Is chronic pain caused by central sensitization? A review and critical point of view.

Chronic pain causes disability and loss of health worldwide. Yet, a mechanistic explanation for it is still missing. Frequently, neural phenomena, and among them, Central Sensitization (CS), is presented as causing chronic pain. This narrative review explores the evidence substantiating the relationship between CS and chronic pain: four expert researchers were divided in two independent teams that reviewed the available evidence. Three criteria were established for a study to demonstrate a causal relationship: (1) confirm presence of CS, (2) study chronic pain, and (3) test sufficiency or necessity of CS over chronic pain symptoms. No study met those criteria, failing to demonstrate that CS can cause chronic pain. Also, no evidence reporting the occurrence of CS in humans was found. Worryingly, pain assessments are often confounded with CS measures in the literature, omitting that the latter is a neurophysiological and not a perceptual phenomenon. Future research should avoid this misconception to directly interrogate what is the causal contribution of CS to chronic pain to better comprehend this problematic condition.

Diclofenac sodium adsorption on activated carbon: experimental, modeling and bayesian statistics.

The present study modeled the adsorption process of the drug diclofenac sodium on activated charcoal. For this purpose, a mass balance-based model was used considering a fixed bed column. The mass transfer rate in the solid phase was represented by a driving force model proposed in this study, and a gamma exponent with a range of 0 > γ ≤ 2 was assigned to the model. Different isotherms were adopted to represent the equilibrium at the solid/liquid interface: the Langmuir, Freundlich, Sips and Redlich-Peterson isotherms. The modeling was approached from the perspective of Bayesian statistics, and the Markov chain Monte Carlo method was used for parameter estimation. Model validation was performed with experimental data obtained under different operating conditions of initial concentration ($C_{0.

Reconceptualizing sensitization in pain: back to basics.

Fillingim RB. Redefining sensitization could be a sensitive issue. PAIN Rep 2024;9:e1126.

Medication-induced mood disorders following epidural steroid injections in patients with pain: A case series.

Key Clinical Message: Medication-induced mood disorders following epidural steroid injections are possible therefore should be disclosed to the patient. Abstract: Medication-induced mood disorders have been rarely reported following epidural steroid injections (ESI). This case series presents three patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for substance/medication-induced mood disorder after an ESI. In considering a candidacy for ESI, the rare but significant, side effects of psychiatric side effects should be disclosed to patients.

The effect of high versus low cognitive load on the development of nociceptive hypersensitivity: The roles of sympathetic arousal, sex and pain-related fear.

BACKGROUND: According to limited-capacity theories of attention, less attentional resources remain available when engaging in a high- versus a low-demanding cognitive task. This may reduce the perceived intensity and the evoked cortical responses of concomitant nociceptive stimuli. Whether and how the competition for limited attentional resources between a cognitive task and pain impacts the development of long-lasting hypersensitivity is unclear. METHODS: Eighty-four healthy participants were randomized into a low or high cognitive load group. Low-frequency electrical stimulation (LFS) of the skin was used to induce secondary hypersensitivity. We hypothesized that performing the high-load task during LFS would reduce the development of hypersensitivity. We examined whether painfulness, nonpain-related sympathetic arousal, or sex related to hypersensitivity, by assessing intensity and unpleasantness of mechanical pinprick stimulation. During task execution, we recorded steady-state evoked potentials evoked by LFS and skin conductance level for sympathetic arousal. Afterwards, participants reported task difficulty and LFS-related fear. For the primary outcomes, we used mixed analysis of variances. RESULTS: The results confirmed the difference in cognitive load. Although LFS successfully induced hypersensitivity, the high-load task did not reduce its development. Next, the steady-state evoked potentials did not differ between groups. Hypersensitivity correlated positively with pain-related fear and negatively with skin conductance level before LFS, despite the lack of group differences in skin conductance level. We did not find any sex differences in hypersensitivity. CONCLUSIONS: These results do not confirm that high cognitive load or sex modulate hypersensitivity, but show associations with pain-related fear and non-pain-related sympathetic arousal. SIGNIFICANCE: Previous research has mainly focused on cognitive load effects on the perception of acute painful stimuli. Yet this study extends our understanding by investigating cognitive load effects on the development of long-lasting secondary hypersensitivity, a common aspect in numerous persistent pain conditions. As cognitive tasks are presented during a painful procedure inducing secondary hypersensitivity, we test the long-lasting effects of cognitive load. Additionally, we used psychophysiological measurements to explored potential underlying mechanisms involving limited attentional resources and sympathetic arousal.

