Area Of Secondary Hyperalgesia Research Articles

Reliability of Measuring the Area and Intensity of Secondary Hyperalgesia Induced by High Frequency Stimulation

Reliability of Measuring the Area and Intensity of Secondary Hyperalgesia Induced by High Frequency Stimulation

Progesterone relates to enhanced incisional acute pain and pinprick hyperalgesia in the luteal phase of female volunteers.

The role of sex hormones on postsurgical pain perception is basically unclear. Here, we studied the role of endogenous gonadal hormones for pain and hyperalgesia in human volunteers after experimental incision. A 4-mm incision was made in the volar forearm of 15 female volunteers both in the follicular and the luteal phase (random block design). Somatosensory profiles were assessed at baseline and 1 to 72 hours after incision by quantitative sensory testing, compared between both cycle phases, and related to individual plasma levels of gonadal hormones. Sensory testing at baseline revealed significantly lower pain thresholds (25 vs 46 mN, P < 0.005) and increased pain ratings to pinprick (0.96 vs 0.47, P < 0.0001) in the luteal phase; similarly, 1 hour after incision, pain intensity to incision (38 vs 21/100, P < 0.005), pinprick hyperalgesia by rating (P < 0.05), and area of secondary hyperalgesia (P < 0.001) were enhanced in the luteal phase. Multiple regression analysis revealed that pinprick pain sensitivity at baseline was significantly predicted by progesterone (partial r = 0.67, P < 0.001), follicle-stimulating hormone (FSH) (partial r = 0.61, P < 0.005), and negatively by testosterone (partial r = -0.44, P < 0.05). Likewise, incision-induced pain and pinprick hyperalgesia (rating and area) were significantly predicted by progesterone (partial r = 0.70, r = 0.46, and r = 0.47, respectively; P < 0.05-0.0001) and in part by FSH; the contribution of estrogen, however, was fully occluded by progesterone for all measures. In conclusion, pinprick pain and incision-induced pain and mechanical hyperalgesia were greater in the luteal phase and predicted by progesterone, suggesting a major role for progesterone. Other hormones involved are testosterone (protective) and in part FSH.

Brain resting-state connectivity in the development of secondary hyperalgesia in healthy men.

Central sensitization is a condition in which there is an abnormal responsiveness to nociceptive stimuli. As such, the process may contribute to the development and maintenance of pain. Factors influencing the propensity for development of central sensitization have been a subject of intense debate and remain elusive. Injury-induced secondary hyperalgesia can be elicited by experimental pain models in humans, and is believed to be a result of central sensitization. Secondary hyperalgesia may thus reflect the individual level of central sensitization. The objective of this study was to investigate possible associations between increasing size of secondary hyperalgesia area and brain connectivity in known resting-state networks. We recruited 121 healthy participants (male, age 22, SD 3.35) who underwent resting-state functional magnetic resonance imaging. Prior to the scan session, areas of secondary hyperalgesia following brief thermal sensitization (3min. 45°C heat stimulation) were evaluated in all participants. 115 participants were included in the final analysis. We found a positive correlation (increasing connectivity) with increasing area of secondary hyperalgesia in the sensorimotor- and default mode networks. We also observed a negative correlation (decreasing connectivity) with increasing secondary hyperalgesia area in the sensorimotor-, fronto-parietal-, and default mode networks. Our findings indicate that increasing area of secondary hyperalgesia is associated with increasing and decreasing connectivity in multiple networks, suggesting that differences in the propensity for central sensitization, assessed as secondary hyperalgesia areas, may be expressed as differences in the resting-state central neuronal activity.

