPS (10 μM). Capsazepine, a TRPV1 blocker, inhibited both the effect of capsaicin and MRS1477. Whole-cell patch clamp recordings revealed that capsaicin-evoked TRPV1-mediated current density levels were increased after 3 days incubation with MRS1477 (2 μM). However, the tumor growth in MCF7 tumor-bearing immunodeficient mice was not significantly decreased after treatment with MRS1477 (10 mg/ kg body weight, i.p., injection twice a week). In conclusion, in view of a putative in vivo treatment with MRS1477 or similar compounds further optimization is required.

The Effect of Social Observational Learning, Empathy and Catastrophizing in Chronic Pain Patients During Acute Pain Induction.

In this study, we were interested in determining whether we could alter a pain response in a chronic pain patient population by exposing participants to different videos prior to inducing acute pain. This observational case series study required participants to report their pain level during the cold pressor task after viewing an instruction video. Recruitment and testing took place in a tertiary care multidisciplinary pain center. Forty adults with chronic pain participated in the study and completed the cold pressor test. Prior to testing, questionnaires measuring pain, empathy, and catastrophic thinking were completed and participants were randomized to view an instructional video where an actress either demonstrated pain behavior or a stoic response during the cold pressor test. Participants with higher levels of catastrophizing reported higher pain levels during the cold pressor test. Personal Distress Empathy measures of participants who viewed the pain catastrophizing video were significantly correlated with their final pain reports. Following the cold pressor task, participants' pain reports for their primary chronic pain sites were significantly reduced. These results support previous findings that people with chronic pain show the tendency toward increased acute pain experience if levels of catastrophizing and Personal Distress Empathy measures are higher. Participants reported attenuated chronic pain following induced pain, also in line with previous research suggesting a central endogenous inhibitory effect. Our findings shed light on the role of emotional and social components affecting the experience of pain in individuals with chronic pain.

(186) Relationship between central pain mechanisms and arterial blood pressure in pain free subjects

Studies in humans suggest an interrelationship between blood pressure and pain regulation, where elevated resting blood pressure is associated with decreased pain sensitivity in pain free normotensives. However, it is still unclear whether: 1) this interrelationship involves peripheral and central arterial blood pressure, or 2) central pain mechanisms are involved. We classified 13 pain-free subjects (mean age = 47.46; SD= 7.32) as normotensive (n = 6) or prehypertensive (n = 7) using a systolic blood pressure >135 mm Hg as the cutoff. Heart rate (HR) and peripheral and central blood pressures were measured non-invasively before, during and after experimental pain procedures. Suprathreshold heat pain responses (SHPR) were generated with repeated thermal stimuli, and conditioned pain modulation (CPM) was assessed using SHPR as the experimental stimulus and cold pressor task (7 °C) as the conditioning stimulus. Repeated measures ANOVA showed significant increases (pre, during and post pain) in all measures of peripheral and central blood pressure; however, the time*group (normotensive vs prehypertensive) interaction was significant only for peripheral systolic pressure (F (2,18)=6.07, p=0.01) and central systolic pressure (F(2,18)=3.84, p=0.04). Significant positive associations were found between SHPR and arterial blood pressure (peripheral and central, p< 0.01) only in prehypertensive subjects. There was a significant positive association between the magnitude of CPM and HR difference in all subjects. These preliminary results imply that: 1) the acute response of peripheral and central systolic pressure differs between normotensive and prehypertensive individuals, where normotensives have a more pronounced response to pain induction, and 2) inhibitory (CPM) and facilitatory (SHPR) central pain mechanisms are related to different cardiovascular mechanisms in response to acute pain induction. Further analyses in a larger sample and in chronic pain patients will provide stronger evidence about the interrelationship between blood pressure and central pain mechanisms. Supported by Charlotte Zietlow Research Grant, Indiana State University.

