Hypoalgesia related to elevated resting blood pressure is absent in adolescents and young adults with a history of functional abdominal pain

Elevated resting blood pressure (BP) is hypoalgesic in healthy individuals, but this effect is absent in adults with chronic somatic pain. This study tested whether BP-related hypoalgesia is similarly altered in individuals with a history of chronic visceral pain in childhood. Resting BP was assessed in 94 adolescents and young adults with a known history of childhood functional abdominal pain (FAP) and 55 comparable healthy controls. Responses to an acute heat pain stimulus were then evaluated following exposure to two laboratory stressors. A significant participant type × systolic BP (SBP) interaction (p < .005) revealed that elevated resting SBP was associated with significantly higher heat pain threshold (p < .001) in healthy controls, but was unrelated to pain threshold in the FAP group. A similar pattern was observed for heat pain tolerance, with elevated SBP linked to significantly higher pain tolerance (p < .05) in healthy controls, but unrelated to tolerance in the FAP group. Dysfunction in BP-related hypoalgesia associated with FAP was evident regardless of whether childhood FAP had resolved or still persisted at the time of laboratory testing. Subgroup analyses indicated that BP-related hypoalgesia (in healthy controls) and FAP-linked absence of this hypoalgesia was observed only among females. Result suggest that childhood visceral chronic pain may be associated with relatively long-lasting dysfunction in overlapping systems modulating pain and BP that persists even after FAP resolves. Potential implications for later hypertension risk are discussed.     

The mediating role of pain catastrophizing in the relationship between presurgical anxiety and acute postsurgical pain after hysterectomy

The aim of this study was to examine the joint role of demographic, clinical, and psychological variables as predictors of acute postsurgical pain in women undergoing hysterectomy due to benign disorders. A consecutive sample of 203 women was assessed 24 hours before (T1) and 48 hours after (T2) surgery. Baseline pain and predictors were assessed at T1 and postsurgical pain and analgesic consumption at T2. Several factors distinguished women who had no or mild pain after surgery from those who had moderate to severe pain, with the latter being younger, having more presurgical pain, and showing a less favorable psychological profile. Younger age (odds ratio [OR] = 0.90, P < .001), presurgical pain (OR = 2.50, P <.05), pain due to other causes (OR = 4.39, P = .001), and pain catastrophizing (OR = 3.37, P = .001) emerged as the main predictors of pain severity at T2 in multivariate logistic regression. This was confirmed in hierarchical linear regression (β = −0.187, P < .05; β = 0.146, P < .05; β = 0.136, P < .05; β = 0.245, P < .01, respectively). Presurgical anxiety also predicted pain intensity at T2. Findings revealed an integrative heuristic model that accounts for the joint influence of demographic, clinical, and psychological factors on postsurgical pain intensity and severity. In further mediation analysis, pain catastrophizing emerged as a full mediator between presurgical anxiety and postsurgical pain intensity. The potential clinical implications for understanding, evaluating, and intervening in postsurgical pain are discussed.     

Increased basal mechanical pain sensitivity but decreased perceptual wind-up in a human model of relative hypocortisolism

Clinical data have accumulated showing that relative hypocortisolism, which may be regarded as a neuroendocrinological correlate of chronic stress, may be a characteristic of some functional pain syndromes. However, it has not been clarified yet whether deregulations of the hypothalamus–pituitary–adrenal (HPA) axis may directly alter pain perception and thus be causally involved in the pathophysiology of these disorders. To test this hypothesis, we performed a randomized placebo-controlled crossover trial in N = 20 healthy drug-free volunteers (median age 24 yrs) and analyzed the effects of metyrapone-induced hypocortisolism on quantitatively assessed basal mechanical pain sensitivity (1.5–13 m/s impact stimuli), perceptual wind-up (9 m/s impact stimuli at 1 Hz) and temporal summation of pain elicited by inter-digital web pinching (IWP; 10 N pressure stimuli for 2 min). Experimentally induced hypocortisolism significantly decreased pain detection thresholds and augmented temporal summation of IWP-induced pain (p < .05). The latter effect was dependent on the relative reduction in cortisol levels, and seemed to rely on a potentiated sensitization and not merely on the observed changes in basal pain sensitivity. Perceptual wind-up by contrast was reduced when cortisol synthesis was blocked (p < .05). This result is reminiscent of findings from animal studies showing a reversal of NMDA receptor activation by glucocorticoid receptor antagonists in neuropathic pain models. Our results speak in favor of a potential causal role of HPA axis alterations in pain chronicity.     

