PAIN

Editorial list

2012-02-01

How does topical lidocaine relieve pain

James N. Campbell — 2011-11-07

The report by Krumova et al. in this issue raises important questions about the neural signaling involved in neuropathic pain, and highlights the presence of substantial gaps in our knowledge about how topical lidocaine relieves pain. The authors studied the sensory effects of applying an adhesive patch containing 5% lidocaine (Versatis® 5%) to the skin in normal subjects. The study was double blind and used a validated sensory testing protocol to assess affects on thermal and mechanical sensibility. The authors quantitatively corroborate the clinical impression that though topical lidocaine may relieve neuropathic pain , the effects on sensation are minimal. The study was performed after only six hours of application of the study medication, and one might quibble that this testing interval is insufficient to achieve full effects. Nevertheless it is quite striking that the patch produced no measurable effect on tactile (large fiber) function, and the effects on pain sensibility were typically mild. These findings raise broad questions about the primary afferent mechanisms that contribute to neuropathic pain. In particular, since, the effects of topical lidocaine on clinical pain are often disappointing, are the limitations of therapy driven by its modest sensory effect (and in a sense under-dosing), or is there some other basis for the limited efficacy of topical lidocaine?

Modelling pain in post-traumatic osteoarthritis of the knee

Anne-Marie Malfait — 2011-10-24

Osteoarthritis (OA) pain represents a major unmet medical need. OA is the most common joint disorder, affecting primarily the knees, hips, hands, and spine . A recent American College of Rheumatology task force concluded that pain is the most common symptom of patients with rheumatic disorders, including OA, and pain is the major reason for seeking medical care . Available pharmacologic approaches include NSAIDs or analgesics, and intra-articular viscosupplementation or steroids, which can alleviate mild-to-moderate pain in OA. Treatment of severe OA pain remains inadequate and pain is a major reason for seeking surgical intervention. The number of total joint replacements in the United States keeps increasing, with a projected 600,000 hip and 1.4million knee replacements in the year 2015 . This clearly represents an enormous economic burden.

The role of co-morbidity in accumulating risk of chronic pain

Danielle van der Windt — 2011-11-21

In this issue of Pain Dominick et al. investigate the association between physical and mental co-morbidity and the prevalence of chronic pain in a population-based sample of adults. Numerous studies have shown that many people with chronic pain have other health conditions, and that those with co-morbidities have poorer outcomes. In their new study, however, Dominick et al. take a novel approach by using the principle of allostatic load as the starting point of their analysis. Allostatic load (AL) is the term proposed by McEwen and Stellar to describe cumulative physiological wear and tear resulting from repeated efforts to adapt to stressors over time . By disrupting the physiological regulatory systems that mediate the stress response, cumulative lifetime exposure to social, psychological or environmental stressors are thought to increase the risk of age-related health problems. This means that frequent or long-term activation of the body’s stress response, important for managing acute threats, can damage the body in the long run .

What does an increased prevalence of behavioral and psychological symptoms of dementia in individuals with pain mean?

Stephen J. Gibson — 2011-11-28

There is a growing international interest in the topic of pain in persons with dementia. To date, research efforts have mainly focused on the development of valid and reliable pain assessment tools, particularly for non-verbal, older persons, many of whom may be under-treated for their pain . Other studies have examined possible differences in pain perception and report in persons with dementia . However, one major domain of research that is currently lacking relates to the behavioral, functional, psychological and social impact(s) of unrelieved pain in persons with dementia. Although there is considerable research into the psychosocial and functional impacts of a persistent pain problem in the general population, and state-of-the-art treatment models often emphasize a multidisciplinary approach to pain management in this population, there is little comparable research in persons with dementia.