Intraplantar injection of linalool reduces paclitaxel-induced acute pain in mice

Linalool is the principal component of many essential oils known to possess biological activities. We previously reported that intraplantar injection of linalool reduces the nociceptive response as assayed by the capsaicin test. In this study, we sought to determine whether intraplantar injection of linalool could influence the induction of acute pain (allodynia and hyperalgesia) by paclitaxel in mice. Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it sometimes induces moderate to severe acute pain. Paclitaxel administered intraperitoneally as a single dose of 5, 10 or 20 mg/kg produced mechanical allodynia and hyperalgesia in mice. Paclitaxel-induced mechanical allodynia and hyperalgesia began 1 day after administration of paclitaxel and resolved within 7 days. Linalool injected into the hindpaw caused a significant reduction in paclitaxel-induced mechanical allodynia and hyperalgesia. Pretreatment with naloxone hydrochloride, an opioid receptor antagonist, or naloxone methiodide, a peripherally acting µ-opioid receptor-preferring antagonist, significantly reversed linalool-induced antiallodynia and antihyperalgesia. Our results provide evidence for the involvement of peripheral opioids in antiallodynia and antihyperalgesia induced by linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing paclitaxel-induced mechanical allodynia and hyperalgesia.

Acceptance-Versus Change-Based Pain Management

This study compared two theoretically opposed strategies for acute pain management: an acceptance-based and a change-based approach. These two strategies were compared in a within-subjects design using the cold pressor test as an acute pain induction method. Participants completed a baseline pain tolerance assessment followed by one of the two interventions and another pain tolerance test. The alternate strategy was presented in a separate, but otherwise identical, experimental session. On average, both interventions significantly increased pain tolerance relative to baseline, with no significant difference between the two intervention conditions. Baseline psychological acceptance emerged as a significant moderator of intervention efficacy; individuals with a high level of acceptance benefited significantly more from the acceptance intervention, whereas those with a low level of acceptance benefited more from the change-based intervention. Implications for increasing the effectiveness of psychotherapeutic treatments based on individual differences are discussed.

Shifts in attention biases in response to acute pain induction: Examination of a model of "conversion" among repressors.

Unlike most people, those who are characterized by a repressive coping style report high levels of physical (sensory) pain but low levels of emotional distress (affective pain), which is a discrepancy that may suggest a "conversion" process. In two studies, we tested an attention allocation model, proposing that repressors direct attention away from threatening negative affective information and toward nonthreatening physical pain information during emotionally arousing (painful) situations. In Study 1, 84 participants underwent a cold pressor and then recovered. Repressors reported greater pain during recovery than low- and high-anxious participants, but they reported lower distress than high-anxious participants. Repressors reported significant and large discrepancies between high pain and low distress, whereas these differences were less pronounced for other groups. In Study 2, 77 participants underwent an ischemic pain task while performing a modified dot-probe task with sensory and negative affective pain words as stimuli. Repressors showed increasing biases away from affective pain words and toward sensory pain words as the pain task continued, whereas low- and high-anxious participants did not show these shifts in attention. The results support the notion that conversion among repressors may involve a process by which attention is directed away from emotional distress during noxious stimulation and is focused instead on sensory information from pain.

Anger Management Style Moderates Effects of Attention Strategy During Acute Pain Induction on Physiological Responses to Subsequent Mental Stress and Recovery: A Comparison of Chronic Pain Patients and Healthy Nonpatients

To examine whether high trait anger-out chronic low back (CLBP) patients would show exceptionally large symptom-specific lower paraspinal (LP) responses, compared with healthy nonpatients, during pain induction, a subsequent mental stressor, and recovery when they were urged to suppress awareness of pain and suffering. CLBP patients (n = 93) and nonpatients (n = 105) were assigned randomly to one of four attention strategy conditions for use during pain induction: sensory-focus, distraction, suppression, or control. All participants underwent a cold pressor, and then performed mental arithmetic. They completed the anger-out (AOS) and anger-in (AIS) subscales of the Anger Expression Inventory. General Linear Model procedures were used to test Attention Strategy Condition x Patient/Nonpatient Status x AOS (or AIS) x Period interactions for physiological indices. Significant interactions were found such that: a) high trait anger-out patients in the Suppression condition seemed to show the greatest LP reactivity during the mental arithmetic followed by the slowest recovery compared with other conditions; b) high trait anger-out patients and nonpatients in the Suppression condition seemed to show the slowest systolic blood pressure recoveries compared with other conditions. Results extend previous work by suggesting that an anger-out style moderates effects of how attention is allocated during pain on responses to and recovery from a subsequent mental stressor. Results provide further evidence that trait anger-out and trait anger-in among CLBP patients are associated with increased LP muscle tension during and after pain and mental stress.

