What does local tenderness say about the origin of pain? An investigation of cervical zygapophysial joint pain

BACKGROUND: Mechanical pain sensitivity is assessed in every patient with pain, either by palpation or by quantitative pressure algometry. Despite widespread use, no studies have formally addressed the usefulness of this practice for the identification of the source of pain. We tested the hypothesis that assessing mechanical pain sensitivity distinguishes damaged from healthy cervical zygapophysial (facet) joints. METHODS: Thirty-three patients with chronic unilateral neck pain were studied. Pressure pain thresholds (PPTs) were assessed bilaterally at all cervical zygapophysial joints. The diagnosis of zygapophysial joint pain was made by selective nerve blocks. Primary analysis was the comparison of the PPT between symptomatic and contralateral asymptomatic joints. The secondary end points were as follows: differences in PPT between affected and asymptomatic joints of the same side of patients with zygapophysial joint pain; differences in PPT at the painful side between patients with and without zygapophysial joint pain; and sensitivity and specificity of PPT for 2 different cutoffs (difference in PPT between affected and contralateral side by 1 and 30 kPa, meaning that the test was considered positive if the difference in PPT between painful and contralateral side was negative by at least 1 and 30 kPa, respectively). The PPT of patients was also compared with the PPT of 12 pain-free subjects. RESULTS: Zygapophysial joint pain was present in 14 patients. In these cases, the difference in mean PPT between affected and contralateral side (primary analysis) was −6.2 kPa (95% confidence interval: −19.5 to 7.2, P = 0.34). In addition, the secondary analyses yielded no statistically significant differences. For the cutoff of 1 kPa, sensitivity and specificity of PPT were 67% and 16%, respectively, resulting in a positive likelihood ratio of 0.79 and a diagnostic confidence of 38%. When the cutoff of 30 kPa was considered, the sensitivity decreased to only 13%, whereas the specificity increased to 95%, resulting in a positive likelihood ratio of 2.53 and a diagnostic confidence of 67%. The PPT was significantly lower in patients than in pain-free subjects (P < 0.001). CONCLUSIONS: Assessing mechanical pain sensitivity is not diagnostic for cervical zygapophysial joint pain. The finding should stimulate further research into a diagnostic tool that is widely used in the clinical examination of patients with pain.

Algometry with a clothes peg compared to an electronic pressure algometer: a randomized cross-sectional study in pain patients

Hypersensitivity of the central nervous system is widely present in pain patients and recognized as one of the determinants of chronic pain and disability. Electronic pressure algometry is often used to explore aspects of central hypersensitivity. We hypothesized that a simple pain provocation test with a clothes peg provides information on pain sensitivity that compares meaningfully to that obtained by a well-established electronic pressure algometer. "Clinically meaningful" was defined as a medium (r = 0.3-0.5) or high (r > 0.5) correlation coefficient according to Cohen's conventions.

Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state

Background: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. Methods: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. Results: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6–1.9) (median [95% CI]) to 2.3 g (2.2–2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4–15.5) to 30.0 s (21.8–31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. Conclusions: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

Central hypersensitivity in chronic pain: mechanisms and clinical implications

The available literature consistently shows increased pain sensitivity after sensory stimulation of healthy tissues in patients who have various chronic pain conditions. This indicates a state of hypersensitivity of the CNS that amplifies the nociceptive input arising from damaged tissues. Experimental data indicate that central hypersensitivity is probably induced primarily by nociceptive input arising from a diseased tissue. In patients, imbalance of descending modulatory systems connected with psychologic distress may play a role. There is experimental support in animal studies for the persistence of central hypersensitivity after complete resolution of tissue damage. This is particularly true for neuropathic pain conditions, whereby potentially irreversible plasticity changes of the CNS have been documented in animal studies. Whether such changes are present in musculoskeletal pain states is at present uncertain. Despite the likely importance of central hypersensitivity in the pathophysiology of chronic pain, this mechanism should not be used to justify the lack of understanding on the anatomic origin of the pain complaints in several pain syndromes, which is mostly due to limitations of the available diagnostic tools. Treatment strategies for central hypersensitivity in patients have been investigated mostly in neuropathic pain states. Possible therapy modalities for central hypersensitivity in chronic pain of musculoskeletal origin are largely unexplored. The limited evidence available and everyday practice show, at best, modest efficacy of the available treatment modalities for central hypersensitivity. The gap between basic knowledge and clinical benefits remains large and should stimulate further intensive research.

Hypersensitivity and hyperalgesia in somatoform pain disorders.

