PAIN - Articles in Press

Analgesic antidepressants promote the responsiveness of locus coeruleus neurons to noxious stimulation: Implications for neuropathic pain - Corrected Proof

2012-05-16

TOC summary: The activity of locus coeruleus upon nociceptive stimulation is altered in neuropathic pain conditions, being restored by analgesic antidepressant treatment.Abstract: Antidepressants that block the reuptake of noradrenaline and/or serotonin are among the first-line treatments for neuropathic pain, although the mechanisms underlying this analgesia remain unclear. The noradrenergic locus coeruleus is an essential element of both the ascending and descending pain modulator systems regulated by these antidepressants. Hence, we investigated the effect of analgesic antidepressants on locus coeruleus activity in Sprague-Dawley rats subjected to chronic constriction injury (CCI), a model of neuropathic pain. In vivo extracellular recordings of locus coeruleus revealed that CCI did not modify the basal tonic activity of this nucleus, although its sensory-evoked response to noxious stimuli was significantly altered. Under normal conditions, noxious stimulation evokes an early response, corresponding to the activation of myelinated A fibers, which is followed by an inhibitory period and a subsequent late capsaicin-sensitive response, consistent with the activation of unmyelinated C fibers. CCI provokes an enhanced excitatory early response in the animals and the loss of the late response. Antidepressant administration over 7days (desipramine, 10mg/kg/day or duloxetine, 5mg/kg/day, delivered by osmotic minipumps) decreased the excitatory firing rate of the early response in the CCI group. Moreover, in all animals, these antidepressants reduced the inhibitory period and augmented the late response. We propose that N-methyl-d-aspartate and alpha-2-adrenoceptors are involved in the analgesic effect of antidepressants. Antidepressant-mediated changes were correlated with behavioral effects indicative of analgesia in healthy and neuropathic rats.

Hyperalgesia by low doses of the local anesthetic lidocaine involves cannabinoid signaling: An fMRI study in mice - Corrected Proof

2012-05-11

Summary: Functional magnetic resonance imaging in wild-type and CB1 receptor knockout mice revealed that lidocaine at low doses induces hyperalgesia, predominantly mediated by CB1 receptors located on nociceptors.Abstract: Lidocaine is clinically widely used as a local anesthetic inhibiting propagation of action potentials in peripheral nerve fibers. Correspondingly, the functional magnetic resonance imaging (fMRI) response in mouse brain to peripheral noxious input is largely suppressed by local lidocaine administered at doses used in a clinical setting. We observed, however, that local administration of lidocaine at doses 100× lower than that used clinically led to a significantly increased sensitivity of mice to noxious forepaw stimulation as revealed by fMRI. This hyperalgesic response could be confirmed by behavioral readouts using the von Frey filament test. The increased sensitivity was found to involve a type 1 cannabinoid (CB1) receptor-dependent pathway as global CB1 knockout mice, as well as wild-type mice pretreated systemically with the CB1 receptor blocker rimonabant, did not display any hyperalgesic effects after low-dose lidocaine. Additional experiments with nociceptor-specific CB1 receptor knockout mice indicated an involvement of the CB1 receptors located on the nociceptors. We conclude that low concentrations of lidocaine leads to a sensitization of the nociceptors through a CB1 receptor-dependent process. This lidocaine-induced sensitization might contribute to postoperative hyperalgesia.

Estimating the prevalence of chronic pain: validation of recall against longitudinal reporting (the HUNT pain study) - Corrected Proof

Tormod Landmark, Pål Romundstad, Ola Dale, Petter C. Borchgrevink, Stein Kaasa — 2012-05-10

TOC Summary: Pain reporting in the general population is stable, and recall measures of chronic pain may give valid estimates compared with longitudinal recordings.Abstract: Methods for classifying chronic pain in population studies are highly variable, and prevalence estimates ranges from 11% to 64%. Limited knowledge about the persistence of pain and the validity of recall questions defining chronic pain make findings difficult to interpret and compare. The primary aim of the current study was to characterize the persistence of pain in the general population and to validate recall measures against longitudinal reporting of pain. A random sample of 6419 participants from a population study (the HUNT 3 study in Norway) was invited to report pain on the SF-8 verbal pain rating scale every 3months over a 12-month period and to report pain lasting more than 6months at 12-month follow-up. Complete data were obtained from 3364 participants. Pain reporting was highly stable (intraclass correlation 0.66, 95% confidence interval 0.65 to 0.67), and the prevalence of chronic pain varied considerably according to level of severity and persistence: 31% reported mild pain or more, whereas 2% reported severe pain on 4 of 4 consecutive measurements. When defined as moderate pain or more on at least 3 of 4 consecutive measurements, the prevalence was 26%. Compared with the longitudinal classification, a cross-sectional measure of moderate pain or more during the last week on the SF-8 scale presented a sensitivity of 82% and a specificity of 84%, and a sensitivity of 80% and a specificity of 90% when combined with a 6-month recall question. Thus pain reporting in the general population is stable and cross-sectional measures may give valid prevalence estimates of chronic pain.

The influence of children’s pain memories on subsequent pain experience - Corrected Proof

2012-05-07

Summary: Children’s pain memories were a better predictor of subsequent pain reporting than initial reporting. Children with negatively estimated pain memories experienced increased pain over time.Abstract: Healthy children are often required to repeatedly undergo painful medical procedures (eg, immunizations). Although memory is often implicated in children’s reactions to future pain, there is a dearth of research directly examining the relationship between the 2. The current study investigated the influence of children’s memories for a novel pain stimulus on their subsequent pain experience. One hundred ten healthy children (60 boys) between the ages of 8 and 12years completed a laboratory pain task and provided pain ratings. Two weeks later, children provided pain ratings based on their memories as well as their expectancies about future pain. One month following the initial laboratory visit, children again completed the pain task and provided pain ratings. Results showed that children’s memory of pain intensity was a better predictor of subsequent pain reporting than their actual initial reporting of pain intensity, and mediated the relationship between initial and subsequent pain reporting. Children who had negatively estimated pain memories developed expectations of greater pain prior to a subsequent pain experience and showed greater increases in pain ratings over time than children who had accurate or positively estimated pain memories. These findings highlight the influence of pain memories on healthy children’s expectations of future pain and subsequent pain experiences and extend predictive models of subsequent pain reporting.

Risk factors predictive of chronic postsurgical neuropathic pain: The value of the iliac crest bone harvest model - Corrected Proof

2012-05-04

Summary: Acute neuropathic characteristics and secondary hyperalgesia are independent, additive factors predictive of chronic postsurgical pain after iliac crest bone harvest.Abstract: Nerve lesions and secondary hyperalgesia may both be present after surgery, and their relative contributions to chronic postsurgical neuropathic pain (CPSNP) remain unclear. This prospective study explored the roles of these factors in the development of CPSNP after iliac crest bone harvest. CPSNP was defined as pain in the area of hypoesthesia, with a positive Douleur neuropathique 4 questionnaire (DN4) score 3months after iliac crest bone harvest. The location, intensity, and neuropathic characteristics of pain were evaluated in 82 patients who were followed for 6months. Neuropathic characteristics were assessed by clinical examination and DN4 questionnaire. The area of secondary hyperalgesia was evaluated 48h and 1month after surgery. The area of mechanical hypoesthesia, detection, and mechanical pain threshold were evaluated at 48h and at 1 and 3months. Nineteen patients (23%) had CPSNP at 3months. The patients who developed CPSNP had a larger area of secondary hyperalgesia at 48h (88cm2 vs 33cm2; P=.001), higher pain intensity (numerical rating scale 6.7 vs 4.7; P=.02), and higher neuropathic characteristics score on the DN4 questionnaire (4.3 vs 2.3; P=.001). However, neither the area nor the severity of hypoesthesia differed significantly between patients with and without CPSNP. Two independent, additive predictors of CPSNP were identified: area of secondary hyperalgesia (odds ratio 1.02; P=.004) and DN4 score (odds ratio 1.94; P=.001). These findings suggest that both nerve lesions and central sensitization are involved in CPSNP development and could be seen as early warning signs.