Comparison of postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: Clinical evidence of enhanced pain sensitivity after surgical injury

Staged bilateral total knee arthroplasty (TKA) may provide an ideal clinical model for the study of central sensitization. In staged TKA, hyperalgesia may be induced as a result of repeated surgical injury possibly via central sensitization, which can decrease functional outcomes. Therefore, we hypothesized that in staged bilateral TKA, patients would have greater pain in the second operated knee than in the first. Thirty patients undergoing staged bilateral TKA at a 1-week interval were enrolled. Postoperative pain, which was reported on the basis of a visual analog scale (VAS; primary outcome) at rest and at maximum knee flexion, and the amount of patient-controlled analgesic (i.v. fentanyl) and rescue analgesic (i.v. ketoprofen; secondary outcomes) administered during the 48 h after the operation, were compared between the first and second TKA. VAS scores at rest and at maximum knee flexion were greater on the second operated knee (P < .001 and P < .01, respectively). The cumulative amounts of patient-controlled analgesic and the rescue analgesic were greater in the second than in the first TKA (P < .001 and P < .05, respectively). Patients undergoing staged bilateral TKA experience greater postoperative pain in the second operated knee than the first. This suggests extension of hyperalgesia beyond the initially injured site to remote regions after surgical injury, in which central sensitization may be involved. Therapeutic approaches to reduce such hyperalgesia induced in the course of staged operations are required.     

Widespread sensitization in patients with chronic pain after revision total knee arthroplasty

Pain and sensitization are major issues in patients with osteoarthritis both before and after total knee arthroplasty (TKA) and revision TKA (re-TKA). The aim of this study was to assess sensitization in patients with and without chronic pain after re-TKAs. Twenty patients with chronic knee pain and 20 patients without pain after re-TKA participated. Spreading of pain was evaluated as the number of pain sites using a region-divided body chart. The pressure pain threshold (PPT) and pressure pain tolerance (PTT) were assessed by cuff algometry at the lower leg. Temporal summation of pain was assessed by recordings of the pain intensity on a visual analog scale (VAS) during repeated cuff pressure stimulations. Conditioning pain modulation (CPM) was recorded by experimental tonic arm pain by cuff pressure stimulation and assessment of PPTs on the knee, leg, and forearm using handheld pressure algometry. Participants with pain after re-TKA compared to participants without pain demonstrated: (1) significantly more pain sites (P = .004), (2) decreased cuff PPTs and PTTs at the lower leg (P < .001), (3) facilitated temporal summation (P < .001), and (4) impaired CPM (P < .001). Additionally, significant correlations between knee pain intensity and cuff PPTs, temporal summation, and CPM and between total duration of knee pain and temporal summation were found (P < .05). This study demonstrated widespread sensitization in patients with pain after re-TKA and highlighted the importance of ongoing nociceptive input for the chronification process. This has important implications for future revisions, and precautions should be taken if patients have widespread sensitization.     

Altered experimental pain perception after cerebellar infarction

Animal studies have suggested that the cerebellum, in addition to its motor functions, also has a role in pain processing and modulation, possibly because of its extensive connections with the prefrontal cortex and with brainstem regions involved in descending pain control. Consistently, human imaging studies have shown cerebellar activation in response to painful stimulation. However, it is presently not clear whether cerebellar lesions affect pain perception in humans. In the present study, we used experimental pain testing to compare acute pain perception and endogenous pain inhibition in 30 patients 1 to 11 years after cerebellar infarction and in 30 sex- and age-matched healthy control subjects. Compared to controls, patients exhibited a significantly increased pain perception in response to acute heat stimuli (44°C–48°C, average pain intensity rating for patients 3.4 ± 2.8 and for controls 1.5 ± 1.7 [on a numeric rating scale of 0–10], P < .01) and to repeated 256 mN pinprick stimuli (1.3 ± 1.9 vs 0.6 ± 1.0 [0–10], P < .05). Heat hyperalgesia in patients was more pronounced on the body side ipsilateral to the infarction. In addition, patients showed reduced offset analgesia (change in pain intensity rating: 0.0% ± 15.8% vs −16.9% ± 36.3%, P < .05) and reduced placebo analgesia (change in pain intensity rating: −1.0 ± 1.1 vs −1.8 ± 1.3 [0–10], P < .05) compared to controls. In contrast, heat and pressure pain thresholds were not significantly different between groups. These results show that, after cerebellar infarction, patients perceive heat and repeated mechanical stimuli as more painful than do healthy control subjects and have deficient activation of endogenous pain inhibitory mechanisms (offset and placebo analgesia). This suggests that the cerebellum has a previously underestimated role in human pain perception and modulation.     

