Chronic pain in pachyonychia congenita: evidence for neuropathic origin.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant skin disease, with chronic pain being the most prominent complaint. Histological studies showing alterations in sensory innervation, along with reports on alterations in mechanical sensitivity, suggest that PC may be a form of neuropathy. OBJECTIVES: Here, for the first time, we aim to evaluate systematically the sensory function of patients with PC vs. controls, in order to investigate the pathophysiology of PC. METHODS: Patients (n = 62) and controls (n = 45) completed the McGill and Douleur Neuropathique-4 (DN4) questionnaires. Sensory testing included detection and pain thresholds, pathological sensations, conditioned pain modulation (CPM) and temporal summation of pain. RESULTS: A moderate-to-severe chronic pain in the feet, throbbing and stabbing in quality, was highly prevalent among patients with PC (86%) and was especially debilitating during weight bearing. In addition, the majority of patients had a DN4 score ≥ 4 (62%), static allodynia (55%) and tingling (53%) in the feet. Compared with controls, patients with PC exhibited thermal and mechanical hypoaesthesia and mechanical hyperalgesia in the feet. CPM was reduced among the patients, and was associated with more enhanced mechanical hyperalgesia in the feet. The specific gene and nature of the causative mutation did not affect any of these features. CONCLUSIONS: Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC. The clinical features and DN4 scores support this possibility and therefore neuropathic pain medications may be beneficial for patients with PC.

Electrophysiological and psychophysical correlates of spatial summation to noxious heat: the possible role of A-delta fibers.

Although spatial summation of pain (SSP) is central to the processing of pain intensity and quality, its mechanism is not fully understood. We previously found greater heat SSP in hairy than in glabrous skin, suggesting that perhaps A-mechano-heat II (AMH-II) nociceptors are the dominant subserving system. In order to further explore the role of A-delta fibers in heat-induced SSP, we analyzed the electrophysiological correlates of SSP under conditions that minimize the influence of skin thicknesses. Among 17 subjects, fast rate of rise (70 °C/sec) heat stimuli that induced a pre-fixed, similar, SSP magnitude for hairy and glabrous skin were repeatedly administered using large and small probes, during which time the contact heat-evoked potentials (CHEPs) and pain ratings were recorded. Both N2 and P2 amplitudes were larger in hairy than in glabrous skin, but a differential effect of SSP was found on the CHEPs. Despite similar psychophysical SSP in hairy and glabrous skin, the electrophysiological SSP reflected in N2 but not P2 amplitude was larger in hairy skin. Nevertheless, regardless of skin type, SSP was manifested by an increase in P2 amplitudes. Considering the uniform psychophysical SSP for the two skin types, the fast stimulation rate and lower activity of AMH-II in glabrous skin, a greater electrophysiological SSP in hairy than in glabrous skin may suggest that SSP is mainly subserved by AMH nociceptors. The overall SSP effect, manifested in greater P2 amplitude, may reflect specific brain responses aimed to prepare the individual to an increased potential tissue damage.

Attitudes and emotions towards pain and sensitivity to painful stimuli among people routinely engaging in masochistic behaviour.

BACKGROUND: People engaged in masochistic behaviour (MB) seek to experience pain and the pleasure it evokes in sadomasochistic (S&M) sessions. The sensitivity and attitude to pain in these individuals has hardly been tested. We evaluated pain perception among these individuals and tested whether their experiences and attitudes towards pain are context-related. METHODS: Thirty-four healthy subjects participated; 17 routinely engaged in MB and 17 controls. Pressure pain threshold (PPT) was measured in two body regions. A structured questionnaire on S&M activities and context-related pain experiences and emotions was completed, as well as the pain catastrophizing (CAT) and fear of pain (FOP) questionnaires. RESULTS: PPT was significantly higher among MB individuals and positively correlated with the frequency of S&M sessions. MB individuals also had lower levels of CAT, and FOP correlated negatively with the frequency of MB and the number of body regions involved. Pleasure evoked during S&M sessions correlated positively with pain intensity and number of body regions involved. Pain in everyday life correlated negatively with MB activities. However, the emotional attitude to everyday pain was ambivalent: MB individuals perceived pain intensity and unpleasantness similar to the controls, but simultaneously gained pleasure from the pain. CONCLUSIONS: MB individuals exhibited pain hyposensitivity, presumably resulting from frequent engagement in MB. Alternatively, these subjects may have a predisposition which enables this engagement. Attitudes towards pain in MB individuals are complex. They appear to be context-related with pain experienced as pleasurable and rewarding during S&M sessions, and negative but still pleasurable in everyday life.