Response to letter by Kissin - Corrected Proof

James N. Campbell, M.D. — 2012-05-01

I thank Dr. Kissin for zeroing in on key issues regarding the use of topical lidocaine for neuropathic pain and pointing to several relevant studies that suggest that more pain relief can be achieved with dose optimization. The success of topical therapy derives from several factors. An initial consideration is the extent to which neural signals arising in the skin account for pain—this likely varies from patient to patient. Some patients have what is, in essence, phantom pain, and are unlikely to benefit from topical therapy. Clearly, techniques to enhance anesthetic delivery to the skin need further study. The limits of dosing of lidocaine are well known in terms of systemic safety. In patients with widespread pain, limits on systemic dosing may preclude optimal coverage of the affected area. Another point is that optimal pain control could, in some patients, require doses that anesthetize the skin to the extent that an unpleasant degree of numbness is necessitated. Ideally, patients should be able to titrate dosing to optimize the degree of pain relief vs the degree of numbness within the bounds of safe dosing.

Cancer pain undertreatment and prognostic factors - Corrected Proof

Sebastiano Mercadante — 2012-05-01

Knudsen et al. have performed a secondary analysis of a large sample of patients from the Italian Cancer Pain Outcome Research Study Group . This trial was an observational study to evaluate the pattern and quality of care of cancer pain management. For these reasons, no specific—or even general—protocols were given, and a large number of unselected centers were recruited from different settings, including palliative care and oncological units. The results showed that many patients were undertreated, confirming that pain is poorly controlled even in oncology or palliative care centers in Italy .

Pain catastrophizing, threat, and the informational value of mood: Task persistence during a painful finger pressing task - Corrected Proof

Petra A. Karsdorp, Saskia Ranson, Martien G.S. Schrooten, Johan W.S. Vlaeyen — 2012-04-30

Summary: The relationship between pain catastrophizing and task persistence during a painful finger pressing task is modulated by threat context and the informational value of mood.Abstract: Pain catastrophizing has shown to predict avoidance behavior in acute and chronic pain, but the literature is inconsistent. The present study tested the hypothesis that current mood and threat context moderate the relationship between pain catastrophizing and performance duration. Affective-motivational models postulate that negative and positive moods provide information about whether an activity is respectively threatening or safe. Moreover, it has been proposed that stable cognitive schemas about threat influence behavior particularly in threat-relevant contexts. The present study aimed to establish whether pain catastrophizing is related to less or greater performance duration, when participants experience respectively negative or positive moods, particularly in a high threatening pain context. A 2 mood×2 threat context between-subjects factorial design was applied in 89 healthy participants with pain catastrophizing as covariate and performance duration during a painful finger pressing task as dependent variables. As predicted, higher pain catastrophizing was associated with less performance duration when participants experienced negative moods. The opposite was found when participants experienced positive moods. Moreover, these relationships were most pronounced in a high threatening pain context. This study suggests that the relationship between pain catastrophizing and performance duration during painful activities is moderated by situational factors such as current mood and threat context.

Enhanced affect/cognition-related brain responses during visceral placebo analgesia in irritable bowel syndrome patients - Corrected Proof

2012-04-30

Summary: IBS patients and controls achieve comparable placebo analgesia upon experimentally induced rectal pain. The placebo analgesia during the visceral pain involves enhanced brain activities relating to affect/cognition in IBS patients.Abstract: Placebo analgesia is a psychosocial context effect that is rarely studied in visceral pain. Patients with irritable bowel syndrome (IBS) exhibit visceral hyperalgesia and heightened affective/cognitive brain region activation during visceral stimuli. Psychological factors alter the pain and brain activation pattern, and these changes are more pronounced in IBS patients. Expectation constitutes the major neuropsychological mechanism in the placebo effect. This study confirmed the heightened affective/cognitive brain responses in IBS patients during visceral placebo analgesia using a placebo model with expectation, which was enhanced by suggestion and conditioning. Seventeen IBS patients and 17 age-/sex-matched controls were enrolled. Psychophysical inventories (Hospital Anxiety and Depression Scale [HADS], visual analogue scale, and short-form McGill questionnaire) were completed. Brain activity during placebo intervention and anticipation was assessed in response to rectal distension using 3T-functional magnetic resonance imaging. Suggestion-/conditioning-enhanced placebo was used to convince controls/patients of the efficacy of a newly developed intravenous drug (saline, in actuality) for the relief of rectal distension-induced visceral pain. A comparable visceral placebo analgesia was observed in IBS patients and control subjects. IBS patients demonstrated a higher HADS-anxiety score, which was predictive of a weak placebo effect. Suggestion-/conditioning-enhanced placebo evoked more activity in affective/cognitive brain regions (insula, midcingulate cortex, and ventrolateral prefrontal cortex [VLPFC]) in IBS patients than in healthy controls. VLPFC was also more active during anticipation in IBS patients. In conclusion, IBS patients and control subjects achieved comparable placebo analgesia during experimentally induced rectal pain. The visceral placebo analgesia produced heightened activity in affective/cognitive brain regions in IBS patients.

Chronic compression or acute dissociation of dorsal root ganglion induces cAMP-dependent neuronal hyperexcitability through activation of PAR2 - Corrected Proof

2012-04-30

Summary: Protease-activated receptor 2 activation is critical to induction of neuronal hyperexcitability and cAMP-PKA activation after nerve injury.Abstract: Chronic compression (CCD) or dissociation of dorsal root ganglion (DRG) can induce cyclic adenosine monophosphate (cAMP)-dependent DRG neuronal hyperexcitability and behaviorally expressed hyperalgesia. Here, we report that protease-activated receptor 2 (PAR2) activation after CCD or dissociation mediates the increase of cAMP activity and protein kinase A (PKA) and cAMP-dependent hyperexcitability and hyperalgesia in rats. CCD and dissociation, as well as trypsin (a PAR2 activator) treatment, increased level of cAMP concentration, mRNA, and protein expression for PKA subunits PKA-RII and PKA-c and protein expression of PAR2, in addition to producing neuronal hyperexcitability and, in CCD rats, thermal hyperalgesia. The increased expression of PAR2 was colocalized with PKA-c subunit. A PAR2 antagonistic peptide applied before and/or during the treatment, prevented or largely diminished the increased activity of cAMP and PKA, neuronal hyperexcitability, and thermal hyperalgesia. However, posttreatment with the PAR2 antagonistic peptide failed to alter either hyperexcitability or hyperalgesia. In contrast, an adenylyl cyclase inhibitor, SQ22536, administrated after dissociation or CCD, successfully suppressed hyperexcitability and hyperalgesia, in vitro and/or in vivo. Trypsin-induced increase of the intracellular calcium [Ca2+]i was prevented in CCD or dissociation DRG neurons. These alterations were further confirmed by knockdown of PAR2 with siRNA. In addition, trypsin and PAR2 agonistic peptide-induced increase of cAMP was prevented by inhibition of PKC, but not Gαs. These findings suggest that PAR2 activation is critical to induction of nerve injury-induced neuronal hyperexcitability and cAMP-PKA activation. Inhibiting PAR2 activation may be a potential target for preventing/suppressing development of neuropathic pain.

Obituary Robert G. Addison, MD - Corrected Proof

R. Norman Harden — 2012-04-30

Gifted physician, surgeon, researcher, teacher, and sculptor Robert George Addison died peacefully with his wife, Beverly, at his side, surrounded by family in Bradenton, Florida, on March 15, 2012. He was 90.