One failed clinical trial (of 5HT3 antagonists) does not invalidate the concept

Matti Förster, Ralf Baron — 2011-12-12

In this issue of PAIN, Neziri et al. present data from a well-designed and very significant study of chronic low back pain patients. Pain and signs of central hypersensitivity in chronic low back pain were evaluated in 30 patients after intravenous administration tropisetron (a 5HT3 serotonin receptor antagonist) versus placebo in a randomized, double-blind cross-over trial. Unfortunately – and this much can be revealed ahead – the results turned out to be negative. In spite of this result, the study is a masterpiece of applied translational sciences: findings from basic research smoothly integrate into clinical practice. Additionally, insights from basic research were subsequently used to improve the design of the clinical study. This conclusion is convincingly illustrated by three features:

Estimate at your peril: Imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses

2011-11-07

Patient withdrawal from randomised trials is common in chronic pain trials, and more common for the experimental drug than for placebo . Different analysis strategies can be used to deal with missing data; all come with problems. Simply excluding withdrawals and analysing only for completers may appear honest, but can favour experimental treatment . The alternative is imputing (estimating) missing data by generating values for missing data points, extrapolating the last pain observation made, and carrying it forward to the end of the trial (last-observation-carried-forward, LOCF), or using baseline pain intensity measurement and zero pain relief as end-of-trial outcomes (baseline-observation-carried-forward, BOCF).

Are we neglecting spinal reorganization following nerve damage?

Nanna Brix Finnerup, Lone Nikolajsen, Troels Staehelin Jensen — 2011-11-21

Neuroplastic changes can be demonstrated in the brain following damage to the central and peripheral nervous system using imaging techniques such as positron emission tomography, functional magnetic resonance imaging, and magnetoencephalography . The possibility of assessing functional and structural changes in vivo in the human brain may partly explain why the focus in the last 2 decades has been almost exclusively on cortical reorganization, at the expense of functional and structural changes occurring in spinal and other subcortical structures. The aim of this review is to attract attention to the involvement of subcortical, particularly spinal, mechanisms in neuroplasticity after nerve injury.

Lidocaine patch (5%) produces a selective, but incomplete block of Aδ and C fibers

Elena K. Krumova, Martina Zeller, Andrea Westermann, Christoph Maier — 2011-10-13

Summary: Topical lidocaine (5%) induced a selective, but only partial blockade of Ad- and C-fibers of variable magnitude in healthy subjects, with significantly increased thermal detection and mechanical pain thresholds and decreased mechanical pain sensitivity.Abstract: Topical lidocaine (5%) leads to sufficient pain relief in only 29%–80% of treated patients, presumably by small-fiber block. The reasons for nonresponse are unclear; it may be due to different underlying pain mechanisms or partly insufficient anesthetic effect. Using quantitative sensory testing (QST) following the protocol of the DFNS (German Research Network on Neuropathic Pain), this study aims to assess the type and extent of somatosensory changes after lidocaine application in healthy volunteers. Twenty-six healthy volunteers underwent QST on the volar forearm, including thermal and mechanical detection and pain thresholds, twice before (for baseline retest reliability) and once after 6-hour simultaneous application with lidocaine patch 5% and contralateral placebo in a double-blinded manner. Pre and post differences of QST parameters were analyzed by paired t-test (Bonferroni-corrected alpha 0.0023). QST profiles did not change between the 2 baseline measurements and after the placebo application. Lidocaine application led to a significant change of only the small-fiber-associated thresholds (increase of thermal detection and mechanical pain thresholds, decrease of mechanical pain sensitivity). Tactile detection thresholds representing Aβ function remained unchanged. Interindividually, the extent of the small-fiber block varied widely (eg, thermal detection thresholds: in 54% of the subjects there were only minimal changes; in only 8% were there changes of >60% of the maximal achievable value). Topical lidocaine (5%) induces thermal hypoesthesia and pinprick hypoalgesia, suggesting an isolated but only partial block of Aδ and C fibers of unpredictable extent. Further studies must analyze the influencing factors and determine whether patients with poor analgesic effect, in particular, are those with insufficient small-fiber block.

