Cutaneous Heat Pain Thresholds Research Articles

Cortisol affects pain sensitivity and pain-related emotional learning in experimental visceral but not somatic pain: a randomized controlled study in healthy men and women.

Despite growing interest in the role of stress mediators in pain chronicity, the effects of the stress hormone cortisol on acute pain remain incompletely understood. In a randomized, double-blind, placebo-controlled study with N = 100 healthy volunteers, we tested the effects of oral hydrocortisone (20 mg) in 2 widely used pain models for the visceral and somatic modality. Salivary cortisol was increased in the hydrocortisone group (time × group: P < 0.001). For the visceral modality, assessed using pressure-controlled rectal distensions, hydrocortisone decreased the pain threshold from before to after treatment (time × group: P = 0.011), an effect primarily driven by women (time × sex: P = 0.027). For the somatic modality, cutaneous heat pain thresholds remained unaffected by hydrocortisone. Hydrocortisone did not alter perceived pain intensity or unpleasantness of either modality. Conditioned pain-related fear in response to predictive cues was only observed for the visceral modality (time × modality: P = 0.026), an effect that was significantly reduced by hydrocortisone compared with placebo (time × group: P = 0.028). This is the first psychopharmacological study to support that acutely increased cortisol enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality. Stress-induced visceral hyperalgesia and deficits in emotional pain-related learning could play a role in the pathophysiology of chronic visceral pain.

Predictors of disability and absenteeism in workers with non-specific low back pain: A longitudinal 15-month study

The objective of this study was to identify baseline predictors of disability and absenteeism in workers with a history of non-specific low back pain (LBP). One hundred workers with a history of non-specific LBP participated in three evaluations (baseline, 7 and 15 months follow-up). Current and past history of LBP, clinical pain intensity, disability, absenteeism, fear-avoidance beliefs, pain catastrophizing, pain hypervigilance, work satisfaction and patient stratification based on "risk of poor clinical outcome assessment" (RPCO) were evaluated using questionnaires and interviews. In addition, cutaneous heat pain thresholds, cutaneous heat pain tolerance thresholds, conditioned pain modulation (CPM), trunk kinematics and muscle activity were measured during each evaluation. Logistic regression models were used to determine predictors of LBP disability and absenteeism at 15-months. Sixty-eight workers returned for the 15-month follow-up and among this sample, 49% reported disability and 16% reported absenteeism at follow-up. Baseline clinical pain intensity predicted disability (OR=1.08, 95%CI: 1.03-1.13) at 15-month while work satisfaction (OR=0.93, 95%CI: 0.87-0.99) and RPCO (OR=1.51, 95%CI: 1.05-2.16) predicted absenteeism. These results remained significant after adjustments for age, gender as well as type of work and intervention. This study highlights the importance of clinical pain and psychological factors in the prediction and potentially the prevention of future disability. Screening tools assessing these risk factors can be useful to evaluate workers with past history of low back pain.

Structural alterations of the brainstem in migraine.

Atypical brainstem modulation of pain might contribute to changes in sensory processing typical of migraine. The study objective was to investigate whether migraine is associated with brainstem structural alterations that correlate with this altered pain processing.MRI T1-weighted images of 55 migraine patients and 58 healthy controls were used to: (1) create deformable mesh models of the brainstem that allow for shape analyses; (2) calculate volumes of the midbrain, pons, medulla and the superior cerebellar peduncles; (3) interrogate correlations between regional brainstem volumes, cutaneous heat pain thresholds, and allodynia symptoms.Migraineurs had smaller midbrain volumes (healthy controls = 61.28 mm3, SD = 5.89; migraineurs = 58.80 mm3, SD = 6.64; p = 0.038), and significant (p < 0.05) inward deformations in the ventral midbrain and pons, and outward deformations in the lateral medulla and dorsolateral pons relative to healthy controls. Migraineurs had a negative correlation between ASC-12 allodynia symptom severity with midbrain volume (r = − 0.32; p = 0.019) and a positive correlation between cutaneous heat pain thresholds with medulla (r = 0.337; p = 0.012) and cerebellar peduncle volumes (r = 0.435; p = 0.001).Migraineurs with greater symptoms of allodynia have smaller midbrain volumes and migraineurs with lower heat pain thresholds have smaller medulla and cerebellar peduncles. The brainstem likely plays a role in altered sensory processing in migraine and brainstem structure might reflect severity of allodynia and hypersensitivity to pain in migraine.