OBJECTIVE In psychiatry, pain disorders not explained by structural lesions have been classified for decades as somatoform pain disorders, the underlying concept being somatization. In a parallel move, somatic medicine has defined an expanding group of similar pain disorders, known as functional pain syndromes. Functional pain syndromes are characterized by enhanced pain sensitivity. The aim of our study was to investigate the proportion of patients with somatoform pain disorders who also meet the criteria of functional pain syndromes and the extent to which patients with somatoform pain disorders also show enhanced pain sensitivity. METHODS Data on pain sensitivity in 120 hospitalized patients were obtained by means of two algometric methods. The group of patients with somatoform pain disorders was further divided into two subsets: patients with and those without a co-diagnosis of a functional pain syndrome. Patients with nociceptive pain served as control group. RESULTS Of the 120 in-patients selected, 67 fulfilled the criteria of a somatoform pain disorder of which 41 (61%) also met the co-diagnosis of a functional pain syndrome. Patients with somatoform pain disorder differed from controls in that they showed enhanced pain sensitivity, irrespective of whether a functional pain syndrome was concomitantly present (P<.001). CONCLUSIONS Somatoform pain disorders show considerable overlap with functional pain syndromes, including enhanced pain sensitivity. This suggests the relevance of integrating somatosensory aspects of pain into a modified understanding of somatoform pain disorders.

Nerve Injury-Induced Neuropathic Pain Causes Disinhibition of the Anterior Cingulate Cortex

Neuropathic pain caused by peripheral nerve injury is a debilitating neurological condition of high clinical relevance. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. Changes in cortical areas involved in pain processing contribute to the development of neuropathic pain. Yet, it remains elusive which plasticity mechanisms occur in cortical circuits. We investigated the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. We performed multiple whole-cell recordings from neurons in layer 5 (L5) of the ACC of adult mice after chronic constriction injury of the sciatic nerve of the left hindpaw and observed a striking loss of connections between excitatory and inhibitory neurons in both directions. In contrast, no significant changes in synaptic efficacy in the remaining connected pairs were found. These changes were reflected on the network level by a decrease in the mEPSC and mIPSC frequency. Additionally, nerve injury resulted in a potentiation of the intrinsic excitability of pyramidal neurons, whereas the cellular properties of interneurons were unchanged. Our set of experimental parameters allowed constructing a neuronal network model of L5 in the ACC, revealing that the modification of inhibitory connectivity had the most profound effect on increased network activity. Thus, our combined experimental and modeling approach suggests that cortical disinhibition is a fundamental pathological modification associated with peripheral nerve damage. These changes at the cortical network level might therefore contribute to the neuropathic pain condition.

Vitamin D and central hypersensitivity in patients with chronic pain.

BACKGROUND Low vitamin D is implicated in various chronic pain conditions with, however, inconclusive findings. Vitamin D might play an important role in mechanisms being involved in central processing of evoked pain stimuli but less so for spontaneous clinical pain. OBJECTIVE This study aims to examine the relation between low serum levels of 25-hydroxyvitamin D3 (25-OH D) and mechanical pain sensitivity. DESIGN We studied 174 patients (mean age 48 years, 53% women) with chronic pain. A standardized pain provocation test was applied, and pain intensity was rated on a numerical analogue scale (0-10). The widespread pain index and symptom severity score (including fatigue, waking unrefreshed, and cognitive symptoms) following the 2010 American College of Rheumatology preliminary diagnostic criteria for fibromyalgia were also assessed. Serum 25-OH D levels were measured with a chemiluminescent immunoassay. RESULTS Vitamin deficiency (25-OH D < 50 nmol/L) was present in 71% of chronic pain patients; another 21% had insufficient vitamin D (25-OH D < 75 nmol/L). After adjustment for demographic and clinical variables, there was a mean ± standard error of the mean increase in pain intensity of 0.61 ± 0.25 for each 25 nmol/L decrease in 25-OH D (P = 0.011). Lower 25-OH D levels were also related to greater symptom severity (r = -0.21, P = 0.008) but not to the widespread pain index (P = 0.83) and fibromyalgia (P = 0.51). CONCLUSIONS The findings suggest a role of low vitamin D levels for heightened central sensitivity, particularly augmented pain processing upon mechanical stimulation in chronic pain patients. Vitamin D seems comparably less important for self-reports of spontaneous chronic pain.