Hyperalgesia and functional sensory loss in restless legs syndrome

Pain and other sensory signs in patients with restless legs syndrome (RLS) are still poorly understood, as most investigations focus on motor system dysfunctions. This study aimed to investigate somatosensory changes in patients with primary RLS and the restoration of somatosensory function by guideline-based treatment. Forty previously untreated RLS patients were investigated unilaterally over hand and foot using quantitative sensory testing (QST) and were compared with 40 age- and gender-matched healthy subjects. The predominant finding in RLS patients was 3- to 4-fold increase of sensitivity to pinprick stimuli in both extremities (hand: P < .05; foot: P < .001), a sensory pathway involved in withdrawal reflexes. Pinprick hyperalgesia was not paralleled by dynamic mechanical allodynia. Additional significant sensory changes were tactile hypoesthesia in both extremities (hand: P < .05; foot P < .01) and dysesthesia to non-noxious cold stimuli (paradoxical heat sensation), which was present in the foot in an unusually high proportion (14 of 40 patients; P < .01). In 8 patients, follow-up QST 2 to 20 months after treatment with l-DOPA (L-3,4-dihydroxyphenylalanine) revealed a significant reduction of pinprick hyperalgesia (−60%, P < .001), improved tactile detection (+50%, P < .05), and disappearance of paradoxical heat sensation in half of the patients. QST suggested a type of spinal or supraspinal central sensitization differing from neuropathic pain or human experimental models of central sensitization by the absence of dynamic mechanical allodynia. Reversal of pinprick hyperalgesia by l-DOPA may be explained by impaired descending inhibitory dopaminergic control on spinal nociceptive neurons. Restoration of tactile sensitivity and paradoxical heat sensations suggest that they were functional disturbances resulting from central disinhibition.     

Enhanced pain modulation among triathletes: A possible explanation for their exceptional capabilities

Triathletes and ironman triathletes engage in an extremely intense sport that involves hours of considerable pain, as well as physical and psychological stress, every day. The basic pain modulation properties of these athletes has not been established and therefore it is not clear whether they present with unique features that enable them to engage in such efforts. The aim was to investigate the existence of possible alterations in pain perception and modulation of triathletes, as well as possible underlying factors. Participants were 19 triathletes and 17 non-athletes who underwent measurement of pain threshold, pain tolerance, suprathreshold perceived pain intensity, temporal summation of pain, and conditioned pain modulation (CPM). Participants also completed the fear of pain and the pain catastrophizing questionnaires, and rated the amount of perceived stress. Triathletes exhibited higher pain tolerance (P < .0001), lower pain ratings (P < .001), and lower fear of pain values (P < .05) than controls. The magnitude of CPM was significantly greater in triathletes (P < .05), and negatively correlated with fear of pain (P < .05) and with perceived mental stress during training and competition (P < .05). The results suggest that triathletes exhibit greater pain tolerance and more efficient pain modulation than controls, which may underlie their perseverance in extreme physical efforts and pain during training/competitions. This capability may be enhanced or mediated by psychological factors, enabling better coping with fear of pain and mental stress.     

Functional abdominal pain in childhood and adolescence increases risk for chronic pain in adulthood