Referred pain and cutaneous responses from deep tissue electrical pain stimulation in the groin

Persistent postherniotomy pain is located around the scar and external inguinal ring and is often described as deep rather than cutaneous, with frequent complaints of pain in adjacent areas. Whether this pain is due to local pathology or referred/projected pain is unknown, hindering mechanism-based treatment. Deep tissue electrical pain stimulation by needle electrodes in the right groin (rectus muscle, ilioinguinal/iliohypogastric nerve and perispermatic cord) was combined with assessment of referred/projected pain and the cutaneous heat pain threshold (HPT) at three prespecified areas (both groins and the lower right arm) in 19 healthy subjects. The assessment was repeated 10 days later to assess the reproducibility of individual responses. Deep electrical stimulation elicited pain at the stimulation site in all subjects, and in 15 subjects, pain from areas outside the stimulation area was reported, with 90-100% having the same response on both days, depending on the location. Deep pain stimulation significantly increased the cutaneous HPT (P<0.014). Individual HPT responses before and during deep electrical pain stimulation were significantly correlated (ρ>0.474, P≤0.040) at the two test days for the majority of test areas. Our results corroborate a systematic relationship between deep pain and changes in cutaneous nociception. The individual referred/projected pain patterns and cutaneous responses are variable, but reproducible, supporting individual differences in anatomy and sensory processing. Future studies investigating the responses to deep tissue electrical stimulation in persistent postherniotomy pain patients may advance our understanding of underlying pathophysiological mechanisms and strategies for treatment and prevention. ClinicalTrials.gov (NCT01701427).

Low heat pain thresholds in migraineurs between attacks.

Between attacks, migraine is associated with hypersensitivities to sensory stimuli. The objective of this study was to investigate hypersensitivity to pain in migraineurs between attacks. Cutaneous heat pain thresholds were measured in 112 migraineurs, migraine free for ≥ 48 hours, and 75 healthy controls. Pain thresholds at the head and at the arm were compared between migraineurs and controls using two-tailed t-tests. Among migraineurs, correlations between heat pain thresholds and headache frequency, allodynia symptom severity, and time interval until next headache were calculated. Migraineurs had lower pain thresholds than controls at the head (43.9 ℃ ± 3.2 ℃ vs. 45.1 ℃ ± 3.0 ℃, p = 0.015) and arm (43.2 ℃ ± 3.4 ℃ vs. 44.8 ℃ ± 3.3 ℃, p < 0.001). There were not significant correlations between pain thresholds and headache frequency or allodynia symptom severity. For the 41 migraineurs for whom time to next headache was known, there were positive correlations between time to next headache and pain thresholds at the head (r = 0.352, p = 0.024) and arm (r = 0.312, p = 0.047). This study provides evidence that migraineurs have low heat pain thresholds between migraine attacks. Mechanisms underlying these lower pain thresholds could also predispose migraineurs to their next migraine attack, a hypothesis supported by finding positive correlations between pain thresholds and time to next migraine attack.

Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial

The capsaicin receptor (TRPV1) antagonist ABT-102 demonstrates efficacy in multiple preclinical pain models. However, evolving clinical data for this compound class suggest potentially profound drug-induced thermosensory impairment. Safety and tolerability of ABT-102 were assessed in a multiple-dose, double-blind, placebo-controlled, randomized healthy volunteer trial. Thirty-six participants were randomized in a 2:1 ratio to ABT-102:placebo in 3 dose groups (1 mg, 2 mg, and 4 mg twice a day) and confined to an inpatient research unit for a 7-day treatment period and 3 follow-up days. Outcome measures included: oral and cutaneous cold detection, warm detection (WDT), and heat pain thresholds (HPT); oral perceived heat intensity (oral liquid test); time to hand withdrawal (water bath test); and cutaneous pain intensity (long thermal stimulus). Significant dose-dependent (placebo- and baseline-adjusted) increases in HPT and reduced painfulness of suprathreshold heat were present from days 1–7. For ABT-102 4 mg twice a day, model-based mean differences from placebo (95% confidence interval) were as follows: oral HPT, day 1 = 2.5°C (0.6–4.4), day 5 = 4.4°C (2.5–6.3); cutaneous HPT, day 2 = 3.3°C (1.4–5.3), day 5 = 5.3°C (3.3–7.2); oral WDT, day 1 = 2.6°C (0.5–4.7), day 5 = 2.7°C (0.6–4.9); cutaneous WDT, day 2 = 1.3 (0.0–2.6), day 5 = 1.6 (0.3–2.8) (all P < 0.05). Oral liquid test and water bath test results followed a similar pattern. There was no effect on cutaneous cold detection. All effects were fully reversed by day 10. There were no other relevant safety findings. Core body temperature remained below 39°C in all participants. In conclusion, ABT-102 potently and reversibly increased HPT and reduced painfulness of suprathreshold oral/cutaneous heat. In a randomized, double-blind, placebo-controlled trial, the selective TRPV1 antagonist ABT-102 potently and reversibly increased heat pain threshold and reduced painfulness of suprathreshold oral/cutaneous heat.

