The Journal of Pain - Articles in Press

Depression Shows Divergent Effects on Evoked and Spontaneous Pain Behaviors in Rats - Corrected Proof

Miao Shi, Jin-Yan Wang, Fei Luo — 2010-01-22

Abstract: Although it has been accepted that depression and pain are common comorbidities, their interaction is not fully understood. The present study was aimed to investigate the effects of depression on both evoked pain behavior (thermal-induced nociception and hyperalgesia) and spontaneous pain behavior (formalin pain) in rats. An unpredictable chronic mild stress (UCMS) paradigm was employed to develop a classical depression. The emotional behaviors were assessed by sucrose preference test, open field test, and elevated plus-maze test. The results showed that the depressed rats always exhibited stronger tolerance to noxious thermal stimulation under both normal and complete Freund's adjuvant (CFA)-induced chronic pain conditions, when compared to nondepressed animals. Interestingly, the spontaneous nociceptive behaviors induced by formalin injection were significantly enhanced in rats exposed to UCMS in comparison to those without UCMS. Systemic administration of antidepressant fluoxetine significantly restored the nociceptive behaviors to normal level in depressed animals. An additional finding was that the inflammatory rats tended to display depressive-like behaviors without being exposed to UCMS. These results demonstrated that depression can have different effects on stimulus-evoked pain and spontaneous pain, with alleviation in the former while aggravation in the latter.Perspective: The present study provides evidence that depression can have divergent effects on stimulus-evoked and spontaneous pain by confirming that rats exposed to chronic mild stress tend to exhibit decreased pain sensitivity to experimental stimuli but increased intensity of ongoing pain. This may contribute to further understanding of the perplexing relationship between clinical depression and chronic pain.

Comparison of Pain Measures Among Patients With Osteoarthritis - Corrected Proof

2010-01-22

Abstract: This study compared recalled average pain, assessed at the end of the day, with the average of real-time pain ratings recorded throughout the day among patients with osteoarthritis (OA). Participants (N = 157) with hand, hip, or knee OA completed electronic pain diaries on 1 weekend day and 1 weekday. Diaries included at least 7 pain ratings per day, immediately after waking and every 2 hours following, using a visual analog scale (VAS) scored as 1 to 100 (scores not seen by participants). At the end of each diary day, participants rated their average pain that day on the same VAS. Pearson correlations examined associations between recalled average pain and the average of real-time pain ratings that day. Mixed models, including interaction terms, examined whether associations between recalled and actual average pain ratings differed according to the following patient characteristics: joint site, age, race, gender, study enrollment site, and pain catastrophizing. Correlations between recalled and actual average pain ratings were r = .88 for weekdays and r = .86 for weekends (P < .0001). In mixed models, there were no significant interaction terms for any patient characteristics. In summary, patients with OA accurately recalled their average pain over a 1-day period, and this did not differ according to any patient characteristics examined.Perspective: This study showed that patients with OA accurately recalled their average pain over a single-day period, and this did not differ according to patient characteristics. Results of this study indicate that end-of-day recall is a practical and valid method for assessing patients' average pain during a day.

The Impact of Placebo, Psychopathology, and Expectations on the Response to Acupuncture Needling in Patients With Chronic Low Back Pain - Corrected Proof

2010-01-14

Abstract: Comorbid psychopathology is a variable not explored in the acupuncture RCTs that could explain whether subgroups of patients with chronic low back pain have differential responses to acupuncture or placebo treatments. This was a controlled, blinded, crossover trial of verum acupuncture and validated sham acupuncture in 40 CLBP patients, with a Low or High level of psychiatric comorbidity. They completed a 0 to 10 rating scale for pain at the beginning and end of each treatment session, and rated their expectations for change in pain. Verum acupuncture was performed at Large Intestine 4 on the dorsal right hand for 30 minutes by a licensed acupuncturist. Data analysis used percent improvement in pain as the primary outcome for each of the treatment sessions. Both groups (21 Low and 19 High) reported significant analgesia with verum acupuncture needling, mean 33%, P = .9 for difference between groups; and with placebo, 26%, P = .09. In both groups, expectations were only a significant predictor of verum acupuncture response, P = .002, such that those with greater expectations had greater pain relief. Psychiatric comorbidity does not significantly impact acupuncture or placebo acupuncture analgesia in CLBP. It does not affect the positive impact of expectations on reported pain relief from real acupuncture.Perspective: Psychiatric comorbidity may predict differences between acupuncture and placebo responses, not otherwise seen in the RCTs for low back pain. Using a blinded, crossover design, we report that it does not predict outcome, nor does it seem to modify the effect of expectancy (a known predictor) on acupuncture response.

Assessing Aδ Fiber Function With Lidocaine Using Intraepidermal Electrical Stimulation - Corrected Proof

2010-01-14

Abstract: The functions of small fibers can be impaired in peripheral neuropathies, and screening tests for clinical use are required. To verify whether intraepidermal stimulation (IES) is useful for assessing the functions of Aδ fibers in the superficial layer, we investigated sensory thresholds and evoked cortical responses in healthy volunteers before and after a transdermal administration of lidocaine. Pain and tactile thresholds were studied using IES and transcutaneous electrical stimulation (TS), respectively, in 10 healthy volunteers before, and 1 hour, 3 hours, and 5 hours after a local anesthesia with lidocaine. Cortical potentials evoked with IES and TS were also studied in 12 healthy volunteers before and 5 hours after the anesthesia. Although the local anesthesia had no effect on the evoked potentials or the tactile threshold for TS, it markedly increased the pain threshold and almost abolished the evoked potentials for IES. These results suggest that IES is a sensitive tool for detecting functional changes of cutaneous Aδ fibers.Perspective: Compared with other methods of stimulation used to investigate Aδ fiber function, our method is easy to apply and less invasive and can stimulate any site of the body. Therefore, it should be useful as a screening test for patients with neuropathy.

Perspective on Diffuse Noxious Inhibitory Controls as a Model of Endogenous Pain Modulation in Clinical Pain Syndromes - Corrected Proof

Gerrit van Wijk, Dieuwke S. Veldhuijzen — 2010-01-14

Abstract: Altered function of endogenous pain modulation has been proposed as a mechanism that may underlie chronic pain conditions. Descending modulation of pain can be examined by diffuse noxious inhibitory controls (DNIC). DNIC comprises a spinal-medullary-spinal pathway that is activated when 2 concomitant painful stimuli are applied at the same time. This pain-inhibitory system can be easily triggered in an experimental setting. Therefore, studies on DNIC can help us to evaluate impairments in descending pain modulation, presumably primarily of inhibitory nature. This review summarizes recent findings on human DNIC trials with a specific focus on sex, age, and ethnic differences in DNIC effects and psychological mediators such as attention, expectation, and pain catastrophizing. Furthermore, the clinical relevance of DNIC studies will be discussed. Different methodological approaches used make it difficult to generalize results, but the research to date has shown good potential for DNIC to help in gaining insights in the underlying mechanisms of chronic pain conditions.Perspective: Recent literature on diffuse noxious inhibitory controls as a model of endogenous pain modulation in clinical pain syndromes was reviewed. DNIC may help to identify patients at risk for development of chronic pain and may open alternatives for treatment options.