Attenuation of capsaicin-induced ongoing pain and secondary hyperalgesia during exposure to an immersive virtual reality environment

Introduction:There is growing evidence that virtual reality (VR) can be used in the treatment of chronic pain conditions. However, further research is required to better understand the analgesic mechanisms during sensitised pain states.Objectives:We examined the effects of an immersive polar VR environment on capsaicin-induced ongoing pain and secondary hyperalgesia. We also investigated whether the degree of analgesia was related to baseline conditioned pain modulation (CPM) responses.Methods:Nineteen subjects had baseline CPM and electrical pain perception (EPP) thresholds measured before the topical application of capsaicin cream. Visual analogue scale ratings were measured to track the development of an ongoing pain state, and EPP thresholds were used to measure secondary hyperalgesia. The effects of a passive polar VR environment on ongoing pain and secondary hyperalgesia were compared with sham VR (ie, 2D monitor screen) in responders to capsaicin (n = 15).Results:Virtual reality was associated with a transient reduction in ongoing pain and an increase in EPP thresholds in an area of secondary hyperalgesia. Baseline CPM measurements showed a significant correlation with VR-induced changes in secondary hyperalgesia, but not with VR-induced changes in ongoing pain perception. There was no correlation between VR-induced changes in pain perception and VR-induced changes in secondary hyperalgesia.Conclusion:Virtual reality can reduce the perception of capsaicin-induced ongoing pain and secondary hyperalgesia. We also show that CPM may provide a means by which to identify individuals likely to respond to VR therapy.

High frequency electrical stimulation induces a long-lasting enhancement of event-related potentials but does not change the perception elicited by intra-epidermal electrical stimuli delivered to the area of increased mechanical pinprick sensitivity.

High frequency electrical stimulation (HFS) of the skin induces increased pinprick sensitivity in the surrounding unconditioned skin. The aim of the present study was to investigate the contribution of A-fiber nociceptors to this increased pinprick sensitivity. For this we assessed if the perception and brain responses elicited by low-intensity intra-epidermal electrical stimulation (IES), a method preferentially activating Aδ-fiber nociceptors, are increased in the area of HFS-induced increased pinprick sensitivity. HFS was delivered to one of the two forearms of seventeen healthy volunteers. Mechanical pinprick stimulation and IES were delivered at both arms before HFS (T0), 20 minutes after HFS (T1) and 45 minutes after HFS (T2). In all participants, HFS induced an increase in pinprick perception at the HFS-treated arm, adjacent to the site of HFS. This increase was significant at both T1 and T2. HFS did not affect the percept elicited by IES, but did enhance the magnitude of the N2 wave of IES-evoked brain potentials, both at T1 and at T2. Our results show that HFS induces a long-lasting enhancement of the N2 wave elicited by IES in the area of secondary hyperalgesia, indicating that HFS enhances the responsiveness of the central nervous system to nociceptive A-fiber input. However, we found no evidence that HFS affects the perception elicited by IES, which may suggest that the population of nociceptors that mediate the perception elicited by IES do not contribute to HFS-induced increased pinprick sensitivity.

Quickly responding C-fibre nociceptors contribute to heat hypersensitivity in the area of secondary hyperalgesia.

A recent animal study showed that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C-fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C-fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C-fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. It has recently been shown that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C-fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20min and 45min after HFS, short-lasting (10ms) high-intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15mm2 ) were applied to the area of increased mechanical pinprick sensitivity at the HFS-treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0-100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C-fibre laser-evoked potentials at the HFS-treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C-fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS.

The association between areas of secondary hyperalgesia and volumes of the caudate nuclei and other pain relevant brain structures—A 3-tesla MRI study of healthy men