A few studies of long-term outcomes for pediatric functional abdominal pain (FAP) have assessed acute non-abdominal pain at follow-up, but none has assessed chronic pain. We followed a cohort of pediatric patients with FAP (n = 155) and a well control group (n = 45) prospectively for up to 15 years. Participants ranged in age from 18 to 32 years at a follow-up telephone interview. FAP patients were classified as Resolved (n = 101) versus Unresolved (n = 54) at follow-up, based on whether they reported symptoms consistent with the adult Rome III criteria for a functional gastrointestinal disorder. Headache symptoms and reports of chronic non-abdominal pain also were assessed at follow-up. In the Unresolved group, 48.1% reported one or more sites of chronic non-abdominal pain at follow-up, compared to 24.7% in the Resolved group and 13.3% in the control group, p < 0.01. More than half (57.4%) of the Unresolved group endorsed symptoms consistent with International Headache Society criteria for headache, compared to 44.6% of the Resolved group and 31% of controls, p < 0.05. One-third of the Unresolved group reported both headache and one or more sites of chronic non-abdominal pain at follow-up, compared to 17.8% of the Resolved group and 4.4% of controls. Youth with FAP that persists into adulthood may be at increased risk for chronic pain and headache. Examination of central mechanisms that are common across chronic pain disorders may enhance understanding of this subgroup of FAP.     

Pain referral and regional deep tissue hyperalgesia in experimental human hip pain models

Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (P < .05). Referred pain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (P < .05). PPTs at the injection site were decreased after hypertonic saline injections into GMT and GMM compared with baseline, ALT injections, and isotonic saline. Cuff PPTs from the thigh were decreased after hypertonic saline injections into the ALT compared with baseline, GMT injections, and isotonic saline (P < .05). More subjects had positive joint pain provocation tests after hypertonic compared with isotonic saline injections (P < .05), indicating that this provocation test also assessed hyperalgesia in extra-articular soft tissues. The experimental models may open for better understanding of pain mechanisms associated with painful hip disorders.     

Safety and efficacy of pregabalin in patients with central post-stroke pain

Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long-term efficacy in central post-stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13-week, randomized, double-blind, multicenter, placebo-controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ?18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient-reported sleep and health-related quality-of-life measures. A total of 219 patients were treated (pregabalin n = 110; placebo n = 109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference = -0.2; 95% CI = -0.7, 0.4; P = 0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS-sleep, HADS-A anxiety, and clinician global impression of change (CGIC) P < 0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP.     

Preoperative Predictors of Complex Regional Pain Syndrome Outcomes in the 6 Months Following Total Knee Arthroplasty

This prospective observational study evaluated preoperative predictors of complex regional pain syndrome (CRPS) outcomes in the 6 months following total knee arthroplasty (TKA). Participants were n = 110 osteoarthritis patients (64.5% female) undergoing unilateral TKA with no prior CRPS history. Domains of negative affect (depression, anxiety, catastrophizing), pain (intensity, widespread pain, temporal summation of pain [TSP]), pain interference, sleep disturbance, and pro-inflammatory status (tumor necrosis factor-alpha [TNF-a]) were assessed preoperatively. CRPS outcomes at 6-week and 6-month follow-up included the continuous CRPS Severity Score (CSS) and dichotomous CRPS diagnoses (2012 IASP criteria). At 6 months, 12.7% of participants met CRPS criteria, exhibiting a “warm CRPS” phenotype. Six-week CSS scores were predicted by greater preoperative depression, anxiety, catastrophizing, TSP, pain intensity, sleep disturbance, and TNF-a (P’s < .05). Provisional CRPS diagnosis at 6 weeks was predicted by higher preoperative TSP, sleep disturbance, and TNF-a (P’s < .05). CSS scores at 6 months were predicted by more widespread and intense preoperative pain, and higher preoperative TSP, pain interference, and TNF-a (P’s < .01). CRPS diagnosis at 6 months was predicted only by more widespread and intense pain preoperatively (P’s < .05). Risk for CRPS following TKA appears to involve preoperative central sensitization and inflammatory mechanisms. Preoperative negative affect is unlikely to directly influence long-term CRPS risk.PerspectiveThis article identifies preoperative predictors of CRPS features at 6 months following total knee arthroplasty, including more widespread pain and higher pain intensity, temporal summation of pain, pain interference, and tumor necrosis factor-alpha levels. Findings suggest the importance of central sensitization and inflammatory mechanisms in CRPS risk following tissue trauma.     