Endothelin-A Receptor Antagonism Attenuates Carcinoma-Induced Pain Through Opioids in Mice - Corrected Proof

Phuong N. Quang, Brian L. Schmidt — 2010-01-13

Abstract: We previously reported that endothelin A (ET-A) receptor antagonism attenuates carcinoma-induced pain in a cancer pain mouse model. In this study, we investigated the mechanism of ET-A receptor-mediated antinociception and evaluated the role of endogenous opioid analgesia. Squamous cell carcinoma (SCC) cell culture treated with the ET-A receptor antagonist (BQ-123) at 10−6 M and 10−5 M significantly increased production and secretion of β-endorphin and leu-enkephalin, respectively. Behavioral studies were performed by inducing tumors in the hind paw of female nude mice with local injection of cells derived from a human oral SCC. Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at 4 days after SCC inoculation and lasted to 18 days, the last day of measurement. Local administration of either naloxone methiodide (500 μg/kg), selective antagonists for μ-opioid receptor (CTOP, 500 μg/kg), or δ-opioid receptor (naltrindole, 11 mg/kg) but not κ-opioid receptor (nor-BNI, 2.5 mg/kg) significantly reversed antinociception observed from ET-A receptor antagonism (BQ-123, 92 mg/kg) in cancer animals. These results demonstrate that antagonism of peripheral ET-A receptor attenuates carcinoma pain by modulating release of endogenous opioids to act on opioid receptors in the cancer microenvironment.Perspective: This article proposes a novel mechanism for ET-A receptor antagonist drugs in managing cancer-induced pain. An improved understanding of the role of innate opioid analgesia in ET-A receptor–mediated antinociception might provide novel alternatives to morphine therapy for the treatment of cancer pain.

Pharmacological Treatment of Neuropathic Facial Pain in the Dutch General Population - Corrected Proof

2009-12-17

Abstract: Few drugs are registered for treatment of neuropathic facial pain (NFP), and not much is known about treatment choices for NFP in daily practice. Patients with NFP were identified in the IPCI-database with longitudinal electronic general practitioner (GP) records. We described prescription patterns of pain medication following first symptoms. Off-label, off-guideline use, failure and reasons for failure were assessed. Failure was defined as treatment switch, exacerbation, adverse event, or invasive treatment for NFP. Of 203 NFP cases, 160 (79%) received pharmacological pain treatment. Most patients (90%) were initially treated by a GP with anti-epileptic drugs (55%) or NSAIDs (16%) as monotherapy. The median treatment delay was 0 days (range 0 to 2,478 days). Adverse events were experienced by 16 (10%) of patients. Sixty-two percent of first prescriptions were in adherence to guidelines and 59% were considered on-label while 34% of prescriptions were both off-label and off-guideline. Of the first therapy, 38% failed within 3 months. The median duration until failure was 251 days. General practitioners usually are the first to treat NFP. They usually prescribe drugs licensed for NFP and according to guidelines, but the extent of off-label use is substantial. Initial treatment often failed within a short period after starting therapy.Perspective: This drug-utilization study describes the pharmacological treatment of different forms of neuropathic facial pain in daily practice. Although treatment is mostly initiated rapidly by general practitioners in a correct way, it often contains off-label or off-guideline medication. Failure of the initial treatment is common and occurs rapidly as well.

Effects of Anodal Transcranial Direct Current Stimulation on Chronic Neuropathic Pain in Patients With Multiple Sclerosis - Corrected Proof

2009-12-17

Abstract: Neuropathic pain in patients with MS is frequent and is associated with a great interference with daily life activities. In the present study, we investigated whether anodal transcranial direct current stimulation (tDCS) may be effective in reducing central chronic pain in MS patients. Patients received sham tDCS or real tDCS in a 5-day period of treatment in a randomized, double blind, sham-controlled study. Pain was measured using visual analog scale (VAS) for pain and the short form McGill questionnaire (SF-MPQ). Quality of life was measured using the Multiple Sclerosis Quality of Life-54 scale (MSQoL-54). Depressive symptoms and anxiety were also evaluated as confounding factors using the Beck Depression Inventory (BDI) and VAS for anxiety. Evaluations were performed at baseline, immediately after the end of treatment, and once a week during a 3-week follow-up period. Following anodal but not sham tDCS over the motor cortex, there was a significant pain improvement as assessed by VAS for pain and McGill questionnaire, and of overall quality of life. No depression or anxiety changes were observed. Our results show that anodal tDCS is able to reduce pain-scale scores in MS patients with central chronic pain and that this effect outlasts the period of stimulation, leading to long-lasting clinical effects.Perspective: This article presents a new, noninvasive therapeutic approach to chronic, central neuropathic pain in multiple sclerosis, poorly responsive to current conventional medications. tDCS is known to cause long-lasting changes of neuronal excitability at the site of stimulation and in the connected areas in healthy subjects. This led us to hypothesize that pain decrease may be the result of functional plastic changes in brain structures involved in the pathogenesis of chronic neuropathic pain.

ASIC1 and ASIC3 Play Different Roles in the Development of Hyperalgesia After Inflammatory Muscle Injury - Corrected Proof

2009-12-16

Abstract: Acid-sensing ion channels (ASICs) respond to acidosis that normally occurs after inflammation. We examined the expression of ASIC1, ASIC2, and ASIC3 mRNAs in lumbar dorsal root ganglion neurons before and 24 hours after carrageenan-induced muscle inflammation. Muscle inflammation causes bilateral increases of ASIC2 and ASIC3 but not ASIC1 (neither ASIC1a nor ASIC1b) mRNA, suggesting differential regulation of ASIC1 versus ASIC2 and ASIC3 mRNA. Similar mRNA increases were observed after inflammation in knockout mice: ASIC2 mRNA increases in ASIC3-/- mice; ASIC2 and ASIC3 mRNAs increase in ASIC1-/- mice. Prior behavioral studies in ASIC3-/- mice showed deficits in secondary hyperalgesia (increased response to noxious stimuli outside the site of injury) but not primary hyperalgesia (increased response to noxious stimuli at the site of injury). In this study, we show that ASIC1-/- mice do not develop primary muscle hyperalgesia but develop secondary paw hyperalgesia. In contrast, and as expected, ASIC3-/- mice develop primary muscle hyperalgesia but do not develop secondary paw hyperalgesia. The pharmacological utility of the nonselective ASIC inhibitor A-317567, given locally, was tested. A-317567 reverses both the primary and the secondary hyperalgesia induced by carrageenan muscle inflammation. Thus, peripherally located ASIC1 and ASIC3 play different roles in the development of hyperalgesia after muscle inflammation.Perspective: This study shows changes in ASIC mRNA expression and behavioral hyperalgesia of C57Bl/6 (wild type), ASIC1-/-, and ASIC3-/- mice before and after the induction of muscle inflammation. A-317567 was effective in reversing hyperalgesia in these animals, suggesting the potential of ASICs as therapeutic targets for muscle inflammatory pain.

Evaluation of Nurses' Self-Insight Into Their Pain Assessment and Treatment Decisions - Corrected Proof

Adam T. Hirsh, Mark P. Jensen, Michael E. Robinson — 2009-12-16

Abstract: Research generally indicates that providers demonstrate modest insight into their clinical decision processes. In a previous study utilizing virtual human (VH) technology, we found that patient demographic characteristics and facial expressions of pain were statistically significant predictors of many nurses' pain-related decisions. The current study examined the correspondence between the statistically identified and self-reported influences of contextual information on pain-related decisions. Fifty-four nurses viewed vignettes containing a video of a VH patient and text describing a postsurgical context. VH sex, race, age, and facial expression varied across vignettes. Participants made pain-assessment and treatment decisions on visual analogue scales. Participants subsequently indicated the information they relied on when making decisions. None of the participants reported using VH sex, race, or age in their decision process. Statistical modeling indicated that 28 to 54% of participants (depending on the decision) used VH demographic cues. 76% of participants demonstrated concordance between their reported and actual use of the VH facial expression cue. Vital signs, text-based clinical summary, and VH movement were also reported as influential factors. These data suggest that biases may be prominent in practitioner decision-making about pain, but that providers have minimal awareness of and/or a lack of willingness to acknowledge this bias.Perspective: The current study highlights the complexity of provider decision-making about pain management. The VH technology could be used in future research and education applications aimed at improving the care of all persons in pain.