Repressive coping style and suppression of pain-related thoughts: Effects on responses to acute pain induction

Repressors have shown short-term tolerance of acute pain but long-term sensitivity to chronic pain. To reconcile this discrepancy, we hypothesised that repressors routinely suppress pain-related thoughts during acute pain, and thus paradoxically incur rebound effects (increased accessibility of the to-be-suppressed material) afterwards. Healthy individuals (n=222) were assigned to suppress or not suppress pain-related thoughts during a cold pressor. Recovery and exposure to a massage device followed. Repressors revealed evidence of habitual suppression: nonsuppression/repressors showed a pattern of slow recovery from the cold pressor and unfavourable responses to the massage device similar to that exhibited by suppression/high anxious participants; suppression/repressors showed the slowest recovery and found the massage more unpleasant than any group. Repressors may suffer long-term sensitivity to pain through rebound and contamination effects following attempts to suppress pain-related thoughts.

The role of attentional strategies in moderating links between acute pain induction and subsequent psychological stress: Evidence for symptom-specific reactivity among patients with chronic pain versus healthy nonpatients.

Vulnerability to stressors after pain may depend on the degree to which the strategy used to process information about pain perpetuates thoughts of suffering and distress. Patients with chronic low back pain (CLBP) may show susceptibility to stress after pain through symptom-specific (lower paraspinal [LP]) muscle reactivity. Patients with CLBP (n = 100) and healthy nonpatients (n = 105) underwent a cold pressor, under sensory focus, distraction, suppression, or control conditions, and then performed mental arithmetic. Only patients under the suppression condition revealed increased LP tension during pain that was sustained during mental arithmetic and sustained systolic blood pressure after mental arithmetic. Patients with CLBP who suppress pain may detrimentally affect responses to the next noxious event, particularly through prolonged LP muscle tension, that may contribute to a cycle of pain-stress-pain.

Enhanced dimensional complexity of the EEG during memory for personal pain in chronic pain patients

Associative connections between cortical cell assemblies representing pain-related memories should be stronger and more extensive in subjects with chronic pain. To test this hypothesis, the dimensional complexity of the electroencephalograph (EEG) was examined during the actual experience as well as during memory for pain. Nine chronic pain patients and nine matched healthy controls participated in the study. During acute pain induction, acute pain recall, personal stress and pain recall, the EEG was recorded from 15 scalp sites. Non-linear analysis, based on the theory of deterministic chaos, revealed higher and more widespread EEG complexity in the patients compared to the healthy controls only during the recall of the personal pain scene. The personal stress scene was rated equally aversive but did not induce more EEG complexity. These more extensive and more readily accessible pain memories may be instrumental for the persistence of chronic pain.

Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper

Resiniferatoxin is an extremely irritant diterpene present in the latex of several members of the genus Euphorbia. Its mechanism of action has been shown to be clearly distinct from that of the structurally related phorbol esters. Since resiniferatoxin possesses a 4-hydroxy-3-methoxyphenyl substituent, a key feature of capsaicin, the major pungent ingredient of plants of the genus Capsicum, we examined the ability of resiniferatoxin to induce typical capsaicin responses. We report here that treatment of rats with resiniferatoxin, like treatment with capsaicin, caused hypothermia, neurogenic inflammation, and pain. These responses were followed by loss of thermoregulation, by desensitization to neurogenic inflammation, and by chemical and thermal analgesia, with cross-tolerance between resiniferatoxin and capsaicin. Resiniferatoxin was 3–4 orders of magnitude more potent than capsaicin for the effects on thermoregulation and neurogenic inflammation. Resiniferatoxin was only comparable in potency to capsaicin, however, in the assay for induction of acute pain, and the desensitization to acute pain appeared to require less resiniferatoxin than did desensitization for the other responses. We conclude that resiniferatoxin acts as an ultrapotent capsaicin analog and hypothesize that it may distinguish between subclasses of capsaicin response.