Partial medial meniscectomy produces osteoarthritis pain-related behaviour in female C57BL/6 mice

Chancie Bayer Knights, Clive Gentry, Stuart Bevan — 2011-10-17

Summary: Partial medial meniscectomy produces progressive degenerative joint disease and accompanying evoked pain behaviours in C57Bl/6 mice, providing a model for the study of osteoarthritic pain behaviours.Abstract: Murine models of osteoarthritis (OA) provide a potentially powerful tool to elucidate mechanisms responsible for OA pain. However, few studies have examined pain behaviours in relevant OA models in mice. We have therefore characterized the time course and pharmacological sensitivities of pain-related behaviours in a model of OA in C57Bl/6 mice induced by partial medial meniscectomy. Progressive degenerative joint damage developed in a time-dependent manner and was first detected 4weeks after surgery. Pain was assessed by monitoring weight bearing, mechanical hyperalgesia, cold allodynia, mechanical allodynia and vocalisation in response to knee compression for 12weeks postsurgery. No significant weight-bearing deficits were observed during the course of the study. Significant mechanical allodynia was present in the ipsilateral hind limb from 9weeks after surgery. Hind limb mechanical hyperalgesia and cold allodynia, and increased vocalisation in response to knee compression developed in the ipsilateral limb in 2 phases. An early phase of hypersensitivities lasted for up to 3weeks and was reversed by treatment with a nonsteroidal anti-inflammatory drug (NSAID), diclofenac. Pain then resolved for several weeks, followed by a second phase of NSAID-insensitive pain after 7weeks postsurgery. During this phase, all pain behaviours could be reversed by morphine. In contrast, other analgesic drugs (paracetamol, gabapentin, and tramadol) had selective effects on only 1 or 2 modalities. Pain levels fluctuated during the second phase, with transient periods of reduced pain. At these times, underlying hypersensitivities could be unmasked by administration of naloxone, indicating that reduced pain was due to endogenous opioids.

Unpacking the burden: Understanding the relationships between chronic pain and comorbidity in the general population

Clare H. Dominick, Fiona M. Blyth, Michael K. Nicholas — 2011-11-09

Summary: Accumulated comorbid load is independently associated with chronic pain. Comorbid physical conditions increase risk additively, while anxiety/depression interacts with 2 specific conditions, increasing risk synergistically.Abstract: We investigated the association of chronic pain with physical and mental comorbidity in the New Zealand population by measuring chronic pain status separate from comorbid conditions. Models of allostatic load provided a conceptual basis for considering multi-morbidity as accumulated comorbid load and for using both discrete conditions and cumulative measures in analyses. The nationally representative cross-sectional survey data included self-reported doctor-diagnosed chronic physical and mental health conditions, Kessler 10-item scale scores, an independent measure of chronic pain, and sociodemographic characteristics. The population prevalence of chronic pain is 16.9%, and a quarter (26%) of the population report 2 or more comorbid physical conditions statistically associated with chronic pain (unadjusted P<0.01). Results indicate that accumulated comorbid load is independently associated with chronic pain. Six physical conditions independently associated with chronic pain (adjusted odds range from 1.4 to 3.9) increase the risk of chronic pain in an additive manner, and residual accumulated load further increases risk for 2 or more conditions (adjusted odds 1.6). Anxiety/depression interacts synergistically with arthritis and neck/back disorders to increase the odds of reporting chronic pain beyond an additive model. This synergistic effect is not apparent for other conditions or for additional comorbid load. Results imply that measurement of chronic pain independent of comorbid conditions and adjustment for comorbid conditions is important for more accurate prevalence estimates and understanding relationships between conditions. Future epidemiological research might usefully incorporate independent measurement of chronic pain alongside adjustment for specific physical and mental health conditions as well as accumulated comorbid load.