Smoking Status and Pain Level Among Head and Neck Cancer Patients - Corrected Proof

2009-12-16

Abstract: Smoking is a risk factor for cancer of the upper aerodigestive tract with recidivism rates high even after diagnosis. Nicotine, a major product in tobacco, is a complex drug with multiple characteristics including analalgesic properties. The goal of the study was to examine pain levels in the context of smoking status among patients recently diagnosed with cancer of the upper aerodigestive tract who have not yet received any treatment including radiation, surgery, or chemotherapy. A convenience sample of 112 newly diagnosed head and neck cancer patients (78 men and 34 women) was recruited from clinics at the University of Florida. Smoking rates were: 32% never smoked, 34% former smokers, 34% current smokers. Among current smokers, 62% reported plans to quit in the next 3 months and 38% had tried to quit more than 3 times in the past 5 years. Current smokers reported higher general (sensory and affective) and oral pain levels (spontaneous and functional) and pain-related interference than did never and former smokers (all F's > 8. and P's < .0001) even after controlling for stage of diagnosis. In addition, current smokers reported significantly greater interference from the pain (F2,73 = 10.5 P < .0001).Perspective: This study highlights the importance of understanding self-reported pain in cancer patients who continue to smoke. When pain is elevated, smokers may be motivated to use tobacco as a means of reducing pain, which in turn reinforces smoking behavior. Tobacco cessation programs should include pain management as a component of treatment.

The Impact of Adolescent Chronic Pain on Functioning: Disentangling the Complex Role of Anxiety - Corrected Proof

Lindsey L. Cohen, Kevin E. Vowles, Christopher Eccleston — 2009-12-16

Abstract: A number of adolescents with chronic pain have clinically significant disability across physical, social, and academic activities, and pain severity only explains a portion of the variance in functioning. Thus, it is important to identify therapeutic options to improve adolescents' functioning. In contrast to studies with adults with chronic pain, research in pediatric pain has not consistently found anxiety to be a good predictor of pain-related disability. The present study evaluated pain, anxiety, and functioning in 222 adolescents with chronic pain. Results indicated that pain was consistently and linearly related to disability across measures of physical and social functioning, school attendance, and physician visits. The relation between anxiety and functioning was complex; increased anxiety was related to poorer physical and social functioning and was related to fewer physician visits, although it was not associated with school attendance. Additional analyses revealed that anxiety serves to moderate the relation between pain and functioning. Specifically, at high anxiety, pain was not related to functioning, but at low anxiety, pain consistently predicted disability. In other words, highly anxious adolescents were functioning poorly regardless of the level of pain. The moderating role of anxiety highlights a number of research and clinical possibilities to explore with adolescents with chronic pain-related disability.Perspective: Data suggest that high anxiety is associated with poor functioning irrespective of pain intensity. At low anxiety, higher pain predicted greater disability. Anxiety is important to assess when investigating potential reasons for pain-related disability.

Tonic Pain Abolishes Cortical Habituation of Visual Evoked Potentials in Healthy Subjects - Corrected Proof

2009-12-16

Abstract: We investigated changes in visual cortex excitability by analyzing visual evoked potential (VEP) habituation in healthy subjects during tonic pain evoked by the cold-pressor test (CPT). We tested VEP amplitude habituation (slope of the linear regression line for N1-P1 amplitude from the 1st to 6th block of 100 sweeps) in 19 healthy volunteers during 4 experimental conditions: baseline; no-pain (hand held in warm water, 25°C); pain (hand held in cold water, 2–4°C); and the after-effects of tonic pain. During baseline and no-pain sessions, VEPs habituated normally across the 6 consecutive blocks (mean slope –.28 and –.18%), whereas during pain and its after-effects they failed to decrease (0%, and –.11%). Tonic pain induced by the CPT abolishes normal VEP habituation and the lack of habituation persists after the CPT is stopped. Tonic pain probably abolishes VEP habituation by acting on brainstem neural structures which modulate thalamo-cortical activation thereby changing visual cortex excitability.Perspective: This study shows that tonic pain alters visual cortex excitability, a brain region unrelated to pain processing. These changes probably reflect defensive strategies against pain. Extending the study from healthy volunteers to patients with migraine between attacks would offer the opportunity to investigate visual cortical excitability under conditions when baseline habituation is absent.

Thermal Nociception is Decreased by Hypocretin-1 and an Adenosine A1 Receptor Agonist Microinjected into the Pontine Reticular Formation of Sprague Dawley Rat - Corrected Proof

Sarah L. Watson, Christopher J. Watson, Helen A. Baghdoyan, Ralph Lydic — 2009-12-16

Abstract: Clinical and preclinical data concur that sleep disruption causes hyperalgesia, but the brain mechanisms through which sleep and pain interact remain poorly understood. Evidence that pontine components of the ascending reticular activating system modulate sleep and nociception encouraged the present study testing the hypothesis that hypocretin-1 (orexin-A) and an adenosine receptor agonist administered into the pontine reticular nucleus, oral part (PnO) each alter thermal nociception. Adult male rats (n = 23) were implanted with microinjection guide tubes aimed for the PnO. The PnO was microinjected with saline (control), hypocretin-1, the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA), the hypocretin receptor-1 antagonist N-(2-Methyl-6-benzoxazolyl)-N''-1,5-naphthyridin-4-yl-urea (SB-334867), and hypocretin-1 plus SB-334867. As an index of antinociceptive behavior, the latency (in seconds) to paw withdrawal away from a thermal stimulus was measured following each microinjection. Compared to control, antinociception was significantly increased by hypocretin-1 and by SPA. SB-334867 increased nociceptive responsiveness, and administration of hypocretin-1 plus SB-334867 blocked the antinociception caused by hypocretin-1. These results suggest for the first time that hypocretin receptors in rat PnO modulate nociception.Perspective: Widely distributed and overlapping neural networks regulate states of sleep and pain. Specifying the brain regions and neurotransmitters through which pain and sleep interact is an essential step for developing adjunctive therapies that diminish pain without disrupting states of sleep and wakefulness.

Emotional Regulation and Acute Pain Perception in Women - Corrected Proof

Desireé Ruiz-Aranda, José Martín Salguero, Pablo Fernández-Berrocal — 2009-12-16

Abstract: Emotional regulation is an important variable in the experience of pain. Currently, there are no experimental investigations of the relation between emotional regulation and pain. The goal of the present study work was to analyze differences in pain perception and mood generated by the cold-pressor (CPT) experimental paradigm in women with high and low emotional regulation. Two groups of women were formed as a function of their level of emotional regulation: women with high emotional repair (N = 24) and women with low emotional repair (N = 28), all of whom performed the CPT. The results show that the women with a high score in emotional repair reported having experienced less sensory pain and affective pain during the immersion, as well as a more positive affective state before beginning the task. During the experimental task, they also reported a better mood, thus displaying lower impact of the experience of pain.Perspective: Emotional regulation is proposed as a key element to manage the emotional reaction that accompanies the experience of acute pain experimentally induced by the CPT experimental paradigm in a sample of healthy women.

