Area Of Secondary Hyperalgesia Research Articles

Assessing signs of central sensitization: A critical review of physiological measures in experimentally induced secondary hyperalgesia.

Central sensitization (CS) is believed to play a role in many chronic pain conditions. Direct non-invasive recording from single nociceptive neurons is not feasible in humans, complicating CS establishment. This review discusses how secondary hyperalgesia (SHA), considered a manifestation of CS, affects physiological measures in healthy individuals and if these measures could indicate CS. It addresses controversies about heat sensitivity changes, the role of tactile afferents in mechanical hypersensitivity and detecting SHA through electrical stimuli. Additionally, it reviews the potential of neurophysiological measures to indicate CS presence. Four databases, PubMed, ScienceDirect, Scopus and Cochrane Library, were searched using terms linked to 'hyperalgesia'. The search was limited to research articles in English conducted in humans until 2023. Evidence for heat hyperalgesia in the SHA area is sparse and seems to depend on the experimental method used. Minimal or no involvement of tactile afferents in SHA was found. At the spinal level, the threshold of the nociceptive withdrawal reflex (RIII) is consistently reduced during experimentally induced SHA. The RIII area and the spinal somatosensory potential (N13-SEP) amplitude are modulated only with long-lasting nociceptive input. At the brain level, pinprick-evoked potentials within the SHA area are increased. Mechanical pinprick hyperalgesia is the most reliable behavioural readout for SHA, while the RIII threshold is the most sensitive neurophysiological readout. Due to scarce data on reliability, sensitivity and specificity, none of the revised neurophysiological methods is currently suitable for CS identification at the individual level. Gathering evidence for CS in humans is a crucial research focus, especially with the increasing interest in concepts such as 'central sensitization-like pain' or 'nociplastic pain'. This review clarifies which readouts, among the different behavioural and neurophysiological proxies tested in experimental settings, can be used to infer the presence of CS in humans.

Modulation of the spinal N13 SEP component by high- and low-frequency electrical stimulation. Experimental pain models matter

ObjectiveThe N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of cervical dorsal horn neurons. Neurophysiological studies in healthy participants showed that capsaicin-induced central sensitization causes an increase of the N13 SEP amplitude. Consequently, in human research, this spinal component may serve as a valuable readout of central sensitization.In this study, we wanted to verify if the sensitivity of the N13 SEP for detecting central sensitization is consistent across different experimental pain models inducing central sensitization and secondary hyperalgesia, namely high and low-frequency electrical stimulation (HFS and LFS). MethodsIn 18 healthy participants, we recorded SEP after bilateral ulnar nerve stimulation before and after secondary hyperalgesia was induced through HFS and LFS applied on the ulnar nerve territory of the hand of one side. The area of secondary hyperalgesia was mapped with a calibrated 128-mN pinprick probe, and the mechanical pain sensitivity with three calibrated 16–64-256-mN pinprick probes. ResultsAlthough both HFS and LFS successfully induced secondary hyperalgesia only LFS increased the amplitude of the N13 SEP. ConclusionsThese findings suggest that the sensitivity of the N13 SEP for detecting dorsal horn excitability changes may critically depend on the different experimental pain models. SignificanceOur results indicate that LFS and HFS could trigger central sensitization at the dorsal horn level through distinct mechanisms, however this still needs confirmation by replication studies.

Chronic temporomandibular disorders are associated with higher propensity to develop central sensitization: a case-control study.

Temporomandibular disorders (TMD) include a group of musculoskeletal disorders that may involve increased responsiveness of nociceptive neurons in the central nervous system (ie, central sensitization). To test this hypothesis further, this study examined whether, as compared with healthy subjects, patients with chronic TMD have a greater propensity to develop secondary mechanical hyperalgesia-a phenomenon that can be confidently attributed to central sensitization. In this case-control study, we assessed the area of secondary mechanical hyperalgesia induced experimentally by delivering high-frequency electrical stimulation (HFS) to the volar forearm skin in 20 participants with chronic TMD and 20 matched healthy controls. High-frequency electrical stimulation consisted in 12 trains of constant-current electrical pulses (5 mA) delivered at 42 Hz. The area of secondary mechanical hyperalgesia was evaluated 30 minutes after applying HFS. The area of secondary mechanical hyperalgesia induced by HFS was on average 76% larger in the chronic TMD group (M = 67.7 cm 2 , SD = 28.2) than in the healthy control group (M = 38.4 cm 2 , SD = 14.9; P = 0.0003). Regarding secondary outcomes, there was no group difference in the intensity of secondary mechanical hyperalgesia, but allodynia to cotton after HFS was more frequent in the chronic TMD group. To the best of our knowledge, this is the first study to show that individuals with chronic TMD have an increased propensity to develop secondary hyperalgesia in a site innervated extratrigeminally. Our results contribute to a better understanding of the pathophysiology of chronic TMD.