An enriched-enrolment,randomized withdrawal,flexible-dose,double-blind,placebo-controlled,parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain

Cannabinoids are emerging as potential options for neuropathic pain treatment. This study evaluated an oral cannabinoid, nabilone, in the treatment of refractory human diabetic peripheral neuropathic pain (DPN). We performed a single-center, randomized, double-blind, placebo-controlled, flexible-dose study with an enriched enrolment randomized withdrawal design. DPN subjects with a pain score ?4 (0-10 scale) continued regular pain medications and were administered single-blinded adjuvant nabilone for 4 weeks. Subjects achieving ?30% pain relief (26/37) were then randomized and treated with either flexible-dose nabilone 1-4 mg/day (n = 13) or placebo (n = 13) in a further 5-week double-blind treatment period, with 30% (11/37) of subjects deemed run-in-phase nabilone nonresponders. For nabilone run-in-phase responders, there was an improvement in the change in mean end-point neuropathic pain vs placebo (mean treatment reduction of 1.27; 95% confidence interval 2.29-0.25, P = 0.02), with an average nabilone dose at end point of 2.9 ± 1.1 mg/day, and improvements from baseline for the anxiety subscale of the Hospital Anxiety and Depression Scale, the Medical Outcomes Study sleep scale problems index, and the European Quality of Life-5-Domains index score (each P < 0.05). Nabilone run-in-phase responders reported greater global end-point improvement with nabilone than with placebo (100% vs 31%; P < 0.05). Medication-related confusion led to discontinuation in 2/37 subjects during single-blind nabilone treatment. Potential unmasking occurred in 62% of both groups. Flexible-dose nabilone 1-4 mg/day was effective in relieving DPN symptoms, improving disturbed sleep, quality of life, and overall patient status. Nabilone was well tolerated and successful as adjuvant in patients with DPN.     

Identifying neuropathic back and leg pain: a cross-sectional study

Low back pain is a widespread debilitating problem with a lifetime prevalence of 80%, with the underlying pain mechanism unknown in approximately 90% of cases. We used the painDETECT neuropathic pain screening questionnaire to identify likely pain mechanisms in 343 patients with low back pain with or without leg pain in southeastern England referred for physiotherapy. We related the identified possible pain mechanisms nociceptive, unclear, and neuropathic to standardised measures of pain severity (Numeric Rating Scale), disability (Roland Morris Low Back Pain Disability Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), and quality of life (Short Form 36 Health Survey Questionnaire Version 2). In addition, we investigated any relationship between these possible pain mechanisms and leg pain, passive straight leg raise, and magnetic resonance imaging evidence confirming or eliminating nerve root compression. A total of 59% of participants (n = 204) reported likely nociceptive pain, 25% (n = 85) unclear, and 16% (n = 54) possible neuropathic pain. The possible neuropathic pain group reported significantly higher pain, disability, anxiety, and depression, reduced quality of life and passive straight leg raise compared to the other pain groups (P < .05). A total of 96% of participants with possible neuropathic pain reported pain radiating to the leg (76% below the knee); however, leg pain was still more common in patients with nociceptive pain, suggesting that leg pain is sensitive to, but not specific to, possible neuropathic pain. No relationship was demonstrated between possible neuropathic pain and evidence for or absence of nerve root compression on magnetic resonance imaging scans. These findings suggest possible neuropathic pain is less common in low back pain patients referred through primary care and clarifies the usefulness of clinical tests for identifying possible neuropathic pain.     

The specific disease burden of neuropathic pain: results of a French nationwide survey

We report the first nationwide survey of the impact of neuropathic pain, as opposed to nonneuropathic pain, on quality of life and health care utilization in the French general population. A postal questionnaire was sent to a representative sample of 4554 respondents from an initial nationwide survey of 30,155 subjects with or without chronic pain. It included pain characteristics (Neuropathic Pain Symptom Inventory, DN4), quality of life (Medical Outcomes Short Form 12, SF-12), sleep, anxiety/depressive symptoms (Hospital Anxiety and Depression Scale) and health care utilization. In total, 3899 (85.6%) questionnaires were returned, 3816 (97.9%) could be assessed and 3165 subjects (82.9%) confirmed their pain status. Subjects reporting pain and neuropathic characteristics based on the DN4 displayed a higher degree of impairment of all dimensions relating to quality of life and sleep and had higher anxiety/depression scores than those reporting pain without neuropathic characteristics and those without pain (P < .01). They also made greater use of health care facilities, particularly as concerned neurological treatments and visits to neurologists (21% vs 9%; P < .01). Multivariate analyses showed that the neuropathic characteristics of pain made an independent contribution to quality-of-life impairment (P < .0001 and P = .0005 for the physical and mental scores of the SF-12 respectively). Our study indicates that the disease burden of chronic pain depends on the nature of the pain, independently of its intensity and duration.     