Association of pain with behavioral and psychiatric symptoms among nursing home residents with cognitive impairment: Results from the SHELTER study

2011-11-17

Summary: Evidence from a large sample of frail elderly people in nursing homes reveals an association between pain and behavioral and psychiatric symptoms.Abstract: The etiology of behavioral and psychiatric symptoms is generally considered to be multifactorial, and these symptoms often indicate a need for care or assistance, which may include the presence of uncontrolled pain. The aim of this cross-sectional study was to assess the association of pain with behavioral and psychiatric symptoms in a population of nursing home (NH) residents with cognitive impairment in Europe. Data are from the SHELTER project, which contains information on NH residents in 8 countries. Pain was defined as any type of physical pain or discomfort in any part of the body in the 3days before the assessment. The mean age of 2822 cognitively impaired residents entering the study was 84.1 (standard deviation 9.1)years, and 2110 (74.8%) were women. Of the total sample, 538 residents (19.1%) presented with pain. After adjusting for potential confounders, pain was significantly and positively associated with socially inappropriate behavior (odds ratio [OR] 1.37; 95% confidence interval [CI] 1.04–1.80), resistance to care (OR 1.41; 95% CI 1.08–1.83), abnormal thought process (OR 1.48; 95% CI 1.16–1.90), and delusions (OR 1.48; 95% CI 1.07–2.03). A borderline inverse association was observed with wandering (OR 0.74; 95% CI 0.55–1.00). In conclusion, this cross-sectional study provides evidence from a large sample of frail elderly showing an association between pain and behavioral and psychiatric symptoms. Treatment models that put together assessment and treatment of pain and evaluate their effect on behavioral and psychiatric symptoms are needed.

Effect of intravenous tropisetron on modulation of pain and central hypersensitivity in chronic low back pain patients

2011-11-21

Summary: Single-dose intravenous administration of tropisetron in patients with chronic low back pain failed to affect the intensity of pain and parameters of central hypersensitivity.Abstract: The activation of 5-hydroxytryptamine-3 (5-HT-3) receptors in spinal cord can enhance intrinsic spinal mechanisms of central hypersensitivity, possibly leading to exaggerated pain responses. Clinical studies suggest that 5-HT-3 receptor antagonists may have an analgesic effect. This randomized, double-blind, placebo-controlled crossover study tested the hypothesis that the 5-HT-3 receptor antagonist tropisetron attenuates pain and central hypersensitivity in patients with chronic low back pain. Thirty patients with chronic low back pain, 15 of whom were women (aged 53±14years) and 15 men (aged 48±14years), were studied. A single intravenous injection of 0.9% saline solution, tropisetron 2mg, and tropisetron 5mg was administrated in 3 different sessions, in a double-blind crossover manner. The main outcome was the visual analogue scale (VAS) score of spontaneous low back pain before, and 15, 30, 60, and 90minutes after drug administration. Secondary outcomes were nociceptive withdrawal reflexes to single and repeated electrical stimulation, area of reflex receptive fields, pressure pain detection and tolerance thresholds, conditioned pain modulation, and area of clinical pain. The data were analyzed by analysis of variance and panel multiple regressions. All 3 treatments reduced VAS scores. However, there was no statistically significant difference between tropisetron and placebo in VAS scores. Compared to placebo, tropisetron produced a statistically significant increase in pain threshold after single electrical stimulation, but no difference in all other secondary outcomes was found. A single-dose intravenous administration of tropisetron in patients with chronic low back pain had no significant specific effect on intensity of pain and most parameters of central hypersensitivity.