Temporal and spatial aspects of experimental tonic pain: Understanding pain adaptation and intensification.

BACKGROUND: The underlying mechanisms of adaptations to pain are unclear. In order to explore whether central or peripheral mechanisms predominate, the effects of two centrally mediated phenomena - spatial summation of pain (SSP) and transcutaneous electrical nerve stimulation (TENS) - were examined. The effect of the degree of painfulness, rather than absolute stimulation intensity, was also examined. METHODS: Seventeen participants received several series of individually adjusted tonic noxious-heat stimuli (300 s), inducing an initial perceived pain of 2 (mild pain), 4 (moderate pain) and 6 (strong pain) on a visual analogue scale (VAS). The stimuli were administered to small (2.25 cm2) and large (9 cm2) areas to produce SSP and also during TENS treatment, during which 12 VAS ratings were obtained. RESULTS: Adaptation occurred during VAS-2 stimulation and was minimal, followed by intensification during VAS-4 stimulation, whereas VAS-6 stimulation always induced pain intensification. TENS failed to produce analgesia and SSP did not affect adaptation but affected intensification. Stimulation temperatures affected the magnitude of adaptation and intensification within each degree of painfulness. The mathematical models that best fitted the time trend with VAS-2 and VAS-4 were linear, whereas a power function best fitted VAS-6 stimulation. CONCLUSIONS: The mathematical models and the lack of effect of SSP on adaptation suggest that its dominant component is peripheral. Whereas relative painfulness determines whether pain adaptation or intensification occurs (probably a defence mechanism), absolute stimulation intensities influence the magnitude of the effect. Pain intensification is differentially affected by probe size, depending upon the occurrence of initial adaptation.

Mild closed head injury promotes a selective trigeminal hypernociception: implications for the acute emergence of post-traumatic headache.

BACKGROUND: Headache is one of the most common symptoms following traumatic head injury. The mechanisms underlying the emergence of such post-traumatic headache (PTH) remain unknown but may be related to injury of deep cranial tissues or damage to central pain processing pathways, as a result of brain injury. METHODS: A mild closed head injury in mice combined with the administration of cranial or hindpaw formalin tests was used to examine post-traumatic changes in the nociceptive processing from deep cranial tissues or the hindpaw. Histological analysis was used to examine post-traumatic pro-inflammatory changes in the calvarial periosteum, a deep cranial tissue. RESULTS: At 48 h after head injury, mice demonstrated enhanced nociceptive responses following injection of formalin into the calvarial periosteum, a deep cranial tissue, but no facilitation of the nociceptive responses following injection of formalin into an extracranial tissue, the hindpaw. Mice also showed an increase in the number of activated periosteal mast cells 48 h following mild head trauma, suggesting an inflammatory response. CONCLUSION: Our study demonstrates that mild closed head injury is associated with enhanced processing of nociceptive information emanating from trigeminal-innervated deep cranial tissues, but not from non-cranial tissues. Based on these finding as well as the demonstration of head injury-evoked degranulation of calvarial periosteal mast cells, we propose that inflammatory-evoked enhancement of peripheral cranial nociception, rather than changes in supraspinal pain mechanisms play a role in the initial emergence of PTH. Peripheral targeting of nociceptors that innervate the calvaria may be used to ameliorate PTH pain.

The long-term impact of tissue injury on pain processing and modulation: a study on ex-prisoners of war who underwent torture.