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

ABSTRACT: 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 prospective, randomized assessment of a novel, local antibiotic releasing platform for the prevention of superficial and deep surgical site infections.

BACKGROUND: Despite significant advances in infection control guidelines and practices, surgical site infections (SSIs) remain a substantial cause of morbidity, prolonged hospitalization, and mortality among patients having both elective and emergent surgeries. D-PLEX100 is a novel, antibiotic-eluting polymer-lipid matrix that supplies a high, local concentration of doxycycline for the prevention of superficial and deep SSIs. The aim of our study was to evaluate the safety and efficacy of D-PLEX in addition to standard of care (SOC) in preventing superficial and deep surgical site infections for patients undergoing elective colorectal surgery. METHODS: From October 10, 2018 to October 6, 2019, as part of a Phase 2 clinical trial, we randomly assigned 202 patients who had scheduled elective colorectal surgery to receive either standard of care SSI prophylaxis or D-PLEX100 in addition to standard of care. The primary objective was to assess the efficacy of D-PLEX100 in superficial and deep SSI reduction, as measured by the incidence of SSIs within 30 days, as adjudicated by both an individual assessor and a three-person endpoint adjudication committee, all of whom were blinded to study-group assignments. Safety was assessed by the stratification and incidence of treatment-emergent adverse events. RESULTS: One hundred and seventy-nine patients were evaluated in the per protocol population, 88 in the intervention arm [51 males, 37 females, median age (64.0 range: 19-92) years] and 91 in the control arm [57 males, 34 females, median age 64.5 (range: 21-88) years]. The SSI rate within 30 day post-index surgery revealed a 64% relative risk reduction in SSI rate in the D-PLEX100 plus standard of care (SOC) group [n = 7/88 (8%)] vs SOC alone [n = 20/91 (22%)]; p = 0.0115. There was no significant difference in treatment-emergent adverse events. CONCLUSIONS: D-PLEX100 application leads to a statistically significant reduction in superficial and deep surgical site infections in this colorectal clinical model without any associated increase in adverse events.

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

BACKGROUND: 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. OBJECTIVE: To determine whether multifocal transcranial direct current stimulation (tDCS) targeting the left DLPFC affects the development of secondary mechanical hyperalgesia. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Evidence for alterations to dynamic quantitative sensory tests in patients with chronic temporomandibular myalgia: A systematic review of observational studies with meta-analysis.

BACKGROUND: Conflicting results exist between somatosensory profiles of patients with temporomandibular myalgia (TMDm). The objective of this review was to examine whether adults with TMDm show altered responses to dynamic quantitative sensory tests compared with healthy controls. METHODS: We searched five electronic databases for studies, excluding those without suitable controls or where TMDm was associated with confounding non-musculoskeletal disorders. Risk of bias was assessed with the SIGN case-control study checklist. Findings were structured around dynamic quantitative sensory tests and their localization. Where possible, we performed meta-analysis with a random inverse variance model to compare patients with TMDm and healthy controls. Statistical heterogeneity was estimated with Chi² test and inconsistency index, I². RESULTS: We extracted data from 23 studies comprising 1284 adults with chronic TMDm and 2791 healthy controls. Risk of bias was assessed as high for 20 studies. Mechanical temporal summation, the most studied phenomenon (14 studies), is increased in the upper limb of patients with TMDm (SMD = 0.43; 95% CI: .11 to .75; p = .009) but not in the jaw area (p = .09) or in the cervical area (p = .29). Very little evidence for altered thermal temporal summation (five studies), conditioned pain modulation (seven studies), exercise-induced hypoalgesia (two studies), placebo analgesia (two studies), stress-induced hypoalgesia (one study) and offset analgesia (one study) was found. DISCUSSION: A major limitation of this review was the risk of bias of included studies. Future studies would benefit from following methodological guidelines and consideration of confounding factors.