Effect of tourniquet-induced ischemia on cutaneous thermal thresholds.

The effect of tourniquet-induced ischemia on human thermal thresholds was studied. After the development of the A-fibre block (= a sharp elevation of cool threshold) the heat-pain threshold was still uninfluenced. This result supports previous evidence indicating that C-fibres mediate the liminal heat pain sensation. Thus, the quantitative determination of cutaneous heat pain thresholds provides a rather selective method for testing C-fibre mediated pain sensitivity, at least when a contact thermostimulator with a slow or moderate rise of stimulus temperature is used. The second aim of this study was to examine whether ischemia or mechanical pressure is the cause of the tourniquet-induced block of A-fibres. This was studied by varying the mechanical pressure and the amount of ischemia. With increased ischemia (with muscle work) the A-fibre block (increased cool threshold) came earlier, but this finding was not significant.

Subcutaneous Botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin

The present human study aimed at investigating the effect of subcutaneous administration of Botulinum toxin type A (BoNT/A) on capsaicin-induced trigeminal pain, neurogenic inflammation and experimentally induced cutaneous pain modalities. Fourteen healthy males (26.3±2.6 years) were included in this double-blind and placebo-controlled trial. The subjects received subcutaneous BoNT/A (22.5U) and isotonic saline in the mirror sides of their forehead. Pain and neurogenic inflammation was induced by four intradermal injections of capsaicin (100μg/μL) (before, and days 1, 3 and 7 after treatments). The capsaicin-induced pain intensity, pain area, the area of secondary hyperalgesia, the area of visible flare and vasomotor reactions were recorded together with cutaneous heat, electrical and pressure pain thresholds. BoNT/A reduced the capsaicin-induced trigeminal pain intensity compared to saline (F=37.9, P<0.001). The perceived pain area was smaller for the BoNT/A-treated side compared to saline (F=7.8, P<0.05). BoNT/A reduced the capsaicin-induced secondary hyperalgesia (F=5.3, P<0.05) and flare area (F=10.3, P<0.01) compared to saline. BoNT/A reduced blood flow (F1,26=109.5, P<0.001) and skin temperature (F1,26=63.1, P<0.001) at the capsaicin injection sites compared to saline and its suppressive effect was maximal at days 3 and 7 (P<0.05, post hoc test). BoNT/A elevated cutaneous heat pain thresholds (F=17.1, P<0.001) compared to saline; however, no alteration was recorded for electrical or pressure pain thresholds (P>0.05). Findings from the present study suggest that BoNT/A appears to preferentially target Cfibers and probably TRPV1-receptors, block neurotransmitter release and subsequently reduce pain, neurogenic inflammation and cutaneous heat pain threshold.

Association of striatal dopamine D2/D3 receptor binding potential with pain but not tactile sensitivity or placebo analgesia

Striatal dopamine D2/D3 receptors have been suggested to play a role in pain sensitivity and placebo effect. We studied whether the association of dopamine D2/D3 receptor binding potential (BP) with sensory thresholds is specific to the modality of pain, and whether striatal dopamine D2/D3 receptor BP predicts the magnitude of placebo analgesia. Pain and tactile thresholds, and placebo analgesia were assessed in eight healthy human male subjects who had previously participated in a dopamine D2/D3 receptor positron emission tomography study with [ 11C]raclopride. The results show that the cutaneous heat pain threshold was inversely correlated with dopamine D2/D3 receptor BP in the right putamen, but responses to tactile stimulation did not correlate with striatal dopamine D2/D3 receptor BP. Placebo-induced elevation of the heat pain threshold did not correlate with striatal dopamine D2/D3 receptor BP. These results suggest that the influence of striatal dopamine D2/D3 receptors on sensory thresholds is selective for the modality of pain. Moreover, striatal dopamine D2/D3 receptor BP appears not to predict individual's analgesic response to placebo.