IntroductionCentral sensitization plays a pivotal role in maintenance of pain and is believed to be intricately involved in several chronic pain conditions. One clinical manifestation of central sensitization is secondary hyperalgesia. The degree of secondary hyperalgesia presumably reflects individual levels of central sensitization. The objective of this study was to investigate the association between areas of secondary hyperalgesia and volumes of the caudate nuclei and other brain structures involved in pain processing.Materials and methodsWe recruited 121 healthy male participants; 118 were included in the final analysis. All participants underwent whole brain magnetic resonance imaging (MRI). Prior to MRI, all participants underwent pain testing. Secondary hyperalgesia was induced by brief thermal sensitization. Additionally, we recorded heat pain detection thresholds (HPDT), pain during one minute thermal stimulation (p-TS) and results of the Pain Catastrophizing Scale (PCS) and Hospital Anxiety and Depression score (HADS).ResultsWe found no significant associations between the size of the area of secondary hyperalgesia and the volume of the caudate nuclei or of the following structures: primary somatosensory cortex, anterior and mid cingulate cortex, putamen, nucleus accumbens, globus pallidus, insula and the cerebellum. Likewise, we found no significant associations between the volume of the caudate nuclei and HPDTs, p-TS, PCS and HADS.ConclusionsOur findings indicate that the size of the secondary hyperalgesia area is not associated with the volume of brain structures relevant for pain processing, suggesting that the propensity to develop central sensitization, assessed as secondary hyperalgesia, is not correlated to brain structure volume.

No perceptual prioritization of non-nociceptive vibrotactile and visual stimuli presented on a sensitized body part

High frequency electrical conditioning stimulation (HFS) is an experimental method to induce increased mechanical pinprick sensitivity in the unconditioned surrounding skin (secondary hyperalgesia). Secondary hyperalgesia is thought to be the result of central sensitization, i.e. increased responsiveness of nociceptive neurons in the central nervous system. Vibrotactile and visual stimuli presented in the area of secondary hyperalgesia also elicit enhanced brain responses, a finding that cannot be explained by central sensitization as it is currently defined. HFS may recruit attentional processes, which in turn affect the processing of all stimuli. In this study we have investigated whether HFS induces perceptual biases towards stimuli presented onto the sensitized arm by using Temporal Order Judgment (TOJ) tasks. In TOJ tasks, stimuli are presented in rapid succession on either arm, and participants have to indicate their perceived order. In case of a perceptual bias, the stimuli presented on the attended side are systematically reported as occurring first. Participants performed a tactile and a visual TOJ task before and after HFS. Analyses of participants’ performance did not reveal any prioritization of the visual and tactile stimuli presented onto the sensitized arm. Our results provide therefore no evidence for a perceptual bias towards tactile and visual stimuli presented onto the sensitized arm.

Generalized Pain Sensitization and Endogenous Oxytocin in Individuals With Symptoms of Migraine: A Cross‐Sectional Study

The current study examined pain and neurogenic inflammation responses to topical capsaicin during the interictal period (between headache) and their relationship with plasma oxytocin in individuals with migraine. Individuals with migraine can experience generalized (extracephalic) hyperalgesia, which can persist even between headache attacks. Elevated levels of plasma and cerebrospinal fluid oxytocin have been observed during migraine attacks, oxytocin levels being positively associated with the intensity of migraine symptoms. However, whether oxytocin plays a role in the mechanisms of generalized pain sensitization and neurogenic inflammation during the interictal period has not been studied yet. Understanding migraineurs' interictal pain phenotype and endogenous oxytocin might help identify individuals who would benefit from intranasal oxytocin treatment. Thirty-two subjects with migraine and 26 healthy controls underwent pain testing. The current study compared capsaicin-induced pain, central sensitization (areas of secondary mechanical allodynia and hyperalgesia), and neurogenic inflammation (capsaicin-induced flare) responses on the nondominant volar forearm between migraineurs and healthy controls. Additionally, we studied plasma oxytocin levels and their relationship to migraine symptoms, experimental pain and affect. The results indicated a significant group effect (P = .019): Migraineurs reported greater capsaicin-induced pain unpleasantness (M = 1.2, SD = 1.4) on a 0-10 scale and showed larger areas of flare (LnM = 2.8, SD = 0.4) than healthy controls (M = 0.5, SD = 0.8; LnM = 2.6, SD = 0.4; ps < .032). In a subgroup analysis, enhanced capsaicin-induced pain unpleasantness was found in the chronic (P = .007), but not the episodic (Ps > .200), migraineurs. The oxytocin levels were elevated in migraineurs and accounted for 18% of the group difference in capsaicin-induced pain unpleasantness. Within migraineurs, interictal oxytocin levels were negatively associated with psychological distress (Ps < .030). However, during the interictal period, pain sensitivity in extracephalic regions and plasma oxytocin levels were unrelated to migraine symptom parameters (Ps > .074). Lastly, the results found no group difference in areas of secondary mechanical allodynia and hyperalgesia (Ps >.298). The current study revealed that individuals with migraine exhibit enhanced extracephalic capsaicin-induced pain unpleasantness and flare responses during interictal periods. In addition, migraineurs, especially those with chronic migraine, had slightly elevated interictal oxytocin levels compared to controls, which was associated with their affective component of experimental pain. Therefore, treatment targeting affective pain during the interictal period may help to reduce generalized pain in migraine. Furthermore, endogenous increases in oxytocin may be a compensatory mechanism that may help decrease affective distress in migraineurs. The therapeutic effects of intranasal oxytocin may benefit migraineurs by reducing their affective distress.