Implications of proposed fibromyalgia criteria across other functional pain syndromes

OBJECTIVES In 2010, the American College of Rheumatology (ACR) proposed new criteria for the diagnosis of fibromyalgia (FM) in the context of objections to components of the criteria of 1990. The new criteria consider the Widespread Pain Index (WPI) and the Symptom Severity Score (SSS). This study evaluated the implications of the new diagnostic criteria for FM across other functional pain syndromes. METHOD A cohort of 300 consecutive in-patients with functional pain syndromes underwent a diagnostic screen according to the ACR 2010 criteria. Additionally, systematic pain assessment including algometric and psychometric data was carried out. RESULTS Twenty-five patients (8.3%) had been diagnosed with FM according to the ACR 1990 criteria. Twenty-one of them (84%) also met the new ACR 2010 criteria. In total, 130 patients (43%) fulfilled the new ACR 2010 criteria. A comparison of new vs. old cases showed a high degree of conformity in most of the pain characteristics. The new FM cases, however, revealed a pronounced heterogeneity in the anatomical pain locations, including several types of localized pain syndromes. Furthermore, patients fulfilling the ACR 2010 FM criteria differed from those with other functional pain syndromes; they had increased pain sensitivity scores and increased psychometric values for depression, anxiety, and psychological distress (p<0.01). CONCLUSIONS FM according to the ACR 2010 criteria describes the 'severe half' of the spectrum of functional pain syndromes. By dropping the requirement of 'generalized pain', these criteria result in a blurring of the distinction between FM and more localized functional pain syndromes.

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.

Neural correlates of antinociception in borderline personality disorder

CONTEXT: A characteristic feature of borderline personality disorder (BPD) is self-injurious behavior in conjunction with stress-induced reduction of pain perception. Reduced pain sensitivity has been experimentally confirmed in patients with BPD, but the neural correlates of antinociceptive mechanisms in BPD are unknown. We predicted that heat stimuli in patients with BPD would activate brain areas concerned with cognitive and emotional evaluation of pain. OBJECTIVE: To assess the psychophysical properties and neural correlates of altered pain processing in patients with BPD. DESIGN: Case-control study. SETTING: A university hospital. PARTICIPANTS: Twelve women with BPD and self-injurious behavior and 12 age-matched control subjects. INTERVENTIONS: Psychophysical assessment and blood oxygen level-dependent functional magnetic resonance imaging during heat stimulation with fixed-temperature heat stimuli and individual-temperature stimuli adjusted for equal subjective pain in all the participants. MAIN OUTCOME MEASURE: Blood oxygen level-dependent functional magnetic resonance imaging signal changes during heat pain stimulation. RESULTS: Patients with BPD had higher pain thresholds and smaller overall volumes of activity than controls in response to identical heat stimuli. When the stimulus temperature was individually adjusted for equal subjective pain level, overall volumes of activity were similar, although regional patterns differed significantly. Patient response was greater in the dorsolateral prefrontal cortex and smaller in the posterior parietal cortex. Pain also produced neural deactivation in the perigenual anterior cingulate gyrus and the amygdala in patients with BPD. CONCLUSION: The interaction between increased pain-induced response in the dorsolateral prefrontal cortex and deactivation in the anterior cingulate and the amygdala is associated with an antinociceptive mechanism in patients with BPD.

Loss of pulp sensitivity and pain as the first symptoms of a Ewing's sarcoma in the right maxillary sinus and alveolar process: report of a case

This case report describes the diagnosis and treatment of a Ewing's sarcoma in the right maxillary sinus and alveolar bone of a 19-year-old female patient. The first clinical symptoms were a loss of sensitivity of the premolars and first molar in the right maxilla and acute pain located in the area of these teeth. Initially, the referring dentist had treated these findings as an acute apical periodontitis with root canal medication. Because swellings on the palatal and buccal aspects of the teeth occurred and could not be treated with incision and drainage, the dentist referred the patient. Cone-beam computed tomography revealed a proliferation of soft tissue in the right maxillary sinus, with a radiopaque material at the tip of the mesiobuccal root of the first molar and resorptive signs of the mesiobuccal and distobuccal roots of the first molar. The palatal cortical bone of the right alveolar process seemed to be intact. After explorative surgery with biopsies from the buccal, palatal, and sinus proliferation areas, the pathologist diagnosed the lesion as a Ewing's sarcoma. Treatment of the patient consisted of initial chemotherapy, hemimaxillectomy, and postsurgical chemoradiotherapy.

Factors influencing the attitudes of cattle veterinarians, farmers, and claw trimmers towards the pain associated with the treatment of sole ulcers and the sensitivity to pain of dairy cows

This study assessed the attitudes of personnel involved in therapeutic claw trimming of dairy cattle in Switzerland towards pain associated with sole ulcers and their treatment. Data from 77 farmers, 32 claw trimmers, and 137 cattle veterinarians were used. A large range of factors were associated with whether the respondents thought that anaesthesia during the treatment of sole ulcers was beneficial; these included year of graduation, work experience, attitude to costs of analgesia, perception of competition between veterinarians and claw trimmers, estimation of pain level associated with treatment, estimated sensitivity of dairy cows to pain, knowledge of the obligation to provide analgesia, and whether the respondent thought lesion size and occurrence of defensive behaviour by the cow were important. Respondents' estimation of the pain level associated with sole ulcer treatment was linked to frequency of therapeutic claw trimming, age, farmers' income, estimated knowledge of the benefits of analgesia, and estimated sensitivity of dairy cows to pain. The latter factor was associated with profession, frequency of therapeutic claw trimming, capability of pain recognition, opinion on the benefits of analgesia, knowledge of the obligation to provide analgesia, and self-estimation of the ability to recognise pain. Improving the knowledge of personnel involved in therapeutic claw trimming with regard to pain in dairy cows and how to alleviate it is crucial if management of pain associated with treatment of sole ulcer and the welfare of lame cows are to be optimised.