BACKGROUND: Tissue injury may, in some instances, induce chronic pain lasting for decades. Torture survivors suffer from high rates of chronic pain and hypersensitivity in the previously injured regions. Whether torture survivors display generalized alterations in pain perception and modulation, and whether such alterations underlie their chronic pain is unknown. We aimed at exploring the long-term alterations in pain perception and modulation in torture survivors. METHODS: In order to address these questions, a systematic quantitative somatosensory evaluation was performed in individuals (n = 60) who suffer from chronic pain, and who, decades previously, were tortured, resulting in substantial tissue damage. These individuals were compared with age- and sex-matched individuals (n = 44) of similar background. Testing included the measurement of pain threshold and pain tolerance, perceived suprathreshold stimuli, conditioned pain modulation (CPM) and temporal summation of pain (TSP) in intact body regions. RESULTS: Chronic pain was found highly prevalent (86.6%) among torture survivors, who exhibited higher suprathreshold pain ratings (p < 0.05), poorer CPM (p < 0.0001) and stronger TSP (p < 0.0001) than controls. Significant differences in CPM and TSP were also found between torture survivors and controls with chronic pain. Chronic pain intensity among torture survivors correlated negatively with the magnitude of CPM (r = -0.47, p < 0.01). CONCLUSIONS: Torture appears to induce generalized dysfunctional pain modulation that may underlie the intense chronic pain experienced by torture survivors decades after torture. The results may be generalized to instances where chronic pain exists for decades after severe injury in non-tortured populations and emphasize the importance of preventive care.

International Spinal Cord Injury Pain (ISCIP) Classification: Part 2. Initial validation using vignettes.

STUDY DESIGN: International validation study using self-administered surveys. OBJECTIVES: To investigate the utility and reliability of the International Spinal Cord Injury Pain (ISCIP) Classification as used by clinicians. METHODS: Seventy-five clinical vignettes (case histories) were prepared by the members of the ISCIP Classification group and assigned to a category by consensus. Vignettes were incorporated into an Internet survey distributed to clinicians. Clinicians were asked, for each vignette, to decide on the number of pain components present and to classify each using the ISCIP Classification. RESULTS: The average respondent had 86% of the questions on the number of pain components correct. The overall correctness in determining whether pain was nociceptive was 79%, whereas the correctness in determining whether pain was neuropathic was 77%. Correctness in determining if pain was musculoskeletal was 84%, whereas for visceral pain, neuropathic at-level spinal cord injury (SCI) and below-level SCI pain it was 85%, 57% and 73%, respectively. Using strict criteria, the overall correctness in determining pain type was 68% (versus an expected 95%), but with maximally relaxed criteria, it increased to 85%. CONCLUSIONS: The reliability of use of the ISCIP Classification by clinicians (who received minimal training in its use) using a clinical vignette approach is moderate. Some subtypes of pain proved challenging to classify. The ISCIP should be tested for reliability by applying it to real persons with pain after SCI. Based on the results of this validation process, the instructions accompanying the ISCIP Classification for classifying subtypes of pain have been clarified.

International spinal cord injury pain classification: part I. Background and description. March 6-7, 2009.

STUDY DESIGN: Discussion of issues and development of consensus. OBJECTIVE: Present the background, purpose, development process, format and definitions of the International Spinal Cord Injury Pain (ISCIP) Classification. METHODS: An international group of spinal cord injury (SCI) and pain experts deliberated over 2 days, and then via e-mail communication developed a consensus classification of pain after SCI. The classification was reviewed by members of several professional organizations and their feedback was incorporated. The classification then underwent validation by an international group of clinicians with minimal exposure to the classification, using case study vignettes. Based upon the results of this study, further revisions were made to the ISCIP Classification. RESULTS: An overall structure and terminology has been developed and partially validated as a merger of and improvement on previously published SCI pain classifications, combined with basic definitions proposed by the International Association for the Study of Pain and pain characteristics described in published empiric studies of pain. The classification is designed to be comprehensive and to include pains that are directly related to the SCI pathology as well as pains that are common after SCI but are not necessarily mechanistically related to the SCI itself. CONCLUSIONS: The format and definitions presented should help experienced and non-experienced clinicians as well as clinical researchers classify pain after SCI.

The importance of stimulus parameters for the experience of the thermal grill illusion.