Effect of Intravenous Alfentanil on Nonpainful Thermally Induced Hyperalgesia in Healthy Volunteers.

Experimental interventions that activate specific components of clinical pain are necessary for characterization of underlying mechanisms and pharmacology. Cutaneous hyperalgesia has been described that uses nonpainful heat to induce secondary hyperalgesia. This study evaluated the effect of intravenous alfentanil on experimental cutaneous hyperalgesia created using this method. Eighteen subjects participated in a randomized, double-blinded, placebo-controlled crossover study consisting of 2 sessions, 1 with alfentanil and 1 with placebo. Using a computer-controlled infusion pump, alfentanil or matching placebo was maintained at a constant plasma level of 75 ng/mL for 1 hour followed by the application of a 40°C heat stimulus to the right thenar eminence for 15 minutes. The temperature was raised by 1°C every 15 minutes until the subject reported pain or 45°C was reached. After the end point was reached, the temperature was maintained, and repeat testing was performed. The nonpainful heat created an area of secondary cutaneous hyperalgesia and significant decrease in mechanical pain threshold on heat-treated right vs untreated left during placebo administration. Alfentanil prevented the hypersensitivity when compared to placebo (P < .05) but failed to reduce the area of secondary hyperalgesia created by nonpainful heat when compared to placebo (P = .06). Neither alfentanil nor the heat lamp treatment showed any significant effect on other neurosensory measures. This study demonstrated a reliable production of cutaneous hyperalgesia using a nonpainful stimulus that is affected by the systemic delivery of alfentanil. This model for human cutaneous experimental pain may be a useful method for scientific characterization of analgesics.

(207) Sex differences in the perception of pain from topical capsaicin

Capsaicin, which induces an episodic burning pain sensation and an area of skin flare and secondary hyperalgesia on and around the site of application, has become an increasingly popular tool for evaluating the neurobiological mechanisms of pain. Capsaicin is typically either applied topically or injected locally and heated with a thermode. In most individuals, it produces gradually increasing pain of moderate severity, which plateaus around 25 minutes. However, substantial intra-individual differences exist; and approximately 25% of the population may not experience capsaicin as noxious. Limited research has focused on those who do not experience capsaicin-induced pain. The current secondary analyses sought to examine the characteristics of individuals that do not perceive capsaicin as painful. A total of 88 healthy individuals (43.2% female) who were screened for enrollment in a larger study participated in this subanalysis. A 10% topical capsaicin cream was applied to the dorsum of the non-dominant hand and a thermode was applied, maintaining a constant temperature of 40°Celsius for 30 minutes. Pain ratings were obtained every five minutes, using a 0-100 scale. The area of flare (redness surrounding the capsaicin site) and secondary hyperalgesia (sensitivity around the site, a proxy of central sensitization) were measured and recorded. Sixty participants (68.2%) had a pain rating of 20 or more; and 28 (31.8%) rated their pain as less than 20. Overall, a sex difference was noted in capsaicin-related pain ratings (women x=46.0, SD=28.2 and men x=30.6, SD=28.2) with more men than women rating pain as less than 20 (42% and 18% respectively, p=0.02). No age or race differences in capsaicin-induced pain were demonstrated. These findings suggest that men may be less likely to perceive pain from capsaicin. The underlying mechanisms accounting for these differences warrant further investigation.