Translation to Portuguese and Validation of the Douleur Neuropathique 4 Questionnaire - Corrected Proof

2009-12-16

Abstract: The Douleur Neuropathique 4 (DN4) questionnaire was developed by the French Neuropathic Pain Group and is a simple and objective tool, with the ability to distinguish nociceptive from neuropathic pain. The purpose of this work was to validate the DN4 questionnaire in the Portuguese language in order to allow its use in clinical and research settings. A double-blind, accuracy study was conducted, consisting of translation, back-translation, literal evaluation, semantic equivalence, and communication with the target population. The Portuguese version of the questionnaire was applied in a sample of 101 patients with neuropathic (N = 42) or nociceptive pain (N = 59), ranked according to medical diagnosis. The reproducibility, reliability and validity of the instrument were analyzed, and showed a high diagnostic power for this version of the DN4 questionnaire. The Portuguese version of the DN4 questionnaire presented good validity and reliability, allowing it to identify neuropathic pain and neuropathic characteristics of mixed pain syndromes.Perspective: This article presents the first validated neuropathic pain questionnaire in the Portuguese language and represents a useful tool in the assessment of neuropathic pain both in the clinical setting and in population-based studies. The sensible and quick format of this instrument are key factors that will contribute to its widespread use, permitting a true recognition of patients with neuropathic pain.

Increased Trapezius Pain Sensitivity Is Not Associated With Increased Tissue Hardness - Corrected Proof

2009-12-16

Abstract: Fatiguing exercise can affect muscle pain sensitivity and muscle hardness, as seen with work-related neck and shoulder pain. Objective methods to assess muscle pain sensitivity are important because the reliability of manual assessment is generally poor. The aim of this study was (1) to compare coexistence of tender points identified by manual palpation and pressure algometry or hardness assessments and (2) to examine the influence of exercise on muscle pain sensitivity and hardness. Fourteen sites in the upper trapezius muscle were selected for assessments in 12 healthy subjects. Pressure pain thresholds and muscle hardness were examined by computer-controlled pressure algometry at baseline, immediately after static or dynamic exercise, and 20 minutes after static or dynamic exercise. Before recording of pressure pain thresholds, the trapezius muscle was examined for tender points by manual palpation. Two sites with low pressure pain thresholds were typical locations for tender points, and these were the least hard sites. However, manually detected tender points were often (29%) not colocalized with most sensitive sites according to the pressure algometry. A heterogeneous distribution of pressure pain sensitivity and muscle hardness was found in the upper trapezius. The short duration of exercise until exhaustion did not change muscle sensitivity or muscle hardness in asymptomatic muscles.Perspective: This study confirms clinical findings with heterogeniosity in pain sensitivity and hardness across the upper trapezius muscle. Developments of new techniques that objectively can identify tender points are important, but thus far, manual palpation is best clinical practice.

Spinal Nerve Ligation in Mouse Upregulates TRPV1 Heat Function in Injured IB4-Positive Nociceptors - Corrected Proof

Daniel Vilceanu, Prisca Honore, Quinn H. Hogan, Cheryl L. Stucky — 2009-12-16

Abstract: Peripheral nerve injury leads to neuropathic pain, but the underlying mechanisms are not clear. The TRPV1 channel expressed by nociceptors is one receptor for noxious heat and inflammatory molecules. Lumbar 4 (L4) spinal nerve ligation (SNL) in mice induced persistent heat hyperalgesia 4 to 10 days after injury. The heat hypersensitivity was completely reversed by the TRPV1 antagonist A-425619. Furthermore, DRG neurons were isolated from the injured L4 ganglia or adjacent L3 ganglia 4 to 10 days after L4 SNL. Whole-cell patch-clamp recordings were performed and heat stimuli (22°C to 50°C/3 s) were applied to the soma. Neurons were classified by soma size and isolectin-B4 (IB4) binding. Among directly injured L4 neurons, SNL increased the percentage of small-diameter IB4-positive neurons that were heat-sensitive from 13% (naive controls) to 56% and conversely decreased the proportion of small IB4-negative neurons that were heat-sensitive from 66% (naive controls) to 34%. There was no change in IB4 binding in neurons from the injured ganglia. Surprisingly, in neurons from the adjacent L3 ganglia, SNL had no effect on the heat responsiveness of either IB4-positive or negative small neurons. Also, SNL had no effect on heat responses in medium-large–diameter neurons from either the injured or adjacent ganglia.Perspective: TRPV1 function is upregulated in IB4-positive sensory neurons, and TRPV1 is responsible for the behavioral heat hypersensitivity in the spinal nerve ligation model. Because IB4-positive neurons may contribute to the emotional perception of pain, TRPV1 antagonists, targeting both sensory and affective pain components, could have broad analgesic effects.

Capsaicin-Induced Central Sensitization Evokes Segmental Increases in Trigger Point Sensitivity in Humans - Corrected Proof

John Z. Srbely, James P. Dickey, Leah R. Bent, David Lee, Mark Lowerison — 2009-12-16

Abstract: This study investigated whether inducing central sensitization evokes segmental increases in trigger point pressure sensitivity. We evoked central sensitization at the C5 segment and validated its presence via mechanical cutaneous sensitivity (brush allodynia) testing. Trigger point pressure sensitivity was quantified using the pain pressure threshold (PPT) value. A 50 cm2 area of the C5 dermatome at the right lateral elbow was pretreated with 45° heat for 10 minutes. Test subjects (n = 20) then received topical capsaicin cream (0.075%; Medicis, Toronto, Canada) to the C5 dermatome, whereas control subjects (n = 20) received a topical placebo cream (Biotherm Massage, Montreal, Canada). PPT readings were recorded from the infraspinatus (C5,6) and gluteus medius (L4,5S1) trigger points at zero (pre-intervention), 10, 20, and 30 minutes after intervention; all PPT readings were normalized to pre-intervention (baseline) values. The difference between the PPT readings at the 2 trigger point sites represents the direct influence of segmental mechanisms on the trigger point sensitivity at the infraspinatus site (PPTseg). Test subjects demonstrated statistically significant increases in Total Allodynia scores and significant decreases in PPTseg at 10, 20, and 30 minutes after application, when compared with control subjects. These results demonstrate that increases in central sensitization evoke increases in trigger point pressure sensitivity in segmentally related muscles.Perspective: Myofascial pain is the most common form of musculoskeletal pain. Myofascial trigger points play an important role in the clinical manifestation of myofascial pain syndrome. Elucidating the role of central sensitization in the pathophysiology of trigger points is fundamental to developing optimal strategies in the management of myofascial pain syndrome.