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

The influence of a manipulation of threat on experimentally-induced secondary hyperalgesia.

Pain is thought to be influenced by the threat value of the particular context in which it occurs. However, the mechanisms by which a threat achieves this influence on pain are unclear. Here, we explore how threat influences experimentally-induced secondary hyperalgesia, which is thought to be a manifestation of central sensitization. We developed an experimental study to investigate the effect of a manipulation of threat on experimentally-induced secondary hyperalgesia in 26 healthy human adults (16 identifying as female; 10 as male). We induced secondary hyperalgesia at both forearms using high-frequency electrical stimulation. Prior to the induction, we used a previously successful method to manipulate threat of tissue damage at one forearm (threat site). The effect of the threat manipulation was determined by comparing participant-rated anxiety, perceived threat, and pain during the experimental induction of secondary hyperalgesia, between the threat and control sites. We hypothesized that the threat site would show greater secondary hyperalgesia (primary outcome) and greater surface area (secondary outcome) of induced secondary hyperalgesia than the control site. Despite a thorough piloting procedure to test the threat manipulation, our data showed no main effect of site on pain, anxiety, or threat ratings during high-frequency electrical stimulation. In the light of no difference in threat between sites, the primary and secondary hypotheses cannot be tested. We discuss reasons why we were unable to replicate the efficacy of this established threat manipulation in our sample, including: (1) competition between threats, (2) generalization of learned threat value, (3) safety cues, (4) trust, and requirements for participant safety, (5) sampling bias, (6) sample-specific habituation to threat, and (7) implausibility of (sham) skin examination and report. Better strategies to manipulate threat are required for further research on the mechanisms by which threat influences pain.

Multichanneltranscranial direct current stimulation over the left dorsolateral prefrontalcortex may modulate the induction of secondary hyperalgesia, a double-blinded cross-over study in healthy volunteers.

Central sensitization is thought to play a critical role in the development of chronic pain, and secondary mechanical hyperalgesia is considered one of its hall-mark features. Consequently, interventions capable of modulating its development could have important therapeutic value. Non-invasive neuromodulation of the left dorsolateral prefrontal cortex (DLPFC) has shown potential to reduce pain, both in healthy volunteers and in patients. Whether it can modulate the induction of central sensitization, however, is less well known. To determine whether multifocal transcranial direct current stimulation (tDCS) targeting the left DLPFC affects the development of secondary mechanical hyperalgesia. In this within-subjects, cross-over, double-blinded study, eighteen healthy volunteers participated in three experimental sessions. After 20 minutes of either anodal, cathodal, or sham multichannel tDCS over the left DLPFC, secondary mechanical hyperalgesia was induced using high-frequency electrical stimulation (HFS) of the volar forearm. We assessed intensity of perception to 128 mN mechanical pinprick stimuli at baseline and up to 240 minutes after HFS. We also mapped the area of mechanical hyperalgesia. HFS resulted in a robust and unilateral increase in the intensity of perception to mechanical pinprick stimuli at the HFS arm, which was not different between tDCS stimulation conditions. However, the area of hyperalgesia was reduced after anodal tDCS compared to sham. Anodal tDCS over the left DLPFC modestly modulates the size of the HFS-induced area of secondary mechanical hyperalgesia, suggesting that non-invasive neuromodulation targeting the left DLPFC may be a potential intervention to limit the development of central sensitization.