Heat pain thresholds and cerebral event-related potentials following painful CO 2 laser stimulation in chronic tension-type headache

Current opinion concerning the pathophysiology of tension-type headache (TTH) and its related pericranial muscle tenderness proposes a primary role of central sensitization at the level of dorsalhorn/trigeminal nucleus as well as the supraspinal level. Investigation of these phenomena can be conducted using laser-evoked potentials (LEPs), which are objective and quantitative neurophysiological tools for the assessment of pain perception. In the present study we examined features of LEPs, as well as cutaneous heat-pain thresholds to laser stimulation, in relation to the tenderness of pericranial muscles in chronic TTH resulting from pericranial muscle disorder, during a pain-free phase. Twelve patients with TTH and 11 healthy controls were examined using the Total Tenderness Scoring (TTS) system. The stimulus was a laser pulse generated by a CO 2 laser. The dorsum of the hand and the cutaneous zones corresponding to pericranial muscles were stimulated. Subjective perception of stimulus intensity was assessed by a visual analogue scale. Two responses, the earlier named N2a and the last named P2, were considered; the absolute latency was measured at the highest peak of each response. The N2a–P2 components' peak-to-peak amplitude was detected. The heat pain threshold was similar in TTH patients and controls at the level of both the hand and pericranial skin. The TTS scores at almost all pericranial sites were higher in TTH patients than in normal controls. The amplitude of the N2a–P2 complex elicited by stimulation of the pericranial zone was greater in TTH patients than in controls; the amplitude increase was significantly associated with the TTS score. Our findings suggest that pericranial tenderness may be a primary phenomenon that precedes headache, and is mediated by a greater pain-specific hypervigilance at the cortical level.

Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity

The pain modulatory role of dopamine D2 receptors of the human forebrain was studied by determining the association between dopamine D2 receptor binding potential and the response to experimental pain. Nineteen healthy male volunteers participated in a dopamine D2 receptor positron emission tomography study. The extrastriatal regions of interest studied with [ 11C]FLB 457 as radioligand ( n=11) were the anterior cingulum, the medial and lateral thalamus, the medial and lateral frontal cortex, and the medial and lateral temporal cortex. The striatal regions of interest studied with [ 11C]raclopride ( n=8) were the caudate nucleus and the putamen. The latency to the ice water-induced cold pain threshold and tolerance were determined in a separate psychophysical test session. Moreover, the cutaneous heat pain threshold and its elevation by concurrent cold pain in the contralateral hand were determined in each subject. Cold pain threshold was inversely correlated with D2 binding potential in the right putamen and the cold pain tolerance was inversely correlated with D2 binding potential in the right medial temporal cortex. The magnitude of heat pain threshold elevation induced by concurrent cold pain was directly correlated with D2 binding potential in the left putamen. Other correlations of D2 binding potentials in varying brain regions with sensory responses were not significant. A psychophysical control study ( n=10) showed that cold pain responses were identical in the right and left hand. The results indicate that dopamine D2 receptor binding potential in the human forebrain, particularly in the striatum, may be an important parameter in determining the individual cold pain response and the potential for central pain modulation. Accordingly, an individual with only few available D2 receptors in the forebrain is likely to have a high tonic level of pain suppression, combined with a low capacity to recruit more (dopaminergic) central pain inhibition by noxious conditioning stimulation.

Effect of systemic medetomidine, an alpha 2 adrenoceptor agonist, on experimental pain in humans.

The effect of systemic (intravenous) medetomidine, an alpha-2 adrenoceptor agonist, on pain thresholds was studied in healthy human subjects (n = 6). Medetomidine produced a dose-dependent (cumulative doses: 25 and 50 micrograms) sedative effect evaluated by visual analog scale. Also, a dose-dependent decrease of blood pressure but not of heart rate was seen after administration of medetomidine. Pain threshold to electric stimulation of the tooth pulp and cutaneous heat pain threshold were uninfluenced by medetomidine. An index of cutaneous thermal sensitivity to innocuous stimuli, the width of the thermoneutral zone, also was uninfluenced by medetomidine. Medetomidine produced a significant attenuation of the affective-motivational component (unpleasantness) of tourniquet-induced ischemic pain, whereas the sensory-discriminative component (pain magnitude estimate) of the ischemic pain was not attenuated. The results suggest that systemic medetomidine alone at subanesthetic but sedative and hypotensive doses does not significantly influence the intensity and thresholds of experimental pain, whereas the affective-motivational component of pain can be attenuated.