Preliminary Psychometric Properties of the Chinese Version of the Chronic Pain Coping Inventory (ChCPCI) in a Hong Kong Chinese Population - Corrected Proof

Wing S. Wong, Mark P. Jensen, Kan H. Mak, Barry K.H. Tam, Richard Fielding — 2009-12-16

Abstract: The Chronic Pain Coping Inventory (CPCI) is a frequently used measure that assesses 8 categories of coping strategies that patients might use to cope with chronic pain. Despite its good psychometric properties and widespread use, the instrument has not been tested for its applicability and validity in non-Western populations, such as among Chinese. This study evaluated the reliability and validity of a Chinese translation of the 42-item CPCI (ChCPCI-42) in a sample of Chinese patients with chronic pain (n = 208). In addition to the ChCPCI-42, the patients were administered the Chronic Pain Grade (CPG) questionnaire, the Pain Catastrophizing Scale (PCS), the Centre for Epidemiological Studies–Depression Scale (CES-D), and questions assessing sociodemographic characteristics. Results of confirmatory factor analyses revealed that of the ChCPCI-42 8 scales, 6 demonstrated acceptable-to-good data-model fit (CFI ≥ 0.90) and 2 demonstrated medium fit (CFI ≥ 0.85). The 8 scales demonstrated adequate to good internal consistency (Cronbach α, 0.69 to 0.79) and correlated with CES-D, PCS, pain intensity, and disability in expected directions. Results of hierarchical multiple regression analyses showed that the ChCPCI-42 scales predicted concurrent depression (F (8,177) = 3.07, P < .01) and pain disability (F (1, 179) = 4.35, P < .001) scores, the Task Persistence scale being the strongest unique predictor among the 8 scales. The findings support the factorial validity and reliability of a 42-item CPCI that can be used among Chinese patients with chronic pain.Perspective: The report outlines the first validation of the CPCI for use in Hong Kong Chinese. This makes available a suitable instrument for chronic pain research in the Southern Chinese population and will help to elucidate similarities and differences in pain coping between Chinese and other ethnic groups.

A Principal Components Analysis of Negative Affect-Related Constructs Relevant to Pain: Evidence for a Three Component Structure - Corrected Proof

Charlotte Mounce, Edmund Keogh, Christopher Eccleston — 2009-12-16

Abstract: A number of negative affect-related constructs are important in pain. Some are general, such as anxiety, depression and negative affectivity, whereas others are more specifically pain-related (eg, fear of pain, pain anxiety, and pain catastrophizing). In addition, some more specific fear-related constructs, such as anxiety sensitivity, illness/injury sensitivity, and fear of negative evaluation have emerged as important to pain. Although these various constructs are considered conceptually separate, there is likely to be overlap between them. Since the extent of this overlap is unknown, the aim of the current study was to investigate these constructs in 1 sample in order to identify their common and unique features. Frequently used psychological measures were completed by 508 pain-free participants. Principal components analysis resulted in the extraction of three components: 1) General distress; 2) Fear of pain from injury/insult; and 3) Cognitive intrusion of pain. The results presented here suggest that there is indeed commonality between constructs, which may be due to either an overlap between items within measures or to close conceptual relatedness. The implications of these core dimensions are discussed with reference to future research and theory.Perspective: This article explores the relationships between various negative-affect pain-related measures and discusses the results from a principal components analysis. The findings show that some questionnaires may measure the same latent construct. A measure could be developed to measure these 3 core components more concisely for both clinical and research purposes.

Mechanisms Mediating Vibration-induced Chronic Musculoskeletal Pain Analyzed in the Rat - Corrected Proof

Olayinka A. Dina, Elizabeth K. Joseph, Jon D. Levine, Paul G. Green — 2009-12-04

Abstract: While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and reexposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60–80Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a proinflammatory cytokine or reexposure to vibration. Exposure of a hind limb to vibration-produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for ∼2 weeks. When nociceptive thresholds had returned to baseline, exposure to a proinflammatory cytokine or reexposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cε, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-α (TNFα) receptor. Finally, in TNFα-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged.Perspective: These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFα and the second messenger protein kinase Cε as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome.

A Randomized Controlled Trial of Oxycodone vs Placebo in Patients With PostHerpetic Neuralgia and Painful Diabetic Neuropathy Treated With Pregabalin - Corrected Proof

2009-12-04

Abstract: The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the pain-intensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain.Perspective: Peripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in ∼40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin.

Bilateral Mechanical-Pain Sensitivity Over the Trigeminal Region in Patients With Chronic Mechanical Neck Pain - Corrected Proof

2009-11-30

Abstract: The aim of this study was to investigate bilateral pressure-pain sensitivity over the trigeminal region, the cervical spine, and the tibialis anterior muscle in patients with mechanical chronic neck pain. Twenty-three patients with neck pain (56% women), aged 20 to 37 years old, and 23 matched controls (aged 20 to 38 years) were included. Pressure pain thresholds (PPTs) were bilaterally assessed over masseter, temporalis, and upper trapezius muscles, the C5-C6 zygapophyseal joint, and the tibialis anterior muscle in a blinded design. The results showed that PPT levels were significantly decreased bilaterally over the masseter, temporalis, and upper trapezius muscles, and also the C5-C6 zygapophyseal joint (P < .001), but not over the tibialis anterior muscle (P = .4) in patients with mechanical chronic neck pain when compared to controls. The magnitude of PPT decreases was greater in the cervical region as compared to the trigeminal region (P < .01). PPTs over the masseter muscles were negatively correlated to both duration of pain symptoms and neck-pain intensity (P < .001). Our findings revealed pressure-pain hyperalgesia in the trigeminal region in patients with mechanical chronic neck pain, suggesting spreading of sensitization to the trigeminal region in this patient population.Perspective: This article reveals the presence of bilateral pressure-pain hypersensitivity in the trigeminal region in patients with idiopathic neck pain, suggesting a sensitization process of the trigemino-cervical nucleus caudalis in this population. This finding has implications for development of management strategies.

A New Transient Sham TENS Device Allows for Investigator Blinding While Delivering a True Placebo Treatment - Corrected Proof

2009-11-30

Abstract: This study compared a new transient sham transcutaneous electrical nerve stimulation (TENS) that delivers current for 45 seconds to an inactive sham and active TENS to determine the degree of blinding and influence on pain reduction. Pressure-pain thresholds (PPT), heat-pain thresholds (HPT), and pain intensities to tonic heat and pressure were measured in 69 healthy adults before and after randomization. Allocation investigators and subjects were asked to identify the treatment administered. The transient sham blinded investigators 100% of the time and 40% of subjects compared to the inactive sham that blinded investigators 0% of the time and 21% of subjects. Investigators and subjects were blinded only 7% and 13% of the time, respectively, with active TENS. Neither placebo treatment resulted in significant changes in PPT, HPT, or pain intensities. Subjects using higher active TENS amplitudes (≥17 mAs) had significantly higher PPTs and lower pain intensities to tonic pressure than subjects using lower amplitudes (<17 mAs). HPTs and pain intensities to tonic heat were not significantly changed. The transient TENS completely blinds investigators to treatment and does not reduce pain, thereby providing a true placebo treatment.Perspective: This article presents the benefits of a new transient sham TENS device for use in prospective, randomized, clinical trials. This device facilitates blinding of subjects and investigators to eliminate expectation bias and determine the true efficacy of TENS for use in clinical populations.

Learned Avoidance From Noxious Mechanical Simulation But Not Threshold Semmes Weinstein Filament Stimulation After Nerve Injury in Rats - Corrected Proof

Hsiang-En Wu, Geza Gemes, Vasiliki Zoga, Takashi Kawano, Quinn H. Hogan — 2009-11-30

Abstract: Noxious mechanical stimulation evokes a complex and sustained hyperalgesic motor response after peripheral nerve injury that contrasts with a brief and simple withdrawal seen after noxious stimulation in control animals or after threshold punctate mechanical stimulation by the von Frey technique. To test which of these behaviors indicate pain, the aversiveness of the experience associated with each was determined using a passive avoidance test in rats after sciatic nerve ligation (SNL) or skin incision alone. After 18 days, step-down latency was measured during 9 sequential trials at 10-minute intervals. At each trial, rats received either no stimulus, needle stimuli, or threshold Semmes Weinstein (SW) filament stimuli after stepping down. Reactions were either a hyperalgesic response or a brief reflexive withdrawal. In SNL animals, needle stimulation produced substantial learned avoidance when animals showed hyperalgesic responses but produced minimal prolonged latency in SNL animals that showed only simple withdrawal responses. No learned avoidance developed using threshold SW testing in SNL animals. These findings show that needle stimulation is aversive in rats responding with hyperalgesic behavior. In contrast, SW stimulation, as well as needle stimulation that produced mere withdrawal, is minimally aversive.Perspective: The validity of measures of pain in animals is open to question. We demonstrated that needle stimulation is aversive in rats that respond with hyperalgesic-type behavior and is therefore a valid indicator of pain. Stimulation by SW is minimally aversive and is a problematic indicator of pain.