Muscular factor in the development of musculoskeletal pain. Treatment options

The importance of the muscular factor, which is traditionally considered in myofascial pain syndrome (MFPS), in the development and maintenance of musculoskeletal pain (MSP) is actively discussed. The hypothesis of the leading role of myofascial trigger points (MTPs) in muscle pain remains debatable. Probably, muscle pain is secondary to the underlying disease. The MTP phenomenon is considered as an area of secondary hyperalgesia resulting from neurogenic inflammation in muscles that were not initially structurally and physiologically damaged. According to these ideas, MFPS is a complex form of neuromuscular dysfunction, which is represented by soft tissue damage with the development of peripheral and central sensitization as a result of neurogenic inflammation, changes in the functioning of limbic system structures. MFPS is a clinical diagnosis, based on the presence of painful spasmodic muscles, painful muscle indurations, active trigger points with zones of reflected pain. The sensitivity and specificity of clinical tests for MFPS have not been determined. Currently, there are no proven universally accepted criteria (such as biomarkers, electrophysiological evaluation, imaging, diagnostic blocks, etc.) for objectifying or quantifying MTPs. Nonpharmacological interventions with the most proven effectiveness include therapeutic exercises and psychotherapeutic techniques, other methods are of secondary importance. The effectiveness of aceclofenac (Aertal®) and the muscle relaxant tolperisone (Mydocalm®) in the of MSP treatment is discussed. It is noted that a new form of tolperisone – Mydocalm®-Long 450 mg - can reduce the frequency of drug administration, provide a proven and predictable therapeutic effect, and increase treatment adherence.

Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.

Functional brain response to painful mechanical stimulation and painful stimulation in areas of secondary mechanical hyperalgesia: A meta-analysis

This study evaluated brain activity in response to painful and nonpainful mechanical stimuli within an area of secondary mechanical hyperalgesia (SMH) compared to non-sensitized areas. We performed a meta-analysis summarizing responses to three different types of stimuli. Furthermore, we summarize reported results of contrast maps comparing brain responses to mechanical stimuli in SMH that in non-sensitized regions. We investigated 3 categories of brain responses to 1) nonpainful mechanical stimuli in 226 participants across 16 studies, 2) painful mechanical stimuli in 164 participants across 11 studies, 3) mechanical stimuli in SMH in 84 participants across 7 studies, and 4) contrast maps of brain responses to mechanical stimuli in SMH versus painful mechanical stimuli in 107 participants across 7 studies. We used GingerALE 3.0.2 to create meta-analytic statistical parametric maps. We generated summary Z-maps by subtracting negative maps from positive maps. Maps were Z-value thresholded at 3.29 and a cluster size of 272 mm3. Nonpainful mechanical stimuli activated bilateral parietal operculum (PO), right inferior frontal gyrus (IFG) and inferior parietal lobule. Painful mechanical stimuli activated bilateral PO, bilateral IFG pars opercularis, and deactivation in bilateral superior occipital gyri. Mechanical stimuli in SMH activated bilateral PO, bilateral dorsal anterior insula, left postcentral gyrus and supragenual anterior cingulate cortex. The contrast of mechanical stimuli in SMH versus painful mechanical stimuli included greater activation in right thalamus, left lateral periaqueductal gray, right dorsolateral prefrontal (DLPFC), right Rolandic opercular, bilateral primary somatosensory, anterior midcingulate, and right middle insular cortices. Contrast results revealed greater activation during SMH compared to painful mechanical stimulation in right thalamus, right DLPFC, and left lateral periaqueductal gray. These areas are involved in pain modulation (hyperalgesic and analgesic), while responses in mid insula and mid cingulate cortices are prominent in processing salient and painful stimuli. Neurosurgery Pain Research Institute, Postdoctoral Scholarship (TJM). This study evaluated brain activity in response to painful and nonpainful mechanical stimuli within an area of secondary mechanical hyperalgesia (SMH) compared to non-sensitized areas. We performed a meta-analysis summarizing responses to three different types of stimuli. Furthermore, we summarize reported results of contrast maps comparing brain responses to mechanical stimuli in SMH that in non-sensitized regions. We investigated 3 categories of brain responses to 1) nonpainful mechanical stimuli in 226 participants across 16 studies, 2) painful mechanical stimuli in 164 participants across 11 studies, 3) mechanical stimuli in SMH in 84 participants across 7 studies, and 4) contrast maps of brain responses to mechanical stimuli in SMH versus painful mechanical stimuli in 107 participants across 7 studies. We used GingerALE 3.0.2 to create meta-analytic statistical parametric maps. We generated summary Z-maps by subtracting negative maps from positive maps. Maps were Z-value thresholded at 3.29 and a cluster size of 272 mm3. Nonpainful mechanical stimuli activated bilateral parietal operculum (PO), right inferior frontal gyrus (IFG) and inferior parietal lobule. Painful mechanical stimuli activated bilateral PO, bilateral IFG pars opercularis, and deactivation in bilateral superior occipital gyri. Mechanical stimuli in SMH activated bilateral PO, bilateral dorsal anterior insula, left postcentral gyrus and supragenual anterior cingulate cortex. The contrast of mechanical stimuli in SMH versus painful mechanical stimuli included greater activation in right thalamus, left lateral periaqueductal gray, right dorsolateral prefrontal (DLPFC), right Rolandic opercular, bilateral primary somatosensory, anterior midcingulate, and right middle insular cortices. Contrast results revealed greater activation during SMH compared to painful mechanical stimulation in right thalamus, right DLPFC, and left lateral periaqueductal gray. These areas are involved in pain modulation (hyperalgesic and analgesic), while responses in mid insula and mid cingulate cortices are prominent in processing salient and painful stimuli. Neurosurgery Pain Research Institute, Postdoctoral Scholarship (TJM).