Test-retest reliability of the nociceptive withdrawal reflex and electrical pain thresholds after single and repeated stimulation in patients with chronic low back pain

Recent studies have shown that the nociceptive withdrawal reflex threshold (NWR-T) and the electrical pain threshold (EP-T) are reliable measures in pain-free populations. However, it is necessary to investigate the reliability of these measures in patients with chronic pain in order to translate these techniques from laboratory to clinic. The aims of this study were to determine the test-retest reliability of the NWR-T and EP-T after single and repeated (temporal summation) electrical stimulation in a group of patients with chronic low back pain, and to investigate the association between the NWR-T and the EP-T. To this end, 25 patients with chronic pain participated in three identical sessions, separated by 1 week in average, in which the NWR-T and the EP-T to single and repeated stimulation were measured. Test-retest reliability was assessed using intra-class correlation coefficient (ICC), coefficient of variation (CV), and Bland-Altman analysis. The association between the thresholds was assessed using the coefficient of determination (r (2)). The results showed good-to-excellent reliability for both NWR-T and EP-T in all cases, with average ICC values ranging 0.76-0.90 and average CV values ranging 12.0-17.7%. The association between thresholds was better after repeated stimulation than after single stimulation, with average r (2) values of 0.83 and 0.56, respectively. In conclusion, the NWR-T and the EP-T are reliable assessment tools for assessing the sensitivity of spinal nociceptive pathways in patients with chronic pain.

Blockade of the sinuvertebral nerve for the diagnosis of lumbar diskogenic pain: an exploratory study

In this exploratory study we evaluated sensitivity and target specificity of sinuvertebral nerve block (SVNB) for the diagnosis of lumbar diskogenic pain. Diskography has been the diagnostic gold standard. Fifteen patients with positive diskography underwent SVNB via interlaminar approach to the posterior aspect of the disk. Success was defined as > or = 80% pain reduction or excellent relief of physical restrictions after the block. The sensitivity was 73.3% (95% CI: 50.9%-95.7%). The target specificity was 40% (15.2%-64.8%). The results indicate that SVNB cannot yet replace diskography but encourage future studies to improve its target specificity.

Decision making in patients with acute abdominal pain at a university and at a rural hospital: Does the value of abdominal sonography differ?

Introduction and objectives Abdominal sonography is regarded as a quick and effective diagnostic tool for acute abdominal pain in emergency medicine. However, final diagnosis is usually based on a combination of various clinical examinations and radiography. The role of sonography in the decision making process at a hospital with advanced imaging capabilities versus a hospital with limited imaging capabilities but more experienced clinicians is unclear. The aim of this pilot study was to assess the relative importance of sonography and its influence on the clinical management of acute abdominal pain, at two Swiss hospitals, a university hospital (UH) and a rural hospital (RH). Methods 161 patients were prospectively examined clinically. Blood tests and sonography were performed in all patients. Patients younger than 18 years and patients with trauma were excluded. In both hospitals, the diagnosis before and after ultrasonography was registered in a protocol. Certainty of the diagnosis was expressed on a scale from 0% to 100%. The decision processes used to manage patients before and after they underwent sonography were compared. The diagnosis at discharge was compared to the diagnosis 2 – 6 weeks thereafter. Results Sensitivity, specificity and accuracy of sonography were high: 94%, 88% and 91%, respectively. At the UH, management after sonography changed in only 14% of cases, compared to 27% at the RH. Additional tests were more frequently added at the UH (30%) than at the RH (18%), but had no influence on the decision making process-whether to operate or not. At the UH, the diagnosis was missed in one (1%) patient, but in three (5%) patients at the RH. No significant difference was found between the two hospitals in frequency of management changes due to sonography or in the correctness of the diagnosis. Conclusion Knowing that sonography has high sensitivity, specificity and accuracy in the diagnosis of acute abdominal pain, one would assume it would be an important diagnostic tool, particularly at the RH, where tests/imaging studies are rare. However, our pilot study indicates that sonography provides important diagnostic information in only a minority of patients with acute abdominal pain. Sonography was more important at the rural hospital than at the university hospital. Further costly examinations are generally ordered for verification, but these additional tests change the final treatment plan in very few patients.