Response to letter by Mercadante - Corrected Proof

2012-04-30

We appreciate the interest in our recent publication . Our study aimed to decide which domains to include in a cancer pain classification system. Six domains were identified as predictors of pain intensity and/or pain relief after 2weeks: initial pain intensity and initial pain relief, incident pain, pain localisation, cancer diagnosis, and (younger) age. Among these, initial pain intensity emerged as the strongest predictor.

Integrating outcome data collection into the care of the patient with pain - Corrected Proof

Michael A. Ashburn, Lisa Witkin — 2012-04-30

Individuals who suffer from chronic pain are all too aware of the toll pain takes on many aspects of their lives. In addition to suffering, chronic pain can impact every life dimension, including physical and mental wellbeing. Moreover, the impact extends beyond the individual, involving family and society as a whole due to major disruptions of the family function to the burden of lost work and the cost of ongoing healthcare.

Structure equals function: Cortical correlates of pain - Corrected Proof

Arne May — 2012-04-30

In this issue of PAIN, Erpelding et al. quite nicely show that a strong correlation exists between greater thermal and pain sensitivity and the cortical thickness of pain transmitting structures, most notably in the somatosensory cortex. Basically, individuals with higher sensitivity to pain had more cortical gray matter in these areas and this could serve as a state marker for (gradually more) sensitive individuals. Or could it?

Validation of the Pain Sensitivity Questionnaire in chronic pain patients - Corrected Proof

2012-04-27

Summary: Pain Sensitivity Questionnaire scores correlate with results of experimental pain testing and reflect generalized enhancement of pain perception in chronic pain patients.Abstract: Recently, a self-rating measure for pain perception based on imagined painful daily life situations, the Pain Sensitivity Questionnaire (PSQ), has been developed and shown to correlate with experimentally obtained pain intensity ratings in healthy subjects. Here, we assessed the validity of the PSQ for investigation of general pain perception (ie, pain perception outside the site of clinical pain) in chronic pain patients. PSQ scores were obtained in 134 chronic pain patients and compared to those of 185 healthy control subjects. In a subgroup of 46 chronic pain patients, we performed experimental pain testing outside the clinical pain site, including different modalities (heat, cold, pressure, and pinprick) and different measures (pain thresholds, pain intensity ratings). Results show that PSQ scores were significantly correlated with both experimental pain intensity ratings (Pearson’s r=0.71, P<.001) and experimental pain thresholds (r=−0.52, P<.001). In addition, chronic pain patients exhibited significantly elevated PSQ scores as compared to healthy controls, consistent with the generalized increase of experimentally determined pain perception that has repeatedly been reported in chronic pain patients. These results demonstrate that the PSQ constitutes a valid self-rating measure of pain perception outside the clinical pain site in chronic pain patients and might serve as an alternative to experimental assessment of pain perception outside the clinical pain site in situations where experimental pain testing is not feasible.

Should we still use the Hospital Anxiety and Depression Scale? - Corrected Proof

Joanna M. Zakrzewska — 2012-04-26

The Hospital Anxiety and Depression Scale (HADS) introduced in 1983 is used very frequently in pain studies, but I was intrigued as to why Bouhassira et al. , in their study of herpes zoster, reported on the HADS as a mean score. I have used the HADS for some 20years following a meeting I had with one of the authors of the scale, and had reported results only as no case, mild case, or severe case . This led me to search the literature on its use. In 2002, a review of its use and validity was done by Bjelland et al. . They identified 747 studies using the HADS, but only 19 reporting factor analysis, and concluded that it performs well as a screening tool. Mitchell et al. assessed its validity in the cancer and palliative care setting and suggested that it was not to be recommended for case finding, but could play a role in screening. Cosco et al have just published a 10-year review (2000–2010) on the structure of the HADS, and they throw further doubt on its validity. They point out that HADS was shown to be consistently satisfactory, but no tests were done at the time on its bidimensional accuracy; that is, can HADS really differentiate between anxiety and depression? Using modern statistical methods, they show that its ability to differentiate between anxiety and depression is unclear, and suggest that perhaps it should be used as a total score to indicate emotional distress. Coyne and van Sonderen , in their editorial in reply to their article, also suggest that the use of British colloquial expressions such as “butterflies in the stomach” must make for difficulties in translation. They also point out that the avoidance of somatic problems such as eating and sleep means that currently 2 recognised features of depression are omitted. Coyne and van Sonderen suggest that no further research is needed and the scale should be abandoned. However, it may remain useful as a total score to suggest emotional distress but, as Mitchell et al. imply, 14 questions is a long screening questionnaire and perhaps all we need are the 2 questions proposed many years ago by Whooley et al. and now adopted by the UK NICE guidelines CG90 on treatment and management of depression in adults (www.nice.org.uk/CG90): during the last month, have you often been bothered by feeling down, depressed, or hopeless? During the last month, have you often been bothered by having little interest or pleasure in doing things?

Response to Letter by Roosink - Corrected Proof

Kenneth L. Casey — 2012-04-25

We thank Dr. Roosink for expressing interest in our report on brain nociceptive excitability among healthy participants and patients with impaired heat sensation with and without central pain syndrome . Our colleague is correct to note, as we did, the presence of several potentially significant pathophysiological differences between and within our patient populations; this is one of the reasons we chose to use a more conservative nonparametric analysis to detect group differences in the distribution of excitability changes. Despite these potential confounds, including the remarkably widespread brain excitability changes associated with single central lesions in both patient groups, we found that our patients with central pain were unique in the frequency with which they showed hyperresponsiveness within the sensorimotor cortex and intralaminar thalamus. Our choice of a somatic stimulus (heat) that selectively excites spinothalamic pathways almost certainly accounts for the particular pattern of activation we observed. A detailed discussion of why all possible confounds failed to obscure our finding, and what possible effects each may have had on other neurological functions, was beyond the scope and intent of our report.

Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy controls - Corrected Proof

Meyke Roosink — 2012-04-25

With great enthusiasm I read the recent article by Casey et al. reporting increased excitability in the thalamus and sensory-motor cortex in patients with central pain (CP) . The extensive assessment of bilateral psychophysical and cerebral responses and the inclusion of 2 control groups suggested a well designed, high-quality study. However, several important methodological issues are not addressed in this report. As such, conclusions on the nature and pathophysiological role of the observed hyperresponsiveness are not warranted.

Does injury compensation lead to worse health after whiplash? A systematic review - Corrected Proof

Natalie M. Spearing, Luke B. Connelly, Susan Gargett, Michele Sterling — 2012-04-23

Summary: Reverse causality is an important source of bias that has not been addressed in studies on the association between compensation-related factors and health outcomes after whiplash.Abstract: One might expect that injury compensation would leave injured parties better off than they would otherwise have been, yet many believe that compensation does more harm than good. This study systematically reviews the evidence on this “compensation hypothesis” in relation to compensable whiplash injuries. PubMed, CINAHL, EMBASE, PEDro, PsycInfo, CCTR, Lexis, and EconLit were searched from the date of their inception to April 2010 to locate longitudinal studies, published in English, comparing the health outcomes of adults exposed/not exposed to compensation-related factors. Studies concerning serious neck injuries, using claimants only, or using proxy measures of health outcomes were excluded. Eleven studies were included. These examined the effect of lawyer involvement, litigation, claim submission, or previous claims on pain and other health outcomes. Among the 16 results reported were 9 statistically significant negative associations between compensation-related factors and health outcomes. Irrespective of the compensation-related factor involved and the health outcome measured, the quality of these studies was similar to studies that did not find a significant negative association: most took some measures to address selection bias, confounding, and measurement bias, and none resolved the potential for reverse causality bias that arises in the relationship between compensation-related factors and health. Unless ambiguous causal pathways are addressed, one cannot draw conclusions from statistical associations, regardless of their statistical significance and the extent of measures to address other sources of bias. Consequently, there is no clear evidence to support the idea that compensation and its related processes lead to worse health.