A randomized controlled evaluation of an online chronic pain self management program

Linda S. Ruehlman, Paul Karoly, Craig Enders — 2011-12-02

Summary: Use of the Chronic Pain Management Program was associated with significant decreases in pain-related, functional, and mental health outcomes and an increase in pain knowledge.Abstract: Internet-based educational and therapeutic programs (e-health applications) are becoming increasingly popular for a variety of psychological and physical disorders. We tested the efficacy of an online Chronic Pain Management Program, a comprehensive, fully self-directed and self-paced system that integrates social networking features and self-management tools into an interactive learning environment. Of 305 adult participants (196 women, 109 men), a total of 162 individuals with chronic pain were randomly assigned unsupervised access to the program for approximately 6weeks; 143 were assigned to the wait-listed control group with treatment as usual. A comprehensive assessment was administered before the study and approximately 7 and 14weeks thereafter. All recruitment, data collection, and participant involvement took place online. Participation was fully self-paced, permitting the evaluation of program effectiveness under real-world conditions. Intent-to-treat analysis that used linear growth models was used as the primary analytic tool. Results indicated that program utilization was associated with significant decreases in pain severity, pain-related interference and emotional burden, perceived disability, catastrophizing, and pain-induced fear. Further, program use led to significant declines in depression, anxiety, and stress. Finally, as compared to the wait-listed control group, the experimental group displayed a significant increase in knowledge about the principles of chronic pain and its management. Study limitations are considered, including the recognition that not all persons with chronic pain are necessarily good candidates for self-initiated, self-paced, interactive learning.

Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy persons

2011-11-30

Summary: Patients with central pain have a more hyperresponsive intralaminar thalamus and sensory–motor cortex than healthy individuals or patients with central lesions and painless sensory loss.Abstract: Patients with central pain (CP) typically have chronic pain within an area of reduced pain and temperature sensation, suggesting an impairment of endogenous pain modulation mechanisms. We tested the hypothesis that some brain structures normally activated by cutaneous heat stimulation would be hyperresponsive among patients with CP but not among patients with a central nervous system lesion causing a loss of heat or nociceptive sensation with no pain (NP). We used H215O positron emission tomography to measure, in 15 healthy control participants, 10 NP patients, and 10 CP patients, increases in regional cerebral blood flow among volumes of interest (VOI) from the resting (no stimulus) condition during bilateral contact heat stimulation at heat detection, heat pain threshold, and heat pain tolerance levels. Both patient groups had a reduced perception of heat intensity and unpleasantness on the clinically affected side and a bilateral impairment of heat detection. Compared with the HC group, both NP and CP patients had more hyperactive and hypoactive VOI in the resting state and more hyperresponsive and hyporesponsive VOI during heat stimulation. Compared with NP patients, CP patients had more hyperresponsive VOI in the intralaminar thalamus and sensory–motor cortex during heat stimulation. Our results show that focal CNS lesions produce bilateral sensory deficits and widespread changes in the nociceptive excitability of the brain. The increased nociceptive excitability within the intralaminar thalamus and sensory–motor cortex of our sample of CP patients suggests an underlying pathophysiology for the pain in some central pain syndromes.

Patient perspective on herpes zoster and its complications: An observational prospective study in patients aged over 50years in general practice

2011-12-05

Summary: Despite early diagnosis and treatment with antiviral agents, many herpes zoster patients report persistent pain and marked long-term reduction in health-related quality of life.Abstract: Understanding the effect of herpes zoster and zoster-related pain should inform care to improve health-related quality of life in elderly patients. A 12-month, longitudinal, prospective, multicenter observational study conducted in primary care in France enrolled patients aged ⩾50years with acute eruptive herpes zoster. Patient-reported zoster-related pain was assessed by validated questionnaires (Douleur Neuropathique en 4 Questions [DN4], Zoster Brief Pain Inventory [ZBPI], and Neuropathic Pain Symptom Inventory [NPSI]) on days 0 and 15, and at months 1, 3, 6, 9, and 12. Health-related quality of life was assessed by the 12-item short-form health survey (SF-12) and the Hospital Anxiety and Depression scale on day 0 and at months 3, 6, and 12. Of 1358 patients included, 1032 completed follow-up. Mean±standard deviation age was 67.7±10.7 (range, 50–95) years; 62.2% were women. Most patients (94.1%) were prescribed antiviral drugs. The prevalence of zoster-related pain on day 0 and at months 3, 6, 9, and 12 was 79.6%, 11.6%, 8.5%, 7.4%, and 6.0%, respectively. Patients with persistent pain had lower scores on the physical and mental component summaries of the SF-12 and the ZBPI interference score than those without pain. By logistic regression analysis, main predictive factors on day 0 for postherpetic neuralgia at month 3 were age, male sex, ZBPI interference score, Physical Component Summary score of the SF-12, and neuropathic quality of pain (DN4 score ⩾4). Despite early diagnosis and treatment with antiviral agents, many patients with herpes zoster experience persistent pain and marked long-term reduction in health-related quality of life.