Neonatal Bladder Inflammation Produces Functional Changes and Alters Neuropeptide Content in Bladders of Adult Female Rats - Corrected Proof

2009-11-30

Abstract: Neonatal bladder inflammation has been demonstrated to produce hypersensitivity to bladder re-inflammation as an adult. The purpose of this study was to investigate the effects of neonatal urinary bladder inflammation on adult bladder function and structure. Female Sprague-Dawley rats were treated on postnatal days 14 to 16 with intravesical zymosan or anesthesia alone. At 12 to 16 weeks of age, micturition frequency and cystometrograms were measured. Similarly treated rats had their bladders removed for measurement of plasma extravasation after intravesical mustard oil, for neuropeptide analysis (calcitonin gene-related peptide or Substance P) or for detailed histological examination. Rats treated with zymosan as neonates exhibited increased micturition frequency, reduced micturition volume thresholds, greater extravasation of Evans blue after intravesical mustard oil administration, and greater total bladder content of calcitonin gene-related peptide and Substance P. In contrast, there were no quantitative histological changes in the thickness, fibrosis, or mast cells of bladder tissue due to neonatal zymosan treatments. Functional changes in urologic systems observed in adulthood, coupled with the increased neuropeptide content and neurogenic plasma extravasation in adult bladders, suggest that the neonatal bladder inflammation treatment enhanced the number, function, and/or neurochemical content of primary afferent neurons. These data support the hypothesis that insults to the urologic system in infancy may contribute to the development of adult bladder hypersensitivity.Perspective: Inflammation of the bladder early in life in the rat has multiple sequelae, including laboratory measures that suggest an alteration of the neurophysiological substrates related to the bladder. Some painful bladder syndromes in humans have similar characteristics and so may be due to similar mechanisms.

Increased Cold-Pain Thresholds in Major Depression - Corrected Proof

Christiane Schwier, Anna Kliem, Michael Karl Boettger, Karl-Jürgen Bär — 2009-11-30

Abstract: Most previous studies indicated that patients suffering from major depressive disorder (MDD) showed a decreased sensitivity for external or skin surface pain, eg, for heat or electrical stimuli, as compared to healthy controls. Here, we investigated cold-pain thresholds in 20 unmedicated patients suffering from MDD and 20 matched controls. We applied the ascending method of limits which has previously been used for heat-pain assessment in patients with depression. Similar to previous results for heat-pain thresholds we found a decreased sensitivity for cold pain in patients with MDD as indicated by increased cold-pain thresholds. This difference was significant on the right arm, whereas only a trend was obtained on the left arm, thus suggesting a certain degree of lateralization, similar to that seen in heat-pain perception in patients suffering from MDD or adjustment disorder. The study confirms our previous results of a lower sensitivity for externally induced pain in patients with MDD. Moreover, it adds weight to the assumption of a lateralized perception of thermal pain in depression.Perspective: This investigation provides further evidence for reduced pain perception of externally applied stimuli in major depression. Thus, central-nervous correlates for this altered pain perception in major depression are worth examining in future studies in order to gain more insight into mechanisms of pain perception on the one hand, and pathology of depression on the other.

Gender Differences in Risk Factors for Aberrant Prescription Opioid Use - Corrected Proof

2009-11-30

Abstract: This is a longitudinal predictive study to examine gender differences in the clinical correlates of risk for opioid misuse among chronic pain patients prescribed opioids for pain. Two hundred seventy-five male and 335 female patients prescribed opioids for chronic noncancer pain were asked to complete a series of baseline questionnaires, including the revised Screener and Opioid Assessment for Pain Patients (SOAPP-R). After 5 months, the subjects were administered a structured prescription drug use interview (Prescription Drug Use Questionnaire; PDUQ) and submitted a urine sample for toxicology assessment. Their treating physicians also completed a substance misuse behavior checklist (Prescription Opioid Therapy Questionnaire; POTQ). At 5-month follow-up, women showed higher scores on the PDUQ (P < .05), whereas men had a higher incidence of physician-rated aberrant drug behavior on the POTQ (P < .05). An item analysis of the SOAPP-R, PDUQ, and POTQ showed that women tended to score higher on items relating to psychological distress, whereas the male patients tended to report having more legal and behavioral problems. These results suggest that risk factors associated with prescription opioid misuse may differ between men and women.Perspective: Understanding gender differences in substance abuse risk among chronic pain patients is important for clinical assessment and treatment. This study suggests that women are at greater risk to misuse opioids because of emotional issues and affective distress, whereas men tend to misuse opioids because of legal and problematic behavioral issues.

ALO-01 (Morphine Sulfate and Naltrexone Hydrochloride) Extended-Release Capsules in the Treatment of Chronic Pain of Osteoarthritis of the Hip or Knee: Pharmacokinetics, Efficacy, and Safety - Corrected Proof

Nathaniel Katz, Stephen Sun, Franklin Johnson, Joseph Stauffer — 2009-11-30

Abstract: ALO-01 (EMBEDA [morphine sulfate and naltrexone hydrochloride] extended-release capsules [King Pharmaceuticals, Inc, Bridgewater, NJ]), indicated for chronic moderate-to-severe pain, is designed to release naltrexone upon tampering (eg, by crushing), reducing morphine-induced subjective effects. This multicenter, randomized, double-blind, crossover study assessed pharmacokinetics, efficacy, and safety of ALO-01 and compared them with extended-release morphine sulfate (ERMS, KADIAN [morphine sulfate extended-release] capsules [Actavis US, Morristown, NJ]) in adults (N = 113) with osteoarthritis pain. Study periods included washout until pain flare (intensity ≥5, 0 to 10; 0 = no pain, 10 = worst pain); dose titration with ERMS (20 to 160mg BID); and randomization to 2 (crossover) 14-day treatment periods with ERMS or ALO-01, separated by 7 days of open-label ERMS. Assessments included pharmacokinetics (morphine, naltrexone), pain scores (0 to 10), Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index; Patient Global Assessment of Medication (1 to 5; poor to excellent). Mean score at pain flare was 7.1. Morphine exposure from both formulations at steady state was similar. Plasma naltrexone concentrations were below limit-of-quantification for most patients and, when present, did not impact pain scores. During treatment, mean pain intensity (day 14: ERMS, 2.4; ALO-01, 2.3, P = .31), WOMAC change-from-baseline (mean pain, physical function, composite scores), and adverse event frequency were similar. ALO-01 and ERMS provided similar relief of osteoarthritis pain.Perspective: We present data demonstrating that ALO-01 has steady-state morphine exposure, efficacy, and safety similar to marketed ERMS capsules. Results highlight the potential for morphine in ALO-01 to manage moderate-to-severe osteoarthritis pain, while the sequestered naltrexone does not interfere with efficacy.