Selective impairment of spinal mu-opioid receptor mechanism by plasticity of serotonergic facilitation mediated by 5-HT2A and 5-HT2B receptors - Corrected Proof

2012-04-23

Summary: Plasticity of serotonergic neurotransmission mediated by 5-HT2A and 5-HT2B receptors impairs spinal mu-opioid of receptor efficacy during neuropathic pain, including upregulation of receptor expression in mu-opioid receptor containing neurons.Abstract: Opioid analgesia is compromised by intracellular mediators such as protein kinase C (PKC). The phosphatidylinositol hydrolysis-coupled serotonin receptor 5-HT2 is ideally suited to promote PKC activation. We test the hypothesis that 5-HT2A and 5-HT2B receptors, which have been previously shown to become pro-excitatory after spinal nerve ligation (SNL), can negatively influence the ability of opioids to depress spinal excitation evoked by noxious input. Spinal superfusion with (100nM) mu-opioid receptor (MOR)-agonist DAMGO significantly depressed C fiber-evoked spinal field potentials. Simultaneous administration of subclinical 5-HT2AR antagonist 4F 4PP (100nM) or 5-HT2BR antagonist SB 204741 (100nM) significantly reduced the IC50 value for DAMGO in nerve-ligated rats (97.56nM±1.51 and 1.20nM±1.28 respectively, relative to 104nM±1.08 at the baseline condition), but not in sham-operated rats. Both antagonists failed to alter depression induced by delta-opioid receptor (DOR)-agonist D-ala2-deltorphin II after SNL as well as in the sham condition. Western blot analysis of dorsal horn homogenates revealed bilateral upregulation of 5-HT2AR and 5-HT2BR protein band densities after SNL. As assessed from double immunofluorescence labeling for confocal laser scanning microscopy, scarce dorsal horn cell processes showed co-localization color overlay for 5-HT2AR/MOR, 5-HT2BR/MOR, 5-HT2AR/DOR, or 5-HT2BR/DOR in sham-operated rats. Intensity correlation-based analyses showed significant increases in 5-HT2AR/MOR and 5-HT2BR/MOR co-localizations after SNL. These results indicate that plasticity of spinal serotonergic neurotransmission can selectively reduce spinal MOR mechanisms via 5-HT2A and 5-HT2B receptors, including upregulation of the latter and increased expression in dorsal horn neurons containing MOR.

A measure of pediatric pain intensity across ages and clinical conditions - Corrected Proof

C. Celeste Johnston, Carl L. von Baeyer — 2012-04-23

Measurement of pain intensity is necessary in order to make decisions about analgesic treatment and to conduct analgesic clinical trials. It would be convenient if a measure of pain intensity existed which, like a heart rate monitor, could cover a wide variety of ages and clinical conditions. However, rapid developmental changes in infancy and childhood make such a measure unattainable. A self-report pain intensity scale that is easy for most eight-year-olds cannot be used by most four-year-olds, and a graded self-report of pain intensity is impossible for infants and toddlers. In the past, this quandary has been addressed by developing numerous self-report and observational pain intensity scales for different populations and settings . The profusion of published scales leads to confusion and conflict among pain clinicians, educators, and researchers.

Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain - Corrected Proof

Anna M.W. Taylor, Maria Osikowicz, Alfredo Ribeiro-da-Silva — 2012-04-23

Summary: Ablation of nonpeptidergic nociceptive afferents exacerbated the nociceptive responses following a neuropathic lesion, suggesting a complex role in the development of neuropathic pain.Abstract: Damage to peripheral nerves causes significant remodeling of peripheral innervation and can lead to neuropathic pain. Most nociceptive primary afferents are unmyelinated (C fibers) and subdivided into peptidergic and nonpeptidergic fibers. Previous studies have found nerve injury in the trigeminal system to induce changes in small-diameter primary afferent innervation and cause significant autonomic sprouting into the upper dermis of the lower-lip skin of the rat. In this study, we used the ribosomal toxin, saporin, conjugated to the lectin IB4 to specifically ablate the nonpeptidergic nociceptive C fibers, to see if loss of these fibers was enough to induce autonomic fiber sprouting. IB4-saporin treatment led to specific and permanent ablation of the IB4-positive, P2X3-immunoreactive fibers and led to sprouting of parasympathetic fibers into the upper dermis, but not of sympathetic fibers. These changes were associated with significant increase in glial-derived nerve growth factor levels in the lower-lip skin. While IB4-saporin treatment had no effect on evoked mechanical thresholds when von Frey hairs were applied to the lower-lip skin, ablation of nonpeptidergic fibers in a chronic constriction injury model caused significant sympathetic and parasympathetic fiber sprouting, and led to an exacerbated pain response. This was an unexpected finding, as it has been suggested that nonpeptidergic fibers play a major role in mechanical pain, and suggests that these fibers play a complex role in the development of neuropathic pain.

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain - Corrected Proof

2012-04-23

Summary: Activation of peripheral 5-HT2B receptor both prevents and reduces mechanical allodynia induced by chronic constriction of the sciatic nerve via blood-derived macrophage bearing the receptor.Abstract: Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT2B receptor in dorsal root ganglia (DRG) and the sciatic nerve. We showed that 5-HT2B receptor activation both prevents and reduces CCI-induced allodynia. Intrathecal administration of 5-HT2B receptor agonist BW723C86 significantly attenuated established mechanical and cold allodynia; this effect was prevented by co-injection of RS127445, a selective 5-HT2B receptor antagonist. A single application of BW723C86 on the sciatic nerve concomitantly to CCI dose-dependently prevented mechanical allodynia and significantly reduced cold allodynia 17days after CCI. This behavioral effect was accompanied with a marked decrease in macrophage infiltration into the sciatic nerve and, in the DRG, with an attenuated abnormal expression of several markers associated with local neuroinflammation and neuropathic pain. CCI resulted in a marked upregulation of 5-HT2B receptor expression in sciatic nerve and DRG. In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2days after the surgery and before the neuropathic pain emergence, followed by a steady (5-fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT2B receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT2B receptors in blood-derived macrophages.

Worry and catastrophizing about pain in youth: A reappraisal - Corrected Proof

Christopher Eccleston, Emma Alice Fisher, Tine Vervoort, Geert Crombez — 2012-04-20

Catastrophizing about pain is defined as “an exaggerated negative ‘mental set’ brought to bear during actual or anticipated pain experience” . It is a salient form of worry, and one that has proven useful in explaining pain severity, disability, and adaptation to treatment in a range of different conditions and settings . Catastrophizing involves repeated thought about threat as uncontrollable and likely to have awful consequences. These aspects have been captured neatly by Sullivan and colleagues with the labels of “rumination,” “helplessness,” and “magnification” .