Are both the sensory and the affective dimensions of pain encoded in the face?

Miriam Kunz, Stefan Lautenbacher, Nadine LeBlanc, Pierre Rainville — 2011-11-23

Summary: The facial expression of pain is a multidimensional response system that differentially encodes affective and sensory pain qualities.Abstract: The facial expression of pain plays a crucial role in pain communication and pain diagnostics. Despite its importance, it has remained unknown which dimensions of pain (sensory and/or affective) are encoded in the face. To answer this question, we used a well-established cognitive strategy (suggestions) to differentially modulate the sensory and affective dimensions of pain and investigate the effect of this manipulation on facial responses to experimental pain. Twenty-two subjects participated in the study. Their facial expressions, pain intensity, and unpleasantness ratings as well as skin conductance responses to tonic and phasic heat pain were assessed before and after suggestions directed toward increase in affective and sensory qualities of pain, respectively, were provided. Facial expressions were analyzed with the Facial Action Coding system. As expected, suggestions designed to increase the sensory dimension produced a selective increase in pain intensity ratings, whereas suggestions designed to increase pain affect produced increased unpleasantness ratings and elevated skin conductance responses. Furthermore, suggestions for either increased pain affect or pain sensation produced selective modulations in facial response patterns, with facial movements around the eyes mostly encoding sensory aspects, whereas movements of the eyebrows and of the upper lip were closely associated with the affective pain dimension. The facial expression of pain is a multidimensional response system that differentially encodes affective and sensory pain qualities. This differential encoding might have evolved to guarantee that the specific characteristics of one’s pain experience are facially communicated, thereby ensuring adequate help and support from others.

Prevalence and aetiology of neuropathic pain in cancer patients: A systematic review

2011-11-24

Summary: One in 5 cancer pains are neuropathic, and 2 in 5 patients have neuropathic pain. Standard approaches to assess cancer neuropathic pain are needed.Abstract: Pain in cancer patients remains common and is often associated with insufficient prescribing of targeted analgesia. An explanation for undertreatment could be the failure to identify neuropathic pain mechanisms, which require additional prescribing strategies. We wanted to identify the prevalence of neuropathic mechanisms in patients with cancer pain to highlight the need for detailed assessment and to support the development of an international classification system for cancer pain. We searched for studies that included adult and teenage patients (age above 12years), with active cancer and who reported pain, and in which a clinical assessment of their pain had been made. We found 22 eligible studies that reported on 13,683 patients. Clinical assessment methods varied, and only 14 studies reported confirmatory testing for either sensory abnormality or diagnostic lesion to corroborate a diagnosis of neuropathic pain. We calculated that the prevalence of patients with neuropathic pain (95% confidence interval) varied from a conservative estimate of 19% (9.4% to 28.4%) to a liberal estimate of 39.1% (28.9% to 49.5%) when patients with mixed pain were included. The prevalence of pain with a neuropathic mechanism (95% confidence interval) ranged from a conservative estimate of 18.7% (15.3% to 22.1%) to a liberal estimate of 21.4% (15.2% to 27.6%) of all recorded cancer pains. The proportion of pain caused by cancer treatment was higher in neuropathic pain compared with all types of cancer pain. A standardised approach or taxonomy used for assessing neuropathic pain in patients with cancer is needed to improve treatment outcomes.