The Predetermined Sites of Examination for Tender Points in Fibromyalgia Syndrome Are Frequently Associated With Myofascial Trigger Points - Corrected Proof

2009-11-16

Abstract: The aim of this present study is to test the hypotheses that the 18 predetermined sites of examination for tender points (TP sites) in fibromyalgia syndrome (FMS) are myofascial trigger points (MTrPs), and that the induced pain from active MTrPs at TP sites may mimic fibromyalgia pain. Each TP site was evaluated with manual palpation followed by intramuscular electromyographic (EMG) registration of spontaneous electrical activity to confirm or refute the existence of an MTrP in 30 FMS patients. Overall spontaneous pain intensity and pain pattern were recorded before manual identification of MTrPs. Local and referred pain pattern from active MTrPs were drawn following manual palpation at TP sites.Results: showed that most of the TP sites are MTrPs. Local and referred pain from active MTrPs reproduced partly the overall spontaneous pain pattern. The total number of active MTrPs (r = .78, P < .0001), but not latent MTrPs (r = –.001, P = .99), was positively correlated with spontaneous pain intensity in FMS. The current study provides first evidence that pain from active MTrPs at TP sites mimics fibromyalgia pain. MTrPs may relate to generalized increased sensitivity in FMS due to central sensitization.Perspective: This article underlies the importance of active MTrPs in FMS patients. Most of the TP sites in FMS are MTrPs. Active MTrPs may serve as a peripheral generator of fibromyalgia pain and inactivation of active MTrPs may thus be an alternative for the treatment of FMS.

Predictability of Painful Stimulation Modulates Subjective and Physiological Responses - Corrected Proof

2009-10-23

Abstract: Clinical observations suggest that the perceived intensity of a painful event increases as the unpredictability of its occurrence increases. We examined the effect of varying stimulus predictability on the Somatosensory Evoked Potential (SEP), Pupil Diameter Response (PDR), Pain Report (PR), and Fear Report (FR) in 25 healthy female volunteers experiencing repeated noxious fingertip shocks. Each volunteer underwent high- and low-stimulus intensities in 4 stimulus patterns defined by stimulus sequence (SEQ) and interstimulus interval (ISI) as follows: A) serial stimulus intensity SEQ with fixed ISI; B) serial stimulus intensity SEQ with varied ISI; C) random stimulus intensity SEQ with fixed ISI; and D) random stimulus intensity SEQ with varied ISI. Results revealed that: (1) lower stimulus predictability led to higher PR and FR, greater PDR magnitude, and greater SEP amplitude; and (2) the 4 dependent measures showed the same response pattern across levels of stimulus predictability. These findings support the hypothesis that lower stimulus predictability is associated with higher reported pain and fear as well as greater physiological arousal.Perspective: Patients undergoing painful procedures experience more distress when the occurrence of a painful event is unpredictable. Poor predictability increases pain, fear, and associated physiological arousal. Maximizing the predictability of painful events may improve the quality of patient care by minimizing associated levels of pain and fear.

Feasibility study of Transcutaneous Electrical Nerve Stimulation (TENS) for Cancer Bone Pain - Corrected Proof

2009-10-23

Abstract: This multicenter study assessed the feasibility of conducting a phase III trial of transcutaneous electrical nerve stimulation (TENS) in patients with cancer bone pain recruited from palliative care services. Eligible patients received active and placebo TENS for 1 hour at site of pain in a randomized crossover design; median interval between applications 3 days. Responses assessed at 30 and 60 minutes included numerical and verbal ratings of pain at rest and on movement, and pain relief. Recruitment, tolerability, adverse events, and effectiveness of blinding were also evaluated. Twenty-four patients were randomised and 19 completed both applications. The intervention was well tolerated. Five patients withdrew: 3 due to deteriorating performance status, and 2 due to increased pain (1 each following active and placebo TENS). Confidence interval estimation around the differences in outcomes between active and placebo TENS suggests that TENS has the potential to decrease pain on movement more than pain on rest. Nine patients did not consider that a placebo was used; the remaining 10 correctly identified placebo TENS. Feasibility studies are important in palliative care prior to undertaking clinical trials. Our findings suggest that further work is required on recruitment strategies and refining the control arm before evaluating TENS in cancer bone pain.Perspective: Cancer bone pain is common and severe, and partly mediated by hyperexcitability. Animal studies suggest that Transcutaneous Electrical Nerve Stimulation can reduce hyperalgesia. This study examined the feasibility of evaluating TENS in patients with cancer bone pain in order to optimize methods before a phase III trial.

Differential Roles of Peripheral Metabotropic Glutamate Receptors in Bee Venom-Induced Nociception and Inflammation in Conscious Rats - Corrected Proof

Hui-Sheng Chen, Fang Qu, Xiang He, Shuang-Ming Kang, Dan Liao, Su-Jie Lu — 2009-10-23

Abstract: Intraplantar injection of bee venom (BV) produces persistent spontaneous nociception (PSN), hyperalgesia, and inflammatory swelling of the injected paw. The present study was designed to determine the roles of peripheral metabotropic glutamate receptors (mGluRs) in BV-induced nociception and inflammation. We determined the effects of the group I mGluR antagonist AIDA, the group II mGluR agonist ADPC, and the group III mGluR agonist L-AP4 on BV-induced PSN, mechanical hyperalgesia, and inflammatory swelling. Pretreatment with intraplantar injections of AIDA, ADPC or L-AP4 at different doses significantly inhibited BV-induced PSN over the 1-hour observational period. The inhibitory effects of ADPC and L-AP4 were completely abolished by pretreatment with the group II mGluR antagonist LY341495 and the group III mGluR antagonist MSOP, respectively. Pretreatment with ADPC prevented the BV-induced decrease in paw-withdrawal mechanical threshold (PWMT) in a dose-dependent manner, while pretreatment with AIDA or L-AP4 had no effect. The antihyperalgesic effect of ADPC was completely abolished by pretreatment with LY341495. Pretreatment with AIDA, ADPC or L-AP4 at different doses had no effect on the BV-induced increase in the paw volume (PV), a measurement of inflammatory swelling. All contralateral drug treatments at the highest doses had no effect on BV-induced PSN, decreases in PWMT or increases in PV, eliminating the possibility of drug-induced systemic effects. These data suggest that the activation of mGluRs in the periphery may play a differential role in BV-induced nociception and inflammation.Perspective: The present study demonstrated that the intraplantar injection of antagonists or agonists of different mGluRs produced differential effects on bee venom-induced persistent spontaneous nociception and mechanical hyperalgesia. However, no effects on inflammation were observed, suggesting that mGluRs in the periphery have differential roles. Thus, therapies specifically targeting metabotropic glutamate receptors may improve the treatment of patients with persistent spontaneous nociception and hyperalgesia.