Is there an association between lumbosacral epidural lipomatosis and lumbosacral epidural steroid injections? A comprehensive narrative literature review.

BACKGROUND: Exogenous systemic steroid exposure is a well-established risk factor for spinal epidural lipomatosis (SEL), however the association between lumbosacral epidural steroid injections (LESIs) and lumbosacral epidural lipomatosis (LEL) is generally regarded as poorly understood. Our objective was to investigate the rationale and the evidence implicating LESI(s) as a potential cause of LEL as well as the evidence related to use of LESI(s) as a potential pain relieving treatment option for radicular pain in the setting of LEL. METHODS: PubMed, Embase, Google Scholar, OVID were searched from inception until April 2021. Three investigators identified literature that provided original descriptive patient clinical data attributing the development/progression of LEL to LESI(s) or described the use of LESI(s) as a pain relieving modality for radicular pain in the setting of LEL. RESULTS: Fourteen publications were included for review. Overall, the current level of evidence is of low-quality. There are significant methodological gaps on this subject matter and many studies do not account for confounding variables independently associated with LEL. CONCLUSIONS: This review has identified substantial limitations in the literature regarding that which is truly known regarding LESI(s) and LEL, as well as conservative management overall. To provide a well-rounded perspective, we synthesized literature as it pertains to: 1) current knowledge regarding SEL, notable associations and potential implications for corticosteroid exposure; 2) corticosteroid exposure and lipoatrophy; 3) current management recommendations for SEL and 4) areas for future focus. Although LESI(s) have been associated with LEL in the literature, presently due to a lack of rigorous, high-quality studies, the presence or absence of an independent causal relationship between LESI(s) and LEL cannot be stated with confidence.

High-frequency electrical stimulation of cutaneous nociceptors differentially affects pain perception elicited by homotopic and heterotopic electrical stimuli.

Animal studies have shown that high-frequency electrical stimulation (HFS) of peripheral C-fiber nociceptors induces both homosynaptic and heterosynaptic long-term potentiation (LTP) within spinal nociceptive pathways. In humans, when HFS is applied onto the skin to activate nociceptors, single electrical stimuli are perceived more intense at the HFS site compared with a control site, a finding that was interpreted as a perceptual correlate of homosynaptic LTP. The present study aimed to investigate if after HFS the pain elicited by electrical stimuli delivered at the skin next to the HFS site is perceived as more intense compared with the pain at a control site (contralateral arm). To test this, HFS was applied to one of the two ventral forearms of 24 healthy participants. Before and after HFS, single electrical stimuli were delivered through the HFS electrode, through an identical electrode next to the HFS electrode and an identical electrode at the contralateral arm. After HFS, the pain elicited by the single electrical stimuli was reduced at all three sites, with the largest reduction at the HFS site. Nevertheless, electrical stimuli delivered to the skin next to the HFS site were perceived as more intense than control stimuli. This result indicates that higher pain ratings to electrical stimuli after HFS at the HFS site cannot solely be interpreted as a perceptual correlate of homosynaptic changes. Furthermore, we show for the first time, in humans, that HFS can reduce pain elicited by single electrical stimuli delivered through the same electrode.NEW & NOTEWORTHY High-frequency electrical stimulation (HFS) of cutaneous nociceptors can reduce pain perception to single electrical stimuli delivered through the same electrode. Moreover, single electrical stimuli delivered to the skin next to the site at which HFS was applied are perceived as more intense compared with that at the contralateral control site, indicating the presence of heterosynaptic effects for electrical stimuli.

Stuck in the Middle With You: Why a Broad-Brush Approach to Defining Central Sensitization Does Not Help Clinicians and Patients.

SYNOPSIS: Central sensitization is (1) increasingly interpreted as central nervous system hyperexcitability that accounts for a general increase in sensitivity, and (2) used to explain a variety of pain and nonpain symptoms. In this commentary, we argue that such a broad interpretation might not be clinically useful because it fails to distinguish one patient from another based on pathophysiological mechanisms and does not facilitate tailored treatment. We recommend that clinicians use a person-centered approach when assessing and managing patients, considering the different interacting processes/mechanisms that can contribute to a patient's clinical presentation. J Orthop Sports Phys Ther 2021;51(5):204-206. Epub 15 Mar 2021. doi:10.2519/jospt.2021.10340.