AIMS: This study aimed to investigate the quality of the thermal grill illusion (TGI) and the importance of stimulus parameters (distance between, and number of stimulation bars). MATERIAL AND METHODS: Twenty-one different stimuli were applied to a group of 19 healthy subjects on the glabrous skin over the palm and fingers. RESULTS: The TGI was found to be painful (19.42% on the palm; 17.98% on the fingers), mechanical (25.24% on the palm; 5.62% on the fingers), emotional (13.59% on the palm; 14.61% on the fingers) or unusual (42.72% on the palm; 61.8% on the fingers) sensations. A total of 89.5% (palm) and 94.4% (fingers) of the subjects reported TGI. Between 45% (fingers) and 50% (palm) of the stimuli elicited TGI. Neither the distance (2 approximately 10 mm) between adjacent warm (40 +/- 1 degrees C) and cold (20 +/- 1 degrees C) bars nor the number of the stimulation bars (2 approximately 6) significantly affected the occurrence of the TGI (N.S.). The average reaction time was 2.4 +/- 0.1 seconds to the TGI sensation. Females showed longer reaction time than males (P

Characterization of chronic pain and somatosensory function in spinal cord injury subjects.

The pathophysiology of the chronic pain following spinal cord injury (SCI) is unclear. In order to study it's underlying mechanism we characterized the neurological profile of SCI subjects with (SCIP) and without (SCINP) chronic pain. Characterization comprised of thermal threshold testing for warmth, cold and heat pain and tactile sensibility testing of touch, graphesthesia and identification of speed of movement of touch stimuli on the skin. In addition, spontaneously painful areas were mapped in SCIP and evoked pathological pain--allodynia, hyperpathia and wind-up pain evaluated for both groups. Both SCIP and SCINP showed similar reductions in both thermal and tactile sensations. In both groups thermal sensations were significantly more impaired than tactile sensations. Chronic pain was present only in skin areas below the lesion with impaired or absent temperature and heat-pain sensibilities. Conversely, all the thermally impaired skin areas in SCIP were painful while painfree areas in the same subjects were normal. In contrast, chronic pain could be found in skin areas without any impairment in tactile sensibilities. Allodynia could only be elicited in SCIP and a significantly higher incidence of pathologically evoked pain (i.e. hyperpathia and wind-up pain) was seen in the chronic pain areas compared to SCINP. We conclude that damage to the spinothalamic tract (STT) is a necessary condition for the occurrence of chronic pain following SCI. However, STT lesion is not a sufficient condition since it could also be found in SCINP. The abnormal evoked pain seen in SCIP is probably due to neuronal hyperexcitability in these subjects. The fact that apparently identical sensory impairments manifest as chronic pain and hyperexcitability in one subject but not in another implies that either genetic predisposition or subtle differences in the nature of spinal injury determine the emergence of chronic pain following SCI.

Acute pain threshold in subjects with chronic pain following spinal cord injury.

Studies of pain perception in patients with chronic pain have yielded contradictory results. While several studies found that acute pain threshold is raised in chronic pain subjects, others showed that these subjects exhibit a decreased pain threshold compared to pain free subjects. The aim of this study was to further examine this topic by studying pain perception in subjects with chronic pain following partial or complete spinal cord injury (SCI). We found a significant elevation of heat-pain threshold (measured above the level of lesion) in complete SCI subjects with chronic pain (CSCIP) as opposed to complete SCI subjects without pain, incomplete SCI subjects with (ISCIP) and without chronic pain and normal controls. This elevation of pain threshold was completely reversed following a complete relief of the chronic pain by DREZ lesion. Moreover, the CSCIP exhibited significantly higher scores in the McGill pain questionnaire compared to ISCIP, indicative of a more intense chronic pain perceived by these subjects. In addition, the chronic pain below the level of spinal lesion, reported by CSCIP originated from a significantly larger body area than that of ISCIP. These results indicate that a critical level of chronic pain must be perceived in order to induce an elevation in acute pain threshold.

Strain differences in autotomy levels in mice: relation to spinal excitability.

The consequences of combined transection of the sciatic and femoral nerves were investigated in mice of the ICR and C3HEB strains. Whereas all the animals of the C3HEB strain showed very clear self mutilatory behavior of the denervated limb (autotomy) none of the ICR mice showed autotomy. Further tests, using the hot plate and tail flick methods, show that C3HEB mice were more sensitive to noxious thermal stimuli than ICR mice. Finally, spinalization at the lumbar level revealed a markedly higher level of spinal excitability in C3HEB mice as evident from a marked decrease in nociceptive thresholds in these animals. No such threshold decrease was observed in spinalized ICR mice. The results suggest that different levels of spinal excitability underlie the susceptibility for the emergence of autotomy in mice. It is proposed that such different levels of excitability may also underlie the susceptibility for the emergence of neuropathic pain.