Pain and the onset of depressive and anxiety disorders

Patients with pain may be at increased risk of developing a first episode of depressive or anxiety disorder. Insight into possible associations between specific pain characteristics and such a development could help clinicians to improve prevention and treatment strategies. The objectives of this study were to examine the impact of pain symptomatology on depression and anxiety onset and to determine whether these associations are independent of subthreshold depressive and anxiety symptoms. Data from the Netherlands Study of Depression and Anxiety, collected between 2004 and 2011, were used. A total of 614 participants with no previous history and no current depression or anxiety at baseline were followed up for 4 years. Onset of depressive or anxiety disorder was assessed at 2- and 4-year follow-up by Composite International Diagnostic Interview. Baseline pain characteristics were location, duration, and severity, as assessed by chronic pain grade. Onset of depressive or anxiety disorder occurred in 15.5% of participants. Using Cox survival analyses, onset of depression and anxiety was associated with 6 pain locations (neck, back, head, orofacial area, abdomen, and joints; hazard ratio [HR] = 1.96 to 4.02; P < .05), increasing number of pain locations (HR = 1.29; P < .001), and higher severity of pain (HR = 1.57; P < .001). By contrast, there was no association with duration of pain symptoms (HR = 1.47; P = .12). Independent of subthreshold affective symptoms, only joint pain and increasing number of pain locations were still significantly associated with depression and anxiety onset. Clinicians should be aware that regardless of affective symptoms, pain, particularly at multiple locations, is a risk indicator for developing depressive and anxiety disorders.     

Functional abdominal pain patient subtypes in childhood predict functional gastrointestinal disorders with chronic pain and psychiatric comorbidities in adolescence and adulthood

Although pediatric functional abdominal pain (FAP) has been linked to abdominal pain later in life, childhood predictors of long-term outcomes have not been identified. This study evaluated whether distinct FAP profiles based on patterns of pain and adaptation in childhood could be identified and whether these profiles predicted differences in clinical outcomes and central sensitization (wind-up) on average 9years later. In 843 pediatric FAP patients, cluster analysis was used to identify subgroups at initial FAP evaluation based on profiles of pain severity, gastrointestinal (GI) and non-GI symptoms, pain threat appraisal, pain coping efficacy, catastrophizing, negative affect, and activity impairment. Three profiles were identified: high pain dysfunctional, high pain adaptive, and low pain adaptive. Logistic regression analyses controlling for age and sex showed that, compared with pediatric patients with the low pain adaptive profile, those with the high pain dysfunctional profile were significantly more likely at long-term follow-up to meet criteria for pain-related functional gastrointestinal disorder (FGID) (odds ratio: 3.45, confidence interval: 1.95 to 6.11), FGID with comorbid nonabdominal chronic pain (odds ratio: 2.6, confidence interval: 1.45 to 4.66), and FGID with comorbid anxiety or depressive psychiatric disorder (odds ratio: 2.84, confidence interval: 1.35 to 6.00). Pediatric patients with the high pain adaptive profile had baseline pain severity comparable to that of the high pain dysfunctional profile, but had outcomes as favorable as the low pain adaptive profile. In laboratory pain testing at follow-up, high pain dysfunctional patients showed significantly greater thermal wind-up than low pain adaptive patients, suggesting that a subgroup of FAP patients has outcomes consistent with widespread effects of heightened central sensitization.     

Metabolite concentrations in the anterior cingulate cortex predict high neuropathic pain impact after spinal cord injury