High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.

Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

Pain-autonomic interaction: A surrogate marker of central sensitization.

Central sensitization represents a key pathophysiological mechanism underlying the development of neuropathic pain, often manifested clinically as mechanical allodynia and hyperalgesia. Adopting a mechanism-based treatment approach relies highly on the ability to assess the presence of central sensitization. The aim of the study was to investigate potential pain-autonomic readouts to operationalize experimentally induced central sensitization in the area of secondary hyperalgesia. Pinprick evoked potentials (PEPs) and sympathetic skin responses (SSRs) were recorded in 20 healthy individuals. Three blocks of PEP and SSR recordings were performed before and after heat-induced secondary hyperalgesia. All measurements were also performed before and after a control condition. Multivariate analyses were performed using linear mixed-effect regression models to examine the effect of experimentally induced central sensitization on PEP and SSR parameters (i.e. amplitudes, latencies and habituation) and on pinprick pain ratings. The noxious heat stimulation induced robust mechanical hyperalgesia with a significant increase in PEP and SSR amplitudes (p<0.001) in the area of secondary hyperalgesia. Furthermore, PEP and SSR habituation were reduced (p<0.001) after experimentally induced central sensitization. The findings demonstrate that combined recordings of PEPs and SSRs are sensitive to objectify experimentally induced central sensitization and may have a great potential to reveal its presence in clinical pain conditions. Corroborating current pain phenotyping with pain-autonomic markers has the potential to unravel central sensitization along the nociceptive neuraxis and might provide a framework for mechanistically founded therapies. Our findings provide evidence that combined recordings of sympathetic skin responses (SSRs) and pinprick evoked potentials (PEPs) might be able to unmask central sensitization induced through a well-established experimental pain model in healthy individuals. As such, these novel readouts of central sensitization might attain new insights towards complementing clinical pain phenotyping.

The Effect of Preoperative Pentoxifylline on Postoperative Pain and Development of Secondary Hyperalgesia in Patients Undergoing Laparoscopic Appendectomy: A Randomized, Double-Blind, Placebo-Controlled Trial Study.

After surgery and loss of anesthetic effect, postoperative pain can annoy the patient and affect patient satisfaction with treatment. This study was aimed at evaluating the effect of preoperative pentoxifylline (PTX) on postoperative pain and development of secondary hyperalgesia in patients undergoing laparoscopic appendectomy (LA). This randomized, double-blind, placebo-controlled clinical trial study was conducted on 91 eligible subjects with acute appendicitis referred to Shahid Beheshti hospital of Sabzevar, Iran, in 2018. The intervention and control groups were administered with a single oral dose of PTX (10mg/kg) and placebo an hour before surgery, respectively. Postoperative pain was measured within 24hours after surgery using a VAS, and the area of secondary hyperalgesia was measured 24hours after surgery using the Stubhaug et al. method. The mean age of the subjects was 26.74±9.99 years, and 57.14% were female. Pain intensity during rest was significantly greater in the control group as compared to the PTX group 24 hours after surgery (VAS scores 2.19±0.49 and 3.13±0.66, respectively; P<0.001). Moreover, pain intensity during cough was substantially lower in the PTX group compared with the control group 24 hours after surgery (VAS scores 2.65±1.90 and 4.10±2.60, respectively; P=0.003 in turn). The dynamic hyperalgesia was significantly greater in the control group as compared with the PTX group (3.80±1.82 and 7.43±2.38, respectively; P<0.001). Findings suggest that oral administration of PTX 1 hour before surgery in patients undergoing LA can reduce postoperative pain in patients and prevent secondary hyperalgesia at a surgical site.