Cortical thickness correlates of pain and temperature sensitivity - Corrected Proof

Nathalie Erpelding, Massieh Moayedi, Karen D. Davis — 2012-04-19

Summary: Individual pain and temperature sensitivity correlated with cortical thickness of the primary somatosensory, midcingulate, and orbitofrontal cortices, linking thermal and pain perception with structure.Abstract: It is well established that there is individual variability in pain and temperature sensitivity. Functional brain imaging studies have found that interindividual heat pain variability correlates with brain activity in sensory and pain modulation areas. Thus, it is possible that these individual differences are associated with variability in gray matter thickness of cortical regions involved in thermoreception and pain. To test this, we investigated the relationship between thermal thresholds and cortical thickness in 80 healthy subjects. Subjects underwent a psychophysical session to determine their cool detection (CD), warm detection (WD), cold pain (CP), and heat pain (HP) threshold. A high-resolution structural magnetic resonance imaging scan was acquired for each subject. We correlated each threshold measure to cortical thickness of regions associated with thermoreception and pain. The mean (± SD) thresholds were 30.7°C (± 0.8) for CD, 33.8°C (± 0.7) for WD, 11.7°C (± 9.7) for CP, and 45.3°C (± 2.8) for HP. The brain gray matter analysis revealed a strong correlation between greater thermal and pain sensitivity and cortical thickening of the primary somatosensory cortex. Additionally, greater sensitivity to cool stimuli correlated with cortical thickening in the paracentral lobule, and greater WD correlated with cortical thinning in the anterior midcingulate cortex. We also found that greater HP sensitivity correlated with thickening in the posterior midcingulate cortex and the orbitofrontal cortex. These cortical gray matter correlates of thermal and pain sensitivity provide a neural basis for individual differences in thermal sensitivity.

Pain coping skills training and lifestyle behavioral weight management in patients with knee osteoarthritis: A randomized controlled study - Corrected Proof

2012-04-16

Summary: Combined training in pain and weight management in overweight and obese OA patients resulted in improved pain and other outcomes compared to either training alone.Abstract: Overweight and obese patients with osteoarthritis (OA) experience more OA pain and disability than patients who are not overweight. This study examined the long-term efficacy of a combined pain coping skills training (PCST) and lifestyle behavioral weight management (BWM) intervention in overweight and obese OA patients. Patients (n=232) were randomized to a 6-month program of: 1) PCST+BWM; 2) PCST-only; 3) BWM-only; or 4) standard care control. Assessments of pain, physical disability (Arthritis Impact Measurement Scales [AIMS] physical disability, stiffness, activity, and gait), psychological disability (AIMS psychological disability, pain catastrophizing, arthritis self-efficacy, weight self-efficacy), and body weight were collected at 4 time points (pretreatment, posttreatment, and 6months and 12months after the completion of treatment). Patients randomized to PCST+BWM demonstrated significantly better treatment outcomes (average of all 3 posttreatment values) in terms of pain, physical disability, stiffness, activity, arthritis self-efficacy, weight self-efficacy, and weight when compared to the other 3 conditions (Ps<0.05). PCST+BWM also did significantly better than at least one of the other conditions (ie, PCST-only, BWM-only, or standard care) in terms of psychological disability and pain catastrophizing. Interventions teaching overweight and obese OA patients pain coping skills and weight management simultaneously may provide the more comprehensive long-term benefits.

Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information - Corrected Proof

K.T. Martucci, J.C. Eisenach, C. Tong, R.C. Coghill — 2012-04-16

Summary: The magnitude of offset analgesia is not altered by naloxone administration, by remifentanil analgesia, or during opioid-induced hypersensitivity. Offset analgesia is therefore subserved by nonopioid mechanisms.Abstract: The mechanisms supporting temporal processing of pain remain poorly understood. To determine the involvement of opioid mechanisms in temporal processing of pain, responses to dynamic noxious thermal stimuli and offset analgesia were assessed after administration of naloxone, a μ-opioid antagonist, and on a separate day, during and after intravenous administration of remifentanil, a μ-opioid agonist, in 19 healthy human volunteers. Multiple end points were sampled from real-time computerized visual analog scale ratings (VAS, 1 to 10) to assess thermal sensitivity, magnitude and duration of offset analgesia, and painful after sensations. It was hypothesized that the magnitude of offset analgesia would be reduced by direct opioid antagonism and during states of acute opioid-induced hypersensitivity (OIH), as well as diminished by the presence of exogenous opioids. Surprisingly, the magnitude of offset analgesia was not altered after naloxone administration, during remifentanil infusion, or after the termination of remifentanil infusion. Because thermal hyperalgesia was observed after both drugs, 8 of the original 19 subjects returned for an additional session without drug administration. Thermal hyperalgesia and increased magnitude of offset analgesia were observed across conditions of remifentanil, naloxone, and no drug within this subset analysis, indicating that repeated heat testing induced thermal hyperalgesia, which potentiated the magnitude of offset analgesia. Thus, it is concluded that the mechanisms subserving temporal processing of nociceptive information are largely opioid-independent, but that offset analgesia may be potentiated by heat-induced thermal hyperalgesia in a proportion of individuals.

Development and validation of shortened, restructured Treatment Outcomes in Pain Survey instrument (the S-TOPS) for assessment of individual pain patients’ health-related quality of life - Corrected Proof

Simon Haroutiunian, Gary Donaldson, Junhua Yu, Arthur G. Lipman — 2012-04-16

Summary: The S-TOPS questionnaire fulfills the clinical and psychometric criteria required from an instrument for monitoring treatment outcomes of individual patients with chronic pain.Abstract: Chronic pain produces major functional disability and quality-of-life impairment. Monitoring of health-related quality of life (HRQoL) outcomes in chronic pain patients during treatment is of great importance. Nevertheless, monitoring individual chronic pain patients remains a challenge due to the lack of a validated and efficient HRQoL assessment instrument. The Treatment Outcomes in Pain Survey (TOPS) is a validated HRQoL tool with sufficient accuracy and sensitivity to monitor the overall pain experience of individual patients while receiving multidisciplinary chronic pain management. However, the amount of time required to complete the TOPS questionnaire limits routine clinical utility and patient compliance. The full 14 TOPS scales are not needed to monitor routine clinical outcomes. Therefore, we developed and initially validated a shortened and restructured instrument, the S-TOPS, for individual patient monitoring in multidisciplinary chronic pain treatment. The reliability and validity of the S-TOPS were analyzed using data from 964 chronic pain patients who were treated in a single interdisciplinary pain clinic and completed >1 TOPS. The 7 scales of the S-TOPS have excellent construct validity, high reliabilities, and improved sensitivity to change for monitoring individual patient outcomes. Patients accepted the S-TOPS well, finding it brief enough for routine repeated administration.

Placebo manipulations reduce hyperalgesia in neuropathic pain - Corrected Proof

2012-04-16

Summary: Placebo effects in neuropathic pain were investigated. Placebo manipulations reduced the area of hyperalgesia, and this effect was related to low levels of negative affect.Abstract: Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind-up-like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P=.027), and this placebo effect was significantly related to low levels of negative affect (P=.008; R2=0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined.

Mechanisms-based assessment and treatment of pain: The art of fine dissection - Corrected Proof

Philip Siddall — 2012-04-16

It is now some time since an Editorial in this journal advocated a move towards a mechanisms-based approach to the classification of pain . The authors of that paper proposed that systematic identification of pain mechanisms was much more likely to translate into effective treatment than treatment based on a disease or etiology-based classification.

The basis for medical therapy of fibromyalgia with growth hormone - Corrected Proof

Charles J. Malemud — 2012-04-16

A criterion-based analysis of “fibrositis” was defined in 1990 for making the clinical diagnosis of the fibromyalgia syndrome (FMS) . FMS was classified as a chronic musculoskeletal condition with effusive pain in at least 11 tender points from a group of 18 anatomically-defined structures . A new criteria for the diagnosis of FMS that was published in 2010 proposed that the weight given to the tender point count criteria be significantly lessened in favor of placing increased emphasis on the patient’s overall symptoms. Thus, this change in diagnosis criteria for FMS is likely to increase the number of patient’s with this condition, but the revised diagnosis criteria for FMS is also consistent with the idea proposed by Henricksson that FMS should be reclassified as a multisystemic disease rather than being classified as a syndrome. In that regard, it would be unlikely that a generalized hypersensitivity response to innocuous pain stimuli also called allodynia which is commonly associated with FMS would be limited only to tender points . Although it is known that FMS occurs predominately in women, the diagnosis of FMS is also predicated on continuous and persistent pain for a period of at least 3months, the persistency of pain being independent of gender.