Persistent pain is a common reason for reduced quality of life after a spinal cord injury (SCI). Biomarkers of neuropathic pain may facilitate translational research and the understanding of underlying mechanisms. Research suggests that pain and affective distress are anatomically and functionally integrated in the anterior cingulate cortex and can modulate sensory and affective aspects of pain. We hypothesized that severe neuropathic pain with a significant psychosocial impact would be associated with metabolite concentrations (obtained by magnetic resonance spectroscopy) in the anterior cingulate cortex, indicating neuronal and/or glial dysfunction. Participants with SCI and severe, high-impact neuropathic pain (SCI-HPI; n = 16), SCI and moderate, low-impact neuropathic pain (SCI-LPI; n = 24), SCI without neuropathic pain (SCI-noNP; n = 14), and able-bodied, pain-free control subjects (A-B; n = 22) underwent a 3-T magnetic resonance imaging brain scan. Analyses revealed that the SCI-HPI group had significantly higher levels of myoinositol (Ins) (P < .000), creatine (P = .007), and choline (P = .014), and significantly lower levels of N-acetyl aspartate/Ins (P = .024) and glutamate-glutamine (Glx)/Ins (P = .003) ratios than the SCI-LPI group. The lower Glx/Ins ratio significantly discriminated between SCI-HPI and the A-B (P = .006) and SCI-noNP (P = .026) groups, displayed excellent test-retest reliability, and was significantly related to greater pain severity, interference, and affective distress. This suggests that the combination of lower glutamatergic metabolism and proliferation of glia and glial activation are underlying mechanisms contributing to the maintenance of severe neuropathic pain with significant psychosocial impact in chronic SCI. These findings indicate that the Glx/Ins ratio may be a useful biomarker for severe SCI-related neuropathic pain with significant psychosocial impact.     

Improving the acquisition of nociceptive evoked potentials without causing more pain

Following nociceptive heat or laser stimulation, an early contralateral and later vertex potential can be recorded. Although more indicative of the nociceptive input, the acquisition of the contralateral N1 after contact heat stimulation (contact heat-evoked potentials [CHEPs]) remains difficult. An advantage of contact heat is that the baseline skin temperature preceding peak stimulation can be controlled. Increasing the baseline temperature may represent a novel strategy to improve the acquisition of CHEPs without resulting in more subjective pain to stimulation. A study was undertaken in 23 healthy subjects to examine the effects of increasing the baseline temperature but not the perceived intensity of contact heat stimulation. A combined standard averaging and single-trial analysis was performed to disclose how changes in averaged waveforms related to latency jitter and individual trial amplitudes. By increasing the baseline temperature, the acquisition of N1 was improved among subjects with a low-amplitude response (greater than −4 μV) following 35°C baseline temperature stimulation (P < .05). Based on standard averaging, N2/P2 amplitudes were also significantly increased with and without an accompanying change in the rating of perceived pain when the baseline temperature was increased (P < .05). In contrast, automated single-trial averaging revealed no significant difference in N2 amplitude when the baseline temperature was increased to 42°C and the peak temperature reduced. These findings suggest that 2 mechanisms underlie the improved acquisition of CHEPs: increased synchronization of afferent volley, yielding larger-amplitude evoked potentials in response to the same rating of intensity; and reduced inter-trial variability.     

Pressure pain thresholds fluctuate with,but do not usefully predict,the clinical course of painful temporomandibular disorder

Central sensitization elicits pain hypersensitivity and is thought to be causally implicated in painful temporomandibular disorder (TMD). This causal inference is based on cross-sectional evidence that people with TMD have greater sensitivity than controls to noxious stimuli. We tested this inference in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study of 3258 adults with no lifetime history of TMD when enrolled (visit 1). During 5 years of follow-up, 1 group labeled “persistent TMD cases” (n = 72) developed first-onset TMD by visit 2 that persisted ?6 months until visit 3. Another group labeled “transient TMD cases” (n = 75) developed first-onset TMD at visit 2, which resolved by visit 3. Randomly sampled “controls” (n = 126) remained TMD-free throughout all 3 visits. At each visit, pressure pain thresholds (PPTs) were measured by algometry at 10 cranial and bodily sites. In persistent TMD case patients, mean PPTs reduced 43 kPa (P < .0001) between visits 1 and 2 and thereafter did not change significantly. In transient TMD case patients, mean PPTs reduced 41 kPa (P < .001) between visits 1 and 2, and then increased 20 kPa (P < .001) by visit 3. These patterns were similar after excluding cranial sites symptomatic for TMD. Importantly, visit 1 PPTs had no clinically useful prognostic value in predicting first-onset TMD (odds ratio [OR] = 1.07, P = .15). Among first-onset case patients, visit 2 PPTs were modest predictors of persistent TMD (OR = 1.36, P = .002). In this longitudinal study, PPTs reduced when TMD developed then rebounded when TMD resolved. However, premorbid PPTs poorly predicted TMD incidence, countering the hypothesis that PPTs signify mechanisms causing first-onset TMD.