Within- and between-session reliability of secondary hyperalgesia induced by electrical high-frequency stimulation.

An increasing number of studies are focusing on secondary hyperalgesia to better understand central sensitization, as this phenomenon may play an important role in persistent pain. Recent studies have shown that, compared to the classical high-frequency stimulation protocol (HFS) at 100Hz, a protocol using 42Hz stimulation induces a more intense and a larger area of secondary hyperalgesia (SH). The aim of this study was to investigate the within- and between-session reliability of SH induced by this optimized HFS protocol. Thirty-two healthy subjects received HFS to their volar forearm in two sessions, separated by at least 2weeks. SH was assessed by measuring the area size of increased sensitivity to pinprick stimuli after applying HFS, the sensitivity to pinprick stimuli after applying HFS and the change in pinprick sensitivity after versus before HFS. Assessments were made before HFS, and 30, 35 and 40min after HFS. Relative and absolute reliability were analysed using intraclass correlation coefficients (ICCs), coefficients of variation (CVs), standard error of means (SEMs) and the minimum detectable changes (MDCs). The area of SH showed good to excellent within-session and between-session relative reliability (ICCs>0.80), except for the change in pinprick sensitivity, which showed close to poor between-session relative reliability (ICC=0.53). Furthermore, measures of absolute reliability generally demonstrated large between-subject variability and significant fluctuations across repeated measurements. HFS-induced hyperalgesia is suitable to discriminate or compare individuals but it may not be sensitive to changes due to an intervention. It is crucial to evaluate central sensitization adequately in humans. This study formally establishes the reliability of secondary hyperalgesia induced by electrical high-frequency stimulation. The results of this study will improve future studies investigating secondary hyperalgesia in humans.

Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

Areas of secondary hyperalgesia can be assessed using quantitative sensory testing (QST). Delivering noxious electrocutaneous stimulation could provide added benefit by allowing multiple measurements of the magnitude of hyperalgesia. We aimed to characterize the use of electrical pain perception (EPP) thresholds alongside QST as a means by which to measure changes in pain thresholds within an area of secondary mechanical hyperalgesia. EPP and heat pain thresholds (HPTs) were measured at five distinct points at baseline and following 1% capsaicin cream application, one within a central zone and four within a secondary zone. Areas of secondary mechanical hyperalgesia were mapped using QST. In a further 14 participants, capsaicin-induced reduction in EPP thresholds was mapped using a radial lines approach across 24 points. There was a reduction in EPP threshold measured at the four points within the secondary zone, which was within the mapped area of mechanical secondary hyperalgesia. The magnitude of secondary hyperalgesia could be split into a mild (∼4% reduction) and severe (∼21% reduction) area within an individual subject. There was no reduction in HPT within the secondary zone, but there was a reduction in both HPT and EPP threshold within the primary zone. EPP mapping revealed differences in the magnitude and spread of hyperalgesia across all subjects. Measuring capsaicin-induced reduction in EPP thresholds can be used to map hyperalgesic areas in humans. This semi-automated approach allows rapid assessment of the magnitude of hyperalgesia, both within an individual subject and across a study population.

GABAergic modulation of secondary hyperalgesia: A randomized controlled 4-way crossover trial with the α2-subunit preferring GABA positive allosteric modulator, N-desmethyl-clobazam in healthy volunteers.