Do we activate specifically somatosensory thin fibres with the concentric planar electrode? A scalp and intracranial EEG study - Corrected Proof

2012-04-12

Summary: We compare CE-SEPs, Aβ SEPs, and Aδ LEPs in healthy subjects and patients and conclude that there is a lack of nociceptive specificity of the concentric planar electrode.Abstract: Laser-evoked potentials (LEPs) are acknowledged as the most reliable laboratory tool for assessing thermal and pain pathways. Electrical stimulation with a newly developed planar concentric electrode, delivering stimuli limited to the superficial skin layers, has been suggested to provide selective activation of Aδ fibres without the inconveniences linked to laser stimulation. The aim of our study was to compare the scalp and intracranial responses to planar concentric electrode stimulation (CE-SEPs) with those of LEPs and standard somatosensory-evoked potentials (SEPs). Sixteen healthy subjects, 6 patients with intracortical electrodes, and 2 patients with selective lesions of the spinothalamic pathway were submitted to Neodymium:Yttrium-Aluminium-Perovskite laser stimulations, and electrical stimulations using standard electrodes or planar concentric electrodes (CE). In both healthy controls and epileptic implanted patients, CE- and standard SEPs showed significantly shorter latencies than LEPs. This is consistent with Aβ-fibre activation, peripheral activation time being unable to account for longer LEP latencies. In the patients with spinothalamic lesions, LEPs were absent after stimulation of the affected territory, while CE-SEPs were still present. For these 2 reasons, we conclude that the planar CE does not selectively activate the Aδ and C fibers, but coexcites a significant proportion of large myelinated Aβ fibres that dominate the ensuing cortical response. The use of CE-SEPs for the detection of spinothalamic system lesions is therefore not warranted; the planar electrode can, however, represent a useful tool to study nociceptive reflexes, which can be reliably elicited even in the presence of Aβ coactivation.

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations - Corrected Proof

2012-04-11

Abstract: A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo (“assay sensitivity”). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Absence of C–C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model - Corrected Proof

Jiin-Tarng Liou, Hui-Bih Yuan, Chih-Chieh Mao, Ying-Shu Lai, Yuan-Ji Day — 2012-04-11

Summary: The potent proinflammatory potential of CCL5 is highlighted; antagonists may provide for therapeutic intervention in chronic neuropathic pain in the future.Abstract: Accumulated evidence suggests that the C–C motif chemokine ligand 5 (CCL5) modulates migration of inflammatory cells in several pathological conditions. This study tested the hypothesis that lack of CCL5 would modulate the recruitment of inflammatory cells to painful, inflamed sites and could attenuate pain in a murine chronic neuropathic pain model. Nociceptive sensitization, immune cell infiltration, multiple cytokine expression, and opioid peptide expression in damaged nerves were studied in wild-type (CCL5 +/+) and CCL5-deficient (CCL5 −/−) mice after partial sciatic nerve ligation (PSNL). Results indicated that CCL5 −/− mice had less behavioral hypersensitivity after PSNL. Macrophage infiltration and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, and interferon-γ) in damaged nerves following PSNL were significantly decreased in CCL5 −/− mice. Conversely, several antiinflammatory cytokine (IL-4 and IL-10) proteins were significantly increased in CCL5 −/− animals and the expression of enkephalin, β-endorphin, and dynorphin mRNA was significantly lower than in wild-type control mice. These results represent the first evidence that CCL5 is capable of regulating the pathway that controls hyperalgesia at the level of the peripheral injured site in a murine chronic neuropathic pain model. We demonstrated that lack of CCL5 modulated cell infiltration and the proinflammatory milieu within the injured nerve. Attenuated behavioral hypersensitivity in CCL5 −/− mice observed in the current study could be a result of decreased macrophage infiltration, mobilization, and functional ability at injured sites. Collectively, the present study results suggest that CCL5 receptor antagonists may ultimately provide a novel class of analgesics for therapeutic intervention in chronic neuropathic pain.

How does the lidocaine patch (5%) relieve pain? - Corrected Proof

Igor Kissin — 2012-04-11

Krumova et al. convincingly demonstrated that the effects of the lidocaine patch on sensation are minimal. The Campbell commentary suggested that the often disappointing clinical effects of the patch might be because of “underdosing” . This suggestion is very appealing: the higher concentration of lidocaine in the skin (leading to skin anesthesia) could provide pain relief that is more complete and longer lasting.

Contribution of PKMζ-dependent and independent amplification to components of experimental neuropathic pain - Corrected Proof

2012-04-06

TOC summary: PKMζ-dependent amplification contributes to nerve injury-induced aversiveness within the rostral anterior cingulate cortex and to evoked, but not spontaneous, pain in the spinal cord.Abstract: Injuries can induce adaptations in pain processing that result in amplification of signaling. One mechanism may be analogous to long-term potentiation and involve the atypical protein kinase C, PKMζ. The possible contribution of PKMζ-dependent and independent amplification mechanisms to experimental neuropathic pain was explored in rats with spinal nerve ligation (SNL) injury. SNL increased p-PKMζ in the rostral anterior cingulate cortex (rACC), a site that mediates, in part, the unpleasant aspects of pain. Inhibition of PKMζ within the rACC by a single administration of ζ-pseudosubstrate inhibitory peptide (ZIP) reversed SNL-induced aversiveness within 24hours, whereas N-methyl-d-aspartate receptor blockade with MK-801 had no effects. The SNL-induced aversive state (reflecting “spontaneous” pain), was re-established in a time-dependent manner, with full recovery observed 7days post-ZIP administration. Neither rACC ZIP nor MK-801 altered evoked responses. In contrast, spinal ZIP or MK-801, but not scrambled peptide, transiently reversed evoked hypersensitivity, but had no effect on nerve injury-induced spontaneous pain. PKMζ phosphorylation was not altered by SNL in the spinal dorsal horn. These data suggest that amplification mechanisms contribute to different aspects of neuropathic pain at different levels of the neuraxis. Thus, PKMζ-dependent amplification contributes to nerve injury-induced aversiveness within the rACC. Moreover, unlike mechanisms maintaining memory, the consequences of PKMζ inhibition within the rACC are not permanent in neuropathic pain, possibly reflecting the re-establishment of amplification mechanisms by ongoing activity of injured nerves. In the spinal cord, however, both PKMζ-dependent and independent mechanisms contribute to amplification of evoked responses, but apparently not spontaneous pain.

Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy - Corrected Proof

2012-04-05

Summary: Conditioned pain modulation (CPM) predicts efficacy of duloxetine in painful diabetic neuropathy; patients with less efficient CPM are more likely to benefit from the drug.Abstract: This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug’s mechanism of action with the patient’s pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1week of placebo, 1week of 30mg/d duloxetine, and 4weeks of 60mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study’s primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r=0.628, P<.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R2=0.673; P=.012) showed that drug efficacy was predicted only by CPM (P=.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r=−0.411, P=.033). However, this improvement occurred only in patients with less efficient CPM (16.8±16.0 to −1.1±15.5, P<.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy.