Race, Care Seeking, and Utilization for Chronic Back and Neck Pain: Population Perspectives - Corrected Proof

2009-10-23

Abstract: We analyzed a statewide survey of individuals with chronic back and neck pain to determine whether prevalence and care use varied by patient race or ethnicity. We conducted a telephone survey of a random sample of 5,357 North Carolina households in 2006. Adults with chronic (>3 months duration or >24 episodes of pain per year), impairing back or neck pain were identified and were asked to complete a survey about their health and care utilization. 837 respondents (620 white, 183 black, 34 Latino) reported chronic back or neck pain. Whites and blacks had similar rates of chronic back pain. Back pain prevalence was lower in Latinos (10.4% [9.3–11.6] vs 6.3% [3.8–8.8]), likely due to their younger age; and the prevalence of chronic, disabling neck pain was lower in blacks (2.5% [1.9–3.1] vs 1.1% [.04–1.9]). Blacks had higher pain scores in the previous 3 months (5.2 vs 5.9 P < .05), and higher Roland disability scores (0–23 point scale): 14.2 vs 16.8, P < .05. Care seeking was similar among races (83% white, 85% black, 72% Latino). Use of opioids was also similar between races, at 49% for whites, 52% for blacks, and trended lower at 35% for Latinos. We found few racial/ethnic differences in care seeking, treatment use, and use of narcotics for the treatment of chronic back and neck pain.Perspective: This article presents new, population-based data on the issue of racial and ethnic disparities in neck- and back-pain prevalence and care. Few disparities were found; care quality issues may affect all ethnic groups similarly. Previous findings of disparities in chronic-pain management may be decreasing, or may perhaps be site specific.

The Effects of Brief Mindfulness Meditation Training on Experimentally Induced Pain - Corrected Proof

Fadel Zeidan, Nakia S. Gordon, Junaid Merchant, Paula Goolkasian — 2009-10-23

Abstract: This study investigated the effects of brief mindfulness meditation training on ratings of painful electrical stimulation. In Experiment 1, we used a 3-day (20 min/d) mindfulness meditation intervention and measured pain ratings before and after the intervention. Participants' numerical ratings of pain to “low” and “high” electrical stimulation significantly decreased after meditation training. Pain sensitivity, measured by change in stimulus intensity thresholds, also decreased after training. We investigated, in Experiment 2, how well relaxation and a math distraction task attenuated experimental pain. Math distraction but not relaxation reduced high pain ratings. There was no reduction in pain sensitivity in these participants. In Experiment 3, we directly compared the effects of meditation with math distraction and relaxation conditions. Our findings indicated significant effects of both meditation and math distraction. Consistent with what was observed in Experiment 1, these participants also demonstrated a decrease in pain sensitivity after meditation training. Changes in the mindfulness and anxiety assessments suggest that meditation's analgesic effects are related to reduced anxiety and the enhanced ability to focus on the present moment.Perspective: Our findings indicate that a brief 3-day mindfulness meditation intervention was effective at reducing pain ratings and anxiety scores when compared with baseline testing and other cognitive manipulations. The brief meditation training was also effective at increasing mindfulness skills.

Impact of Postherpetic Neuralgia and Painful Diabetic Peripheral Neuropathy on Health Care Costs - Corrected Proof

2009-10-23

Abstract: Knowledge of the health care costs associated with neuropathic pain is limited. Existing studies have not directly compared the health care costs of different neuropathic pain conditions, and patients with neuropathic pain have not been compared with control subjects with the same underlying conditions (for example, diabetes). To determine health care costs associated with postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN), patients with these conditions were selected from 2 different administrative databases of health care claims and respectively matched to control subjects who had a diagnosis of herpes zoster without persisting pain or a diagnosis of diabetes without neurological complications using propensity scores for demographic and clinical factors. Total excess health care costs attributable to PHN and painful DPN and excess costs for inpatient care, outpatient/professional services, and pharmacy expenses were calculated. The results indicated that the annual excess health care costs associated with peripheral neuropathic pain in patients of all ages range from approximately $1600 to $7000, depending on the specific pain condition. Total excess health care costs associated with painful DPN were substantially greater than those associated with PHN, which might reflect the great medical comorbidity associated with DPN.Perspective: The data demonstrate that the health care costs associated with 1 peripheral neuropathic pain condition cannot be extrapolated to other neuropathic pain conditions. The results also increase understanding of the economic burden of PHN and painful DPN and provide a basis for evaluating the impact on health care costs of new interventions for their treatment and prevention.

Sex Differences and Hormonal Influences on Response to Mechanical Pressure Pain in Humans - Corrected Proof

2009-10-23

Abstract: Previous studies have demonstrated that sex differences in pain responsivity can be detected using various models of experimentally induced pain. The present study employed the mechanical pressure test in order to examine potential differences in pain report among men, normally menstruating women (NMW), and women taking monophasic oral contraceptives (OCW). Testing occurred during 5 phases of the menstrual cycle (menstrual, follicular, ovulatory, luteal, and late luteal) and all participants completed 10 sessions (2 sessions per phase). Menstrual-cycle phase was estimated for OCW based on their first day of menses. Men were tested at time points that roughly corresponded to the intervals during which the different phases occurred in NMW. During the mechanical pressure test, 4 different weights were placed on the fingers, one at a time, and ratings of pain were recorded for 30 seconds. The statistical decision-making model and a forced-choice procedure were used to analyze the response data. Two variables, based on signal detection theory, were thus generated: P(A), a measure of sensory pain, and B, a measure of response bias. P(A) is believed to be a measure of pain sensitivity while B measures stoicism. NMW tended to report lower P(A) values, indicating reduced ability to discriminate among different stimulus intensities, during the menstrual and late luteal phases compared to the luteal phase. OCW reported lower B values, indicating less stoicism, during the menstrual compared to the follicular and ovulatory phases. Men tended to have significantly lower B values than OCW, but not NMW. These results demonstrate subtle menstrual-cycle effects in NMW and OCW. Sex differences were few, with more group differences and trends emerging between OCW and men, as opposed to men and NMW.Perspective: The lack of consistent differences between men and NMW underscores the subtle impact of sex and hormonal changes in pain report. In addition, the data obtained in NMW support the notion that changes in hormone levels during the menstrual cycle can lead to changes in pain responsivity as NMW had trends for better discrimination in menstrual phases when estradiol levels were highest.

Activation of NMDA Receptors in the Brainstem, Rostral Ventromedial Medulla, and Nucleus Reticularis Gigantocellularis Mediates Mechanical Hyperalgesia Produced by Repeated Intramuscular Injections of Acidic Saline in Rats - Corrected Proof

Luis F. Da Silva, Josimari M. DeSantana, Kathleen A. Sluka — 2009-10-23

Abstract: Repeated injections of acidic saline into the gastrocnemius muscle induce both muscle and cutaneous hypersensitivity. We have previously shown that microinjection of local anesthetic into either the rostral ventromedial medulla (RVM) or the nucleus reticularis gigantocellularis (NGC) reverses this muscle and cutaneous hypersensitivity. Although prior studies show that NMDA receptors in the RVM play a clear role in mediating visceral and inflammatory hypersensitivity, the role of NMDA receptors in the NGC or in noninflammatory muscle pain is unclear. Therefore, the present study evaluated involvement of the NMDA receptors in the RVM and NGC in muscle and cutaneous hypersensitivity induced by repeated intramuscular injections of acidic saline. Repeated intramuscular injections of acidic saline, 5 days apart, resulted in a bilateral decrease in the withdrawal thresholds of the paw and muscle in all groups 24 hours after the second injection. Microinjection of NMDA receptor antagonists into the RVM reversed both the muscle and cutaneous hypersensitivity. However, microinjection of NMDA receptor antagonists into the NGC only reversed cutaneous but not muscle hypersensitivity. These results suggest that NMDA receptors in the RVM mediate both muscle and cutaneous hypersensitivity, but those in the NGC mediate only cutaneous hypersensitivity after muscle insult.Perspective: The current study shows that NMDA receptors in supraspinal facilitatory sites maintain noninflammatory muscle pain. Clinical studies in people with chronic widespread, noninflammatory pain, similarly, show alterations in central excitability. Thus, understanding mechanisms in an animal model could lead to improved treatment for patients with chronic muscle pain.