Pain catastrophizing may moderate the association between pain and secondary hyperalgesia.

Catastrophizing, a persistent negative mental set characterized by helplessness, rumination, and magnification of pain sensations, has a potent effect on pain report and clinical outcomes. Previous studies have documented an association between cognitive factors and central sensitization. The current analysis sought to test the potential modulating effect of pain catastrophizing on the association between capsaicin pain and the region of secondary hyperalgesia. Thirty-eight healthy individuals (50% women, mean age = 25.7, SD = 5.3) completed the Pain Catastrophizing Scale (PCS), then underwent topical application of 10% capsaicin, which was covered by a thermode maintained at 40°C for 90-min. Following removal of the capsaicin, the region of secondary hyperalgesia was determined. Hayes' PROCESS macro was employed to examine catastrophizing's potential moderating effect, which did not reveal a significant association between capsaicin pain ratings and the region of secondary hyperalgesia (β = 15.1, p = .06). Though PCS was not associated with area of secondary hyperalgesia (β = 23.9, p = .29), a significant interaction was present between PCS and capsaicin pain ratings (β = 3.7, p = .0004). Specifically, those endorsing higher catastrophizing levels and higher pain ratings experienced the greatest areas of secondary hyperalgesia. The Johnson-Neyman technique was used to determine the regional effect of the moderation, which indicated that when PCS scores were ≥10.6, capsaicin pain significantly moderated the association between pain and area of secondary hyperalgesia. These results suggest that catastrophizing plays an important role in the area of secondary hyperalgesia, and potentially central sensitization, warranting further testing in future research.

Heat pain detection threshold is associated with the area of secondary hyperalgesia following brief thermal sensitization: a study of healthy male volunteers.

IntroductionThe area of secondary hyperalgesia following brief thermal sensitization (BTS) of the skin and heat pain detection thresholds (HPDT) may both have predictive abilities in regards to pain sensitivity and clinical pain states. The association between HPDT and secondary hyperalgesia, however, remains unsettled, and the dissimilarities in physiologic properties suggest that they may represent 2 distinctively different pain entities. The aim of this study was to investigate the association between HPDT and BTS-induced secondary hyperalgesia.MethodsA sample of 121 healthy male participants was included and tested on 2 separate study days with BTS (45°C, 3 minutes), HPDT, and pain during thermal stimulation (45°C, 1 minute). Areas of secondary hyperalgesia were quantified after monofilament pinprick stimulation. The pain catastrophizing scale (PCS) and hospital anxiety and depression scale (HADS) were also applied.ResultsA significant association between HPDT and the size of the area of secondary hyperalgesia (p<0.0001) was found. The expected change in area of secondary hyperalgesia due to a 1-degree increase in HPDT was estimated to be −27.38 cm2, 95% confidence interval (CI) of −37.77 to −16.98 cm2, with an R2 of 0.19. Likewise, a significant association between HADS-depression subscore and area of secondary hyperalgesia (p=0.046) was found, with an estimated expected change in secondary hyperalgesia to a 1-point increase in HADS-depression subscore of 11 cm2, 95% CI (0.19–21.82), and with R2 of 0.03. We found no significant associations between secondary hyperalgesia area and PCS score or pain during thermal stimulation.ConclusionHPDT and the area of secondary hyperalgesia after BTS are significantly associated; however, with an R2 of only 19%, HPDT only offers a modest explanation of the inter-participant variation in the size of the secondary hyperalgesia area elicited by BTS.

Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model: a study protocol: A randomized, double-blind, placebo-controlled, crossover trial with an enriched design.

Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion.The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose–response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization.Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm2). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days—days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169 hours after the thermal injury (day 1–4). The secondary outcomes were pin-prick pain thresholds assessed by weighted-pin instrument (8–512 mN) at primary and secondary hyperalgesia areas (days 1–4).The naloxone-induced unmasking of latent sensitization is an interesting model for exploring the transition from acute to chronic pain. The results from the present study may provide valuable information regarding future research in persistent postsurgical pain states.

Protective effects of dexmedetomidine combined with flurbiprofen axetil on remifentanil-induced hyperalgesia: A randomized controlled trial.

High dosages of intra-operative remifentanil are associated with opioid-induced hyperalgesia (OIH). The aim of the present study was to investigate the effect of combined dexmedetomidine and flurbiprofen axetil treatment on remifentanil-induced hyperalgesia. Patients with an American Society of Anesthesiologists physical status of I–II who were diagnosed with hysteromyoma and scheduled for laparoscopic assisted vaginal hysterectomy (LAVH) were randomly divided into three groups. Group hyperalgesia (Group H, n=29) received intra-operative remifentanil, Group hyperalgesia and dexmedetomidine (Group HD, n=28) received remifentanil and a continuous infusion of dexmedetomidine, and Group hyperalgesia, dexmedetomidine and flurbiprofen axetil (Group HDF, n=29) received remifentanil, flurbiprofen axetil and dexmedetomidine. Mechanical pain thresholds were measured during the preoperative visit and postoperatively at 1, 6 and 24-h time points. Visual analog scale (VAS) scores, time to analgesic requirement, total sufentanil consumption and side effects were assessed postoperatively. Mechanical pain threshold at the incision site was significantly lower in Group H compared with Groups HD and HDF (both P<0.05), and significantly higher in Group HDF than in Group HD (P<0.05). The area of secondary hyperalgesia at the incision site was greater in Group H than in the other two groups (both P<0.05), and significantly smaller in Group HDF compared with Group HD (P<0.05). VAS scores and total sufentanil consumption were significantly higher in Group H compared with the other two groups (both P<0.05), and were significantly lower in Group HDF compared with Group HD (P<0.05). Dexmedetomidine combined with flurbiprofen axetil exhibits synergetic effects in the prevention of remifentanil-induced hyperalgesia in patients undergoing LAVH.

Abstract # 1829 Early life adversity associated with enhanced capsaicin-induced spontaneous pain

Human trauma has been associated with an increased risk for chronic pain. Animal research indicates that early life stress induces a persistent pain sensitization that is unmasked by stress during adulthood. These studies suggest adversity enhances pain sensitivity. However, how stressors during childhood alter pain in humans remains understudied. Previous studies from our laboratory showed associations between adversity and central sensitization. The present study examined whether young adults reporting childhood adversity would show enhanced central (secondary hyperalgesia) and peripheral sensitization (spontaneous pain) following stress, a single session of written emotional disclosure (WED) of trauma. We used a 2 (low adversity [M = 1.2, SEM = 0.78], high adversity [M = 12.64, SEM = 0.81]) X 3 (neutral or trauma topics in a safe environment or trauma topic in a neutral environment) factorial design where participants in the top and bottom tertiles of the Traumatic Life Events Questionnaire comprised the high and low adversity groups. Two-way ANCOVAs controlling for experimenter revealed main effects of adversity on capsaicin-induced area of secondary hyperalgesia, F(1,32) = 6.299, p = .017, and spontaneous pain intensity, F(1,32) = 5.332, p = .028, and unpleasantness, F(1,32) = 4.906, p = .034, with the high adversity group reporting greater spontaneous pain during WED. These findings suggest that early life adversity is linked to enhanced central and peripheral sensitization in young adults.

Secondary hyperalgesia is mediated by heat-insensitive A-fibre nociceptors.