How efficient is the orienting of spatial attention to pain? An experimental investigation - Corrected Proof

Stefaan Van Damme, Valéry Legrain — 2012-04-05

Summary: Visual cues orient spatial attention more efficiently to painful compared with nonpainful stimuli, but this effect can be overridden by task strategies.Abstract: This study investigated how efficient spatial attention was oriented to pain in 2 experiments. Participants detected whether painful (pain group) or nonpainful (control group) somatosensory stimuli were delivered to the left or right hand. Each stimulus was preceded by a visual cue presented near to the stimulated hand (valid trial), the opposite hand (invalid trial), or centrally between hands. To examine both exogenous and endogenous orienting of attention, the spatial predictability of somatosensory targets was manipulated. In the first experiment, visual cues were nonpredictive for the location of the pain stimulus, as a result of which, orienting was purely exogenous, i.e., resulting from the occurrence of the visual cue at the location of somatosensory input. In the second experiment, visual cues were spatially predictive, as a result of which, endogenous control was added, i.e., attention driven by expectations of where the somatosensory target will occur. The results showed that only in experiment 1 was spatial attention oriented more efficiently to painful compared with nonpainful somatosensory stimulation. This effect was due to faster responses on valid relative to baseline trials (engagement), rather than slower responses on invalid relative to baseline trials (disengagement), and was significantly correlated with self-reported bodily threat. In experiment 2, prioritization of the pain location was probably overridden by task strategies because it was advantageous for participants’ task performance to attend to the cued location irrespective of whether stimulation was painful or not. Implications of these findings for theories of hypervigilance and attentional management of pain are discussed.

Neuroethical issues related to the use of brain imaging: Can we and should we use brain imaging as a biomarker to diagnose chronic pain? - Corrected Proof

Karen D. Davis, Eric Racine, Beverly Collett — 2012-04-05

There is increasing pressure from the general public, clinical and scientific circles, insurance companies, and legal, government, and military agencies to adopt brain imaging for chronic pain and other health-related diagnostics . Brain imaging is being considered as a diagnostic tool for neurological and psychiatric conditions, particularly for conditions that by their very nature rely on self-report. However, in our experience, we find that most clinicians and other stakeholders do not have a sufficient understanding of the limitations of the technology, despite the enormous impact its misuse could have. The diagnosis of chronic pain can be particularly challenging because, by definition, pain is a subjective experience. Thus, chronic pain “biomarkers” or “predictors” based on brain imaging findings are being sought. Such applications require clear understanding of the technical and physiological capabilities of brain imaging as well as ethical and policy considerations. This review highlights limitations of single-subject functional magnetic resonance imaging (fMRI) and the need to address public understanding of neuroimaging and responsibility of researchers, patient vulnerability, regulatory issues, and discrimination.

Exploring the relationship of pain and development in the neonatal intensive care unit - Corrected Proof

Lorenzo Fabrizi, Rebeccah Slater — 2012-04-05

Why are premature babies admitted to the neonatal intensive care unit (NICU)? The obvious answer is to ensure their survival. The time that a premature infant spends in NICU is a critical and delicate stage for the overall growth and neurodevelopment of the individual. For this reason, the clinical procedures required to assure survival may affect the neurological development during the relatively short hospitalization period and even later in life. Invasive medical interventions are often required to diagnose and treat life-endangering pathophysiological conditions. As a result, pain is an unavoidable aspect of neonatal intensive care and is an experience that deviates most dramatically from what would occur physiologically at an equivalent gestational age in the womb. So the question arises, what are the short and long-term effects of early exposure to painful procedures on the developmental outcomes of premature infants?

Growth hormone treatment for sustained pain reduction and improvement in quality of life in severe fibromyalgia - Corrected Proof

2012-04-02

Summary: Growth hormone might be an effective complementary treatment for pain and fatigue management in fibromyalgia patients, particularly in a subset with low insulin-like growth factor 1 values.Abstract: Functional defects in growth hormone (GH) secretion and its efficacy as a complementary treatment have been suggested for fibromyalgia. This study investigated the efficacy and safety of low-dose GH as an add-on therapy in patients with both severe FM and low insulin-like growth factor 1 levels. A total of 120 patients were enrolled in a multicenter, placebo-controlled study for 18months. They were randomly assigned to receive either 0.006mg/kg/day of GH subcutaneously (group A, n=60) or placebo (group B, n=60) for 6months (blind phase). The placebo arm was switched to GH treatment from month 6 to month 12 (open phase), and a follow-up period after GH discontinuation was performed until month 18. Standard treatment for fibromyalgia (selective serotonin re-uptake inhibitors, opioids, and amitriptyline) was maintained throughout the study. Number and intensity of tender points, Fibromyalgia Impact Questionnaire (FIQ) with its subscales, and EuroQol 5 dimensions test (EQ5D) with visual analogue scale (VAS) were assessed at different time points. At the end of the study, 53% of group A patients obtained fewer than 11 positive tender points, vs 33% of group B patients (P<.05). 39.1% vs 22.4% reached more than 50% improvement in VAS (P<.05). Group A patients showed significantly improved FIQ scores (P=.01) compared with group B. Although GH discontinuation worsened all scores in both groups during follow-up, impairment in pain perception was less pronounced in the GH-treated group (P=.05). In this largest and longest placebo-controlled trial performed in FM (NCT00933686), addition of GH to the standard treatment is effective in reducing pain, showing sustained action over time.

What can we learn from twin studies of pain and analgesia? - Corrected Proof

Christopher Sivert Nielsen — 2012-03-30

Twin studies serve several functions, but the most common is estimating heritability. As progress is made towards identifying genetic variants that are associated with complex phenotypes, heritability estimates are gaining increasing importance. These analyses tell us how much variance can be explained by genetic factors and consequently form a benchmark to gauge our progress. Typically single nucleotide polymorphisms identified in large genome-wide association studies account for a small fraction of the heritability, but exceptions exist – most notably in age-related macular degeneration, where five single nucleotide polymorphisms explain 50% of the heritability . It is too early to say whether pain and analgesia follow the typical or the atypical pattern, but knowing the heritability of our pain phenotypes will be an essential roadmap as research progresses.

Assay sensitivity in clinical trials with chronic pain patients - Corrected Proof

Rolf-Detlef Treede — 2012-03-30

Neuropathic pain has evolved from “chronic intractable pain” into a manageable pain condition with several first- and second-line treatment options . Nevertheless, since many neuropathic pain patients receive inadequate pain relief from existing options, there remains an unmet medical need for more and better treatments. It has been noted in recent clinical trials with chronic neuropathic pain patients that several pharmacologic treatments have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Two factors that have empirically been found to be associated with clinical trial failure are 1: a more recent trial and 2: an increased response rate in the placebo arm . The two are, in fact, related. Indeed, it is tempting to speculate that critical mechanistic contributors to the placebo response – expectation, desire, reward and conditioning – are responsible for this trend in analgesic drug development. Specifically, as more effective treatments become available, patient expectations rise, patients have experience with previous rewards (pain relief) and are now conditioned towards reporting more pain relief from medications. In other words, there is now a greater placebo response in the most recent clinical trials.

Persistent postsurgical pain in a general population: prevalence and predictors in the Tromsø study - Corrected Proof

2012-03-26

TOC summary: Persistent pain after surgery is common, but prevalence of clinically relevant pain may be overestimated. Sensory abnormalities are associated with pain and more intense pain.Abstract: Population-based data on the prevalence of persistent postsurgical pain are scarce. This study aimed to assess the prevalence of persistent postsurgical pain in a general population and to describe associated physical, social, and psychological factors, including symptoms of nerve injury and sensitization. A cross-sectional survey was performed in northern Norway with questionnaire items covering surgery, pain, and sensory abnormalities in the area of surgery. Of the 12,982 participants, 24.0% (3111) had undergone one or more surgical procedures during the 3years preceding the survey. Of these, 2043 had the surgery performed more than 3months before the investigation. Persistent pain in the area of surgery was reported by 40.4% of the patients (826 of 2043), moderate or severe pain by 18.3% (373 of 2043). Hypoesthesia, hyperesthesia, or both was reported by 24.5% (501 of 2043). There were strong associations between sensory abnormalities and persistent pain, increasingly with higher pain intensities; odds ratios were 2.68 for hypoesthesia and 6.27 for hyperesthesia. Of the 826 individuals reporting persistent pain in the anatomical area of surgery, 51.0% reported chronic pain when questioned without specific reference to the surgery. The present study supports evidence from clinical studies of persistent postsurgical pain, indicating a high prevalence, but reveals large discrepancies in report of pain, depending on the questions asked and the context in which the questions are presented. Strong associations between sensory abnormalities and pain indicate neuropathic mechanisms in a major proportion of cases.