Insular responses to transient painful and non-painful thermal and mechanical spinothalamic stimuli recorded using intracerebral EEG.

Brief thermo-nociceptive stimuli elicit low-frequency phase-locked local field potentials (LFPs) and high-frequency gamma-band oscillations (GBOs) in the human insula. Although neither of these responses constitute a direct correlate of pain perception, previous findings suggest that insular GBOs may be strongly related to the activation of the spinothalamic system and/or to the processing of thermal information. To disentangle these different features of the stimulation, we compared the insular responses to brief painful thermonociceptive stimuli, non-painful cool stimuli, mechano-nociceptive stimuli, and innocuous vibrotactile stimuli, recorded using intracerebral electroencephalograpic activity in 7 epileptic patients (9 depth electrodes, 58 insular contacts). All four types of stimuli elicited consistent low-frequency phase-locked LFPs throughout the insula, possibly reflecting supramodal activity. The latencies of thermo-nociceptive and cool low-frequency phase-locked LFPs were shorter in the posterior insula compared to the anterior insula, suggesting a similar processing of thermal input initiating in the posterior insula, regardless of whether the input produces pain and regardless of thermal modality. In contrast, only thermo-nociceptive stimuli elicited an enhancement of insular GBOs, suggesting that these activities are not simply related to the activation of the spinothalamic system or to the conveyance of thermal information.

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

BACKGROUND: 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 100 Hz, a protocol using 42 Hz stimulation induces a more intense and a larger area of secondary hyperalgesia (SH). OBJECTIVES: The aim of this study was to investigate the within- and between-session reliability of SH induced by this optimized HFS protocol. METHODS: Thirty-two healthy subjects received HFS to their volar forearm in two sessions, separated by at least 2 weeks. 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 40 min 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). RESULTS: 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. CONCLUSIONS: HFS-induced hyperalgesia is suitable to discriminate or compare individuals but it may not be sensitive to changes due to an intervention. SIGNIFICANCE: 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.

A highly cognitive demanding working memory task may prevent the development of nociceptive hypersensitivity.

Whether, how, and which cognitive factors modulate the development of secondary hypersensitivity/hyperalgesia after central sensitization is not fully understood. Here, we tested, in 3 subsequent experiments, whether being engaged in non-pain-related cognitive demanding tasks: (1) lessens the amount of hypersensitivity developed after an experimental procedure sensitizing nociceptive pathways; and (2) modulates cortical responses to somatosensory stimuli (measured by electroencephalography, EEG). In the first experiment, we validated a novel model in humans using low-frequency stimulation of the skin and demonstrated that it was able to successfully induce hypersensitivity to mechanical pinprick stimuli in the area surrounding the sensitized site. In the second and third experiments, we engaged participants in tasks of increasing difficulty (the Eriksen Flanker Task in experiment 2, and a modified N-back task in experiment 3). We observed that hypersensitivity to mechanical stimuli still developed in experiment 2, that is, the pinprick stimuli applied on the sensitized arm were perceived as more intense after low-frequency stimulation. By contrast, no statistically significant enhancement of mechanical hypersensitivity was observed in experiment 3, indicating that, at the group level, being engaged in a difficult N-back task may interfere with the development of mechanical hypersensitivity. Contrary to previous studies, which have used different methods to induce sensitization, we did not observe any increase in the cortical response to somatosensory stimuli applied on the sensitized arm. We conclude that (1) the development of pinprick hypersensitivity is modulated by the concomitant execution of a difficult N-back task, and (2) the enhancement of cortical responses to somatosensory stimuli is related to the method used to induce central sensitization.

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.

Central sensitization and pain hypersensitivity: Some critical considerations.

Since its discovery, central sensitization has gained enormous popularity. It is widely used to explain pain hypersensitivity in a wide range of clinical pain conditions. However, at present there is no general consensus on the definition of central sensitization. Moreover, the use of the term central sensitization in the clinical domain has been criticized. The aim of this paper is to foster the discussion on the definition of central sensitization and its use.