It is believed that secondary hyperalgesia (the increased sensitivity to mechanical nociceptive stimuli that develops after cutaneous tissue injury in the surrounding uninjured skin) is mediated by a subclass of nociceptors: the slowly adapting A-fibre mechano-heat nociceptors (AMH-type I). Here we tested this hypothesis. By using intense long-lasting heat stimuli, which are known to activate these slowly adapting AMH-type I nociceptors, we show that the perceived intensity elicited by these stimuli is not increased in the area of secondary hyperalgesia. Moreover, we show that during an A-fibre nerve conduction block the perception elicited by the long-lasting heat stimuli is significantly reduced in a time window that matches the response profile of the AMH-type I nociceptors. AMH-type I nociceptors contribute to the perception of sustained heat, but they do not mediate secondary hyperalgesia. Therefore, we propose that secondary hyperalgesia is mediated by high threshold mechanoreceptors. Secondary hyperalgesia refers to the increase in sensitivity to mechanical nociceptive stimuli delivered outside the area of tissue injury. Previous studies have suggested that secondary hyperalgesia is mediated by a specific class of myelinated nociceptors: slowly adapting A-fibre mechano- and heat-sensitive (AMH) type I nociceptors. Here, we tested this hypothesis by examining whether long-lasting heat stimuli, which are known to activate AMH-type I nociceptors, elicit enhanced responses when delivered to the area of secondary hyperalgesia induced by high frequency electrical stimulation of the skin (HFS). Before and 20min after HFS, sustained 30s radiant heat stimuli were delivered to the area of increased mechanical pinprick sensitivity while participants continuously rated intensity of perception using an online visual analog scale (0-100mm). After HFS, no significant enhancement of heat perception was observed in the area of increased pinprick sensitivity. To establish that myelinated nociceptors actually contribute to the perception of sustained heat, we conducted a second experiment in which sustained heat stimuli were presented before and during an A-fibre nerve conduction block, achieved by applying a rubber band with weights which compresses the superficial radial nerve against the radius. During the block, heat perception was significantly reduced 17-33s after the onset of the heat stimulus (before: mean=53mm, during: mean=31mm; P=0.03), matching the response profile of AMH-type I nociceptors. These results support the notion that AMH-type I nociceptors contribute to the perception of sustained heat, but also show that these afferents do not mediate secondary hyperalgesia.

Is the Volume of the Caudate Nuclei Associated With Area of Secondary Hyperalgesia? - Protocol for a 3-Tesla MRI Study of Healthy Volunteers.

BackgroundExperience and development of pain may be influenced by a number of physiological, psychological, and psychosocial factors. In a previous study we found differences in neuronal activation to noxious stimulation, and microstructural neuroanatomical differences, when comparing healthy volunteers with differences in size of the area of secondary hyperalgesia following a standardized burn injury.ObjectiveWe aim to investigate the degree of association between the volume of pain-relevant structures in the brain and the size of the area of secondary hyperalgesia following brief thermal sensitization.MethodsThe study consists of one experimental day, in which whole-brain magnetic resonance imaging (MRI) scans will be conducted including T1-weighed three-dimensional anatomy scan, diffusion tensor imaging, and resting state functional MRI. Before the experimental day, all included participants will undergo experimental pain testing in a parallel study (Clinicaltrials.gov Identifier: NCT02527395). Results from this experimental pain testing, as well as the size of the area of secondary hyperalgesia from the included participants, will be extracted from this parallel study.ResultsThe association between the volume of pain-relevant structures in the brain and the area of secondary hyperalgesia will be investigated by linear regression of the estimated best linear unbiased predictors on the individual volumes of the pain relevant brain structures.ConclusionsWe plan to investigate the association between experimental pain testing parameters and the volume, connectivity, and resting state activity of pain-relevant structures in the brain. These results may improve our knowledge of the mechanisms responsible for the development of acute and chronic pain.ClinicalTrialDanish Research Ethics Committee (identifier: H-15010473). Danish Data Protection Agency (identifier: RH-2015-149). Clinicaltrials.gov NCT02567318; http://clinicaltrials.gov/ct2/show/NCT02567318 (Archived by WebCite at http://www.webcitation.org/6i4OtP0Oi)

The analgesic effects of exogenous melatonin in humans.