Pain sensitivity and opioid analgesia: a pharmacogenomic twin study - Corrected Proof

2012-03-23

TOC Summary: This twin study demonstrates significant genetic and familial effects for pain sensitivity and opioid analgesia and provides a strong rationale for more detailed genetic studies.Abstract: Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the μ-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12–60% of the observed response variance. Significant familial effects accounting for 24–32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.

Endogenous opioids mediate left dorsolateral prefrontal cortex rTMS-induced analgesia - Corrected Proof

Joseph J. Taylor, Jeffrey J. Borckardt, Mark S. George — 2012-03-23

TOC summary: Naloxone pretreatment significantly reduces left dorsolateral prefrontal cortex rTMS-induced analgesia.Abstract: The concurrent rise of undertreated pain and opiate abuse poses a unique challenge to physicians and researchers alike. A focal, noninvasive form of brain stimulation called repetitive transcranial magnetic stimulation (rTMS) has been shown to produce acute and chronic analgesic effects when applied to dorsolateral prefrontal cortex (DLPFC), but the anatomical and pharmacological mechanisms by which prefrontal rTMS induces analgesia remain unclear. Data suggest that DLPFC mediates top–down analgesia via gain modulation of the supraspinal opioidergic circuit. This potential pathway might explain how prefrontal rTMS reduces pain. The purpose of this sham-controlled, double-blind, crossover study was to determine whether left DLPFC rTMS-induced analgesia was sensitive to μ-opioid blockade. Twenty-four healthy volunteers were randomized to receive real or sham TMS after either intravenous saline or naloxone pretreatment. Acute hot and cold pain via quantitative sensory testing and hot allodynia via block testing on capsaicin-treated skin were assessed at baseline and at 0, 20, and 40minutes after TMS treatment. When compared to sham, real rTMS reduced hot pain and hot allodynia. Naloxone pretreatment significantly reduced the analgesic effects of real rTMS. These results demonstrate that left DLPFC rTMS-induced analgesia requires opioid activity and suggest that rTMS drives endogenous opioidergic pain relief in the human brain. Further studies with chronic dosing regimens of drugs that block or augment the actions of opiates are needed to determine whether TMS can augment opiates in chronic or postoperative pain management.

Different underlying pain mechanisms despite identical pain characteristics: A case report of a patient with spinal cord injury - Corrected Proof

2012-03-23

Summary: Different sensory profiles suggesting different underlying pain mechanisms can be found in a patient with spinal cord injury despite identical pain characteristics.Abstract: Pain following spinal cord injury has been classified as nociceptive (musculoskeletal, visceral) or neuropathic (above, at, below level). There is no clear relation between the etiology and reported symptoms. Thus, due to different underlying mechanisms, the treatment is often ineffective. We report on a patient with spinal cord injury with neurological level of injury at T8 suffering from bilateral burning and prickling pain in the T9-11 dermatomes bilaterally (at-level pain), as well as diffusely in both legs from below the torso (below-level pain), accompanied by musculoskeletal low back pain. Bilateral comparison of quantitative sensory testing (QST) and skin biopsy revealed completely different findings in the dermatome T9 despite identical at-level pain characteristics. On the right side, QST revealed a normal sensory profile; the intraepidermal nerve fiber density (IENFD) was reduced, but not as severe as the contralateral side. On the left side there was a severe sensory loss with a stronger reduction of the IENDF, similar to the areas below the neurological level. These findings were significantly related to the treatment results. Pregabalin induced unilateral pain relief only in the area with remaining sensory function, whereas the left-sided at-level pain was unchanged. Thus, 2 different underlying mechanisms leading to bilaterally neuropathic pain with identical symptoms and with different treatment success were demonstrated in a single patient. The at-level pain in areas with remaining sensory function despite IENFD reduction could be relieved by pregabalin. Thus, in an individual case, QST may be helpful to better understand pain-generating mechanisms and to initiate successful treatment.

Do attentional biases for pain depend on threat value of pain and competing motivation toward non-pain goals? - Corrected Proof

Gordon J.G. Asmundson — 2012-03-22

A number of recent commentaries in PAIN have addressed the issue of attentional biases for pain-related stimuli . This attention reflects favorably on the importance that researchers and clinicians place on this line of inquiry for advancing understanding of cognitive mechanisms of chronic pain and associated treatments. Why is the investigation of attentional biases for pain important? Attentional capture of stimuli with high threat value, including acute pain, can serve to motivate action that promotes the goal of survival . However, sustained attention to stimuli that are not necessarily indicative of threat to survival can negatively impact the effectiveness with which one pursues other goals. In this context, sustained attention to pain-related somatosensory and environmental stimuli might become maladaptive and associated with functional limitations.

Pain, sleeping problems and their many relatives - Corrected Proof

Stefan Lautenbacher — 2012-03-21

Although it has been neglected for quite some time, the mutual relationship between pain and sleeping problems has recently become the focus of significant scientific and clinical interests . The – at first glance – unusual perspective that disturbances of regular night sleep cause or exacerbate pain the next day is now widely acknowledged and even influences recent developments in pain management. For example, first attempts have been made to evaluate the effects of the Cognitive-Behavioral Therapy of insomnia on pain . And not surprisingly, as soon as the association between the pain and sleep disturbance was established, the search for the neurobiological and psychosocial links began. For example, it has been shown that nocturnal episodes of pain lead to changes in sleep architecture and to phases of arousal, which may even trigger awakening . The reciprocal is also true; sleep fragmentation weakens the endogenous pain inhibitory system . As we have gained some new insights, so far, so good. But we have not been asked to give up old ones.

The Diagnosis of CRPS: Are we there yet? - Corrected Proof

R. Norman Harden — 2012-03-16

Prospective studies on the epidemiology and natural history of CRPS are limited due to a variety of issues: notably, failure to use a specified criteria, funding, and access to sufficient and specific populations (in what is a relatively rare disorder). The lack of uniform diagnostic criteria has perhaps been the biggest impediment to good quality research of all types . Before Veldman et al , research in Complex Regional Pain Syndrome/Reflex Sympathetic Dystrophy (CRPS/RSD) was nearly at a standstill, as researchers used idiosyncratic criteria with no possibility of generalizable results. The first reasonably large ‘epidemiological’ study was the (comparatively) large 1993 cohort study by Veldman and colleagues (829 subjects). In this very important observational/ecological study the authors discussed the frequency of signs and symptoms and proposed a first ‘empirical’ diagnostic criteria. Also in 1993 the IASP sponsored an international consensus group in Orlando, Florida to discuss Reflex Sympathetic Dystrophy (RSD) taxonomy and diagnosis. The group agreed on a general taxonomy, CRPS, and produced a very broad and deliberately inclusive diagnostic criteria , which was adopted by the IASP task force on taxonomy in the second edition of the Classification of Chronic Pain . Although these criteria were sporadically used in the research community , they were hindered by the fact that they were based entirely on subjective symptoms or signs (that could be historical), yielding very poor specificity (0.4) . In 1999 the first attempts to statistically derive ‘empirical’ criteria were published (with much improved specificity: 0.96 in the research criteria, 0.69 in the clinical criteria) . These were subjected to another IASP sponsored international consensus process, yielding the ‘Budapest’ criteria and were later statistically re-validated . In general, follow on studies have supported the utility and specificity of this criteria set (see Beerthuizen et al ) and recently the IASP taxonomy committee and executive board have codified and endorsed the re-validated Budapest criteria.