The antihyperalgesic and sedative effects of the α2-subunit preferring GABAA positive allosteric modulator (GAM), N-desmethyl-clobazam (NDMC), 20 and 60mg, were assessed in a randomized, placebo and active-controlled (clonazepam 1,5mg), 4-way crossover study, in healthy volunteers, using the ultraviolet B-induced experimental pain model. Single (20, 40, 60mg) and repeated doses (20mg over 15days) of NDMC pharmacokinetics were evaluated. Thirty-two subjects participated in the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD) relative change was 79 (22)%, 83 (24)%, 77 (30)% and 92 (16)% for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference=2.3cm2 [95% CI 4.0-8.5], p=.462 and 0.4% [-11.9 to 12.6], p=.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference=39mm [30-49] on a visual analogue scale, p<.001) while NDMC was free of sedative effect. NDMC pharmacokinetics after single doses showed poor absorption, but was linear. Steady-state plasma concentrations of NDMC20 were attained within 14days, with low between-subjects variability. Mean steady-state concentration (CS-S , SD) reached 209 (22) ng/ml. NDMC absence of sedative effect and its overall well-characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility. SIGNIFICANCE: This article, presenting the Phase I data of the new antihyperalgesic compound, α2-subunit GABAA positive allosteric modulator, N-desmethyl-clobazam (NDMC) is exploring the modulation of a new target in the treatment of neuropathic pain. Based on these results and on its preclinical properties NDMC would qualify as a good tool compound to seek confirmation of the clinical utility of selective GABA allosteric modulators in neuropathic pain patients.

The focus of spatial attention during the induction of central sensitization can modulate the subsequent development of secondary hyperalgesia

Intense or sustained activation of peripheral nociceptors can induce central sensitization. This enhanced responsiveness to nociceptive input of the central nervous system primarily manifests as an increased sensitivity to painful mechanical pinprick stimuli extending beyond the site of injury (secondary mechanical hyperalgesia) and is thought to be a key mechanism in the development of chronic pain, such as persistent post-operative pain. It is increasingly recognized that emotional and cognitive factors can strongly influence the pain experience. Furthermore, through their potential effects on pain modulation circuits including descending pathways to the spinal cord, it has been hypothesized that these emotional and cognitive factors could constitute risk factors for the susceptibility to develop chronic pain. Here, we tested whether, in healthy volunteers, the experimental induction of central sensitization by peripheral nociceptive input can be modulated by selective spatial attention. While participants performed a somatosensory detection task that required focusing attention towards one of the forearms, secondary hyperalgesia was induced at both forearms using bilateral and simultaneous high-frequency electrical stimulation (HFS) of the skin. HFS induced an increased sensitivity to mechanical pinprick stimuli at both forearms, directly (T1) and 20 min (T2) after HFS, confirming the successful induction of secondary hyperalgesia at both forearms. Most importantly, at T2, the HFS-induced increase in pinprick sensitivity as well as the area of secondary hyperalgesia was greater at the attended arm as compared to the non-attended arm. This indicates that top-down attentional factors can modulate the development of central sensitization by peripheral nociceptive input, and that the focus of spatial attention, besides its modulatory effects on perception, can affect activity-dependent neuroplasticity.

A data science approach to the selection of most informative readouts of the human intradermal capsaicin pain model to assess pregabalin effects.

Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin-based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo-controlled, randomized cross-over study, seven different pain-related readouts were acquired in 16 healthy individuals before and after oral administration of 300mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain-related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.

Hyperalgesia and fentanyl dosing in on-pump coronary artery bypass grafting

Introduction Opioids have many known side-effects. However opioid-induced hyperalgesia (OIH), as a result of central sensitization, remains more obscure. The increase in hyperalgesia is dose-related and postoperatively an increased secondary wound hyperalgesia may be a factor in the development of chronic or persistent pain. This prospective, randomized and double-blind clinical trial aims to investigate the effects of fentanyl on secondary wound hyperalgesia in patients undergoing on-pump coronary artery bypass grafting. Methods Secondary wound hyperalgesia was investigated between two study-groups, respectively a low dose bolus group (n = 14, 3mcg/ kg) and a continuous infusion group (n = 17, Shibutani). The primary endpoint of this study was the area of secondary wound hyperalgesia after 24 hours. The area was measured using a Von Frey filament (256mN). Additionally we looked at hyperalgesia after 48 hours and we investigated following secondary endpoints: time to extubation, ICU/hospital length of stay, PONV, pain scores, the need for additional analgesia and the total dose of opioids administered 24 and 48 hours after surgery. This study is a subgroup analysis of a larger study, in which the possible association between the area of secondary wound hyperalgesia and persistent pain at 3, 6 and 12 months after surgery will be investigated. Results The examination of preliminary results showed no statistically significant difference for the area of secondary wound hyperalgesia after 24 hours (p = 0.3268). However the results became significant after 48 hours, where the area of secondary wound hyperalgesia was smaller in the low dose bolus group (p = 0.0389). No significant differences were found for the other secondary endpoints. Discussion There was less secondary wound hyperalgesia in the low dose bolus group after 48 hours, although at 24 hours this was not statistically significant. These findings are the result of preliminary data. We need to wait for the definitive results of hyperalgesia and for the results regarding chronic pain to draw any conclusions about the clinical significance of OIH.

Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia.

Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans. This randomized, double-blind, placebo-controlled, crossover study explores the antihyperalgesic effect of single and repeated 30-mg dose of oral dextromethorphan in 20 volunteers, using the freeze-injury pain model. This model leads to development of primary and secondary hyperalgesia, which develops away from the site of injury and is associated with central sensitization and activation of N-methyl-D-aspartate receptor in the spinal cord. The primary outcome was antihyperalgesia calculated with the area under the curve of the percentage change in mechanical pain threshold (electronic von Frey) on the area of secondary hyperalgesia. The secondary outcomes were mechanical pain threshold on the area of primary hyperalgesia and cognitive (reaction time) effect. Single 30-mg results are reported. Antihyperalgesia (% · min) is significantly higher on the area of secondary hyperalgesia with dextromethorphan than placebo (median [interquartile range]: 3,029 [746; 6,195] vs. 710 [-3,248; 4,439], P = 0.009, Hedge's g = 0.8, 95% CI [0.1; 1.4]). On primary hyperalgesia area, mechanical pain threshold 2 h after drug intake is significantly higher with dextromethorphan (P = 0.011, Hedge's g = 0.63, 95% CI [0.01; 1.25]). No difference in antinociception is observed after thermal painful stimuli on healthy skin between groups. Reaction time (ms) is shorter with placebo than with dextromethorphan (median [interquartile range]: 21.6 [-37.4; 0.1] vs. -1.2 [-24.3; 15.4], P = 0.015, Hedge's g = 0.75, 95% CI [0.12; 1.39]). Nonserious adverse events occurrence (15%, 3 of 20 volunteers) was similar in both groups. This study shows that low-dose (30-mg) dextromethorphan is antihyperalgesic in humans on the areas of primary and secondary hyperalgesia and reverses peripheral and central neuronal sensitization. Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-D-aspartate receptor may need to be sensitized by pain for dextromethorphan to be effective.

The Acute Effect of Skin Preheating on Capsaicin-Induced Central Sensitization in Humans.

Topical capsaicin is commonly employed to experimentally induce central sensitization (CS) in humans. While previous studies have investigated the effect of skin preheating on the sensitizing effect of capsaicin, no studies have compared the synergistic effect of skin preheating on the magnitude of sensitization via topical capsaicin within the first 30minutes of application. We tested the hypothesis that skin preheating potentiates the sensitizing effect of topical capsaicin by evoking a larger region of secondary hyperalgesia vs. topical capsaicin alone. Twenty young, healthy subjects each received topical capsaicin (Zostrix HP 0.075%) only (CAP), topical capsaicin with preheating (CAP+HEAT), and topical nonsensitizing placebo cream (CON) in a crossover design. Capsaicin and placebo creams were applied to a 50cm2 area of the dorsal forearm. The CAP+HEAT session also included a 10-minute preheating session. Regions of secondary hyperalgesia were assessed using mechanical brush allodynia testing, and skin temperature was assessed via infrared thermography. Outcomes were normalized to baseline and compared at 10, 20, and 30minutes after cream application. The CAP+HEAT session led to a significantly larger area of secondary hyperalgesia compared to the CAP session as measured by brush allodynia (CON: 0±0 cm; CAP: 2.08±0.45 cm; CAP+HEAT: 3.70±0.46cm; P<0.05) and skin temperature (CON: -2.92%±0.03%; CAP: -0.63%±0.09%; CAP+HEAT: 2.50%±0.11%; ( of baseline) P<0.05). Preheating amplifies the sensitizing effect of topical capsaicin within 30minutes of application. The heat-capsaicin technique may be employed to assess differing magnitudes of CS induction and enables future studies investigating the development and progression of CS in humans.