The hormone, melatonin is produced with circadian rhythm by the pineal gland in humans. The melatonin rhythm provides an endogenous synchronizer, modulating e.g. blood pressure, body temperature, cortisol rhythm, sleep-awake-cycle, immune function and anti-oxidative defence. Interestingly, a number of experimental animal studies demonstrate significant dose-dependent anti-nociceptive effects of exogenous melatonin. Similarly, recent experimental- and clinical studies in humans indicate significant analgesic effects. In study I, we systematically reviewed all randomized studies investigating clinical effects of perioperative melatonin. Meta-analyses demonstrated significant analgesic and anxiolytic effects of melatonin in surgical patients, equating reductions of 20 mm and 19 mm, respectively on a VAS, compared with placebo. Profound heterogeneity between the included studies was, however, present. In study II, we aimed to investigate the analgesic, anti-hyperalgesic and anti-inflammatory effects of exogenous melatonin in a validated human inflammatory pain model, the human burn model. The study was performed as a randomized, double blind placebo-controlled crossover study. Primary outcomes were pain during the burn injury and areas of secondary hyperalgesia. No significant effects of exogenous melatonin were observed with respect to primary or secondary outcomes, compared to placebo. Study III and IV estimated the pharmacokinetic variables of exogenous melatonin. Oral melatonin demonstrated a tmax value of 41 minutes. Bioavailability of oral melatonin was only 3%. Elimination t1/2 were approximately 45 minutes following both oral and intravenous administration, respectively. High-dose intravenous melatonin was not associated with increased sedation, in terms of simple reaction times, compared to placebo. Similarly, no other adverse effects were reported. In Study V, we aimed to re-analyse data obtained from a randomized analgesic drug trial by a selection of standard statistical test. Furthermore, we presented an integrated assessment method of longitudinally measured pain intensity and opioid consumption. Our analyses documented that the employed statistical method impacted the statistical significance of post-operative analgesic outcomes. Furthermore, the novel integrated assessment method combines two interdependent outcomes, lowers the risk of type 2 errors, increases the statistical power, and provides a more accurate description of post-operative analgesic efficacy. Exogenous melatonin may offer an effective and safe analgesic drug. At this moment, however, the results of human studies have been contradictory. High-quality randomized experimental- and clinical studies are still needed to establish a genuine analgesic effect of the drug in humans. Other perioperative effects of exogenous melatonin should also be investigated, before melatonin can be introduced for clinical routine use in surgical patients. Despite promising experimental and clinical findings, several unanswered questions also relate to optimal dosage, timing of administration and administration route of exogenous melatonin.

The Area of Secondary Hyperalgesia following Heat Stimulation in Healthy Male Volunteers: Inter- and Intra-Individual Variance and Reproducibility.

IntroductionClinical pain models can be applied when investigating basic physiologic pain responses in healthy volunteers. Several pain models exist; however, only few have been adequately validated. Our primary aim with this prospective study was to investigate the intra- and inter-individual variation in secondary hyperalgesia elicited by brief thermal sensitization (45°C for 3 min) in healthy volunteers.Material and MethodsFifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45°C for 1 min.), and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied.ResultsFor areas of secondary hyperalgesia, an intra-observer intra-person correlation of 0.85, 95% CI [0.78, 0.90], an intra-observer inter-person correlation of 0.03, 95% CI [0.00, 0.16], and a coefficient of variation of 0.17, 95% CI [0.14, 0.21] was demonstrated. Four percent of the study population had areas of secondary hyperalgesia both below the 1st and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006).ConclusionsWe have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary hyperalgesia. We conclude that brief thermal sensitization produce secondary hyperalgesia with a high level of reproducibility, which can be applied to investigate different phenotypes related to secondary hyperalgesia in healthy volunteers.Trial Registrationclinicaltrials.gov NCT02166164