The complement component C5a receptor mediates pain and inflammation in a postsurgical pain model

2011-12-02

Summary: Complement C5a receptor deletion prevents heat and mechanical nociceptive responses and generation of inflammatory and nociceptive mediators in superficial and deep tissues after incision.Abstract: The complement system is an important part of innate immunity. Complement activation generates a set of effector molecules with diverse biological functions. C5a is a crucial terminal component of the complement cascade. Several reports suggest that C5a can support nociceptive sensitization and inflammation in various models, including models of incisional pain. However, information concerning the differential effects of C5a on specific modalities of nociception, the role of C5a in supporting neutrophil infiltration, secondary nociceptive mediator generation, and the location of the relevant populations of C5a receptors supporting incisional sensitization are needed. In these studies we utilized C5a receptor-null mice (C5aR−/−) and matched controls to study nociceptive changes after hind paw incision. Heat hyperalgesia and mechanical allodynia were measured for 4days after incision. We also followed hind paw edema, wound area neutrophil infiltration using the myeloperoxidase assay, and interleukin-1β and nerve growth factor levels using both enzyme-linked immunosorbent assay and immunohistochemical techniques. The main findings were: (1) Heat vs mechanical nociceptive sensitization after incision were differentially reduced in C5aR−/− mice, with thermal sensitization affected throughout the postincisional period but mechanical sensitization affected only at later time points; (2) Edema developed after incision in wild-type mice but only slightly and transiently in C5aR−/− mice, and (3) Deletion of C5aR blocked interleukin-1β and nerve growth factor production near the wound site. These findings demonstrate that the complement system component C5a is a novel biomarker and mediator associated with postsurgical nociceptive processing. C5aR may provide a novel target for the control of pain and inflammation after surgery.

Effects of spatially targeted transcutaneous electrical nerve stimulation using an electrode array that measures skin resistance on pain and mobility in patients with osteoarthritis in the knee: A randomized controlled trial

2011-11-28

Summary: An electrode array enabled transcutaneous electrical nerve stimulation (TENS) treatment at sites of lowest skin resistance which reduced movement-related osteoarthritic knee pain more than adjacent TENS treatment sites.Abstract: A novel device was developed that measured local electrical skin resistance and generated pulsed local electrical currents that were delivered across the skin around the knee for patients with osteoarthritis (termed eBrace TENS). Currents were delivered using an electrode array of 16 small circular electrode elements so that stimulation could be spatially targeted. The aim of this study was to investigate the effects of spatially targeted transcutaneous electrical nerve stimulation (TENS) to points of low skin resistance on pain relief and mobility in osteoarthritis of the knee (OAK). A randomised, controlled, 3-arm, parallel-group trial was designed that compared pain and function following a 30 to 45 minute intervention of TENS at specific locations depending on the local electrical skin resistance. Pain intensity by the visual analogue scale (VAS), 6-minute walk test, maximum voluntary contraction (MVC), and range-of-motion (ROM) were the primary outcomes. Lowest-resistance TENS reduced pain intensity during walking relative to resting baseline compared with random TENS (95% confidence interval of the difference: −20.8mm, −1.26mm). There were no statistically significant differences between groups in distance during the walk test, maximum voluntary contraction (MVC) or range-of-motion (ROM) measures or WOMAC scores. In conclusion, we provide evidence that use of a matrix electrode that spatially targets strong nonpainful TENS for 30 to 45minutes at sites of low resistance can reduce pain intensity at rest and during walking.

Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: An fMRI study in healthy placebo responders and nonresponders

2011-12-05

Summary: In this placebo analgesia study, the expectation of pain relief reduced perceived painfulness of visceral stimuli, which was associated with activity changes in thalamus, and prefrontal and somatosensory cortices.Abstract: This functional magnetic resonance imaging study analysed the behavioural and neural responses during expectation-mediated placebo analgesia in a rectal pain model in healthy subjects. In N=36 healthy subjects, the blood oxygen level–dependent (BOLD) response during cued anticipation and painful rectal stimulation was measured. Using a within-subject design, placebo analgesia was induced by changing expectations regarding the probability of receiving an analgesic drug to 0%, 50%, and 100%. Placebo responders were identified by median split based on pain reduction (0% to 100% conditions), and changes in neural activation correlating with pain reduction in the 0% and 100% conditions were assessed in a regions-of-interest analysis. Expectation of pain relief resulted in overall reductions in pain and urge to defecate, and this response was significantly more pronounced in responders. Within responders, pain reduction correlated with reduced activation of dorsolateral and ventrolateral prefrontal cortices, somatosensory cortex, and thalamus during cued anticipation (paired t tests on the contrast 0%>100%); during painful stimulation, pain reduction correlated with reduced activation of the thalamus. Compared with nonresponders, responders demonstrated greater placebo-induced decreases in activation of dorsolateral prefrontal cortex during anticipation and in somatosensory cortex, posterior cingulate cortex, and thalamus during pain. In conclusion, the expectation of pain relief can substantially change perceived painfulness of visceral stimuli, which is associated with activity changes in the thalamus, prefrontal, and somatosensory cortices. Placebo analgesia constitutes a paradigm to elucidate psychological components of the pain response relevant to the pathophysiology and treatment of chronic abdominal pain.

Double spikes to single electrical stimulation correlates to spontaneous activity of nociceptors in painful neuropathy patients

2011-12-09

Summary: Spontaneously active C nociceptors in painful neuropathy patients reveal multiple firing to single electrical stimuli, suggesting that axonal hyperexcitability contributes to neuropathic pain.Abstract: Multiple firing of C nociceptors upon a single electrical stimulus has been suggested to be a possible mechanism contributing to neuropathic pain. Because this phenomenon maybe based on a unidirectional conduction block, it might also be related to neuropathic changes without a direct link to pain. We investigated painful neuropathy patients using microneurography and analysed nociceptors for the occurrence of multiple spiking and spontaneous activity. In 11 of 105 nociceptors, double spiking was found, with 1fibre even showing triple spikes on electrical stimulation. The interval between the main action potential and the multiple spikes ranged from 13 to 100ms. There was a significant association between spontaneous activity and multiple spiking in C nociceptors, with spontaneous activity being present in 9 of 11 fibres with multiple spiking, but only in 21 of 94 nociceptors without multiple spiking (P<.005, Fisher exact test). Among the 75 C nociceptors without spontaneous activity, only 2 nociceptors showed multiple spiking. In 8 neuropathy patients without pain, double spiking was found only in 4 of 90 nociceptors. Multiple spiking of nociceptors coincides with spontaneous activity in nociceptors of painful neuropathy patients. We therefore conclude that rather than being a generic sign of neuropathy, multiple spiking is linked to axonal hyperexcitability and spontaneous activity of nociceptors. It is still unclear whether it also is mechanistically related to the clinical pain level.

Unmyelinated and myelinated skin nerve damage in Guillain–Barré syndrome: Correlation with pain and recovery

2011-12-12

Summary: Unmyelinated and myelinated skin nerves are diffusely affected in Guillain–Barré syndrome and its variants. Intraepidermal nerve fiber density declines early, remains low over time, correlates with pain severity in the acute phase, and may predict long-term disability.Abstract: We performed a prospective study in 32 patients with Guillain–Barré syndrome (GBS) or its variants to correlate intraepidermal nerve fiber density (IENFD) at the distal leg and lumbar region with pain, autonomic dysfunction, and outcome. In the acute phase, IENFD was reduced in 60% and 61.9% of patients at the distal leg and lumbar region, respectively. In the acute phase, 43.7% of patients complained of neuropathic pain. Their IENFD at the distal leg was significantly lower than in patients without pain (P<.001) and correlated with pain intensity (rs=−0.51; P=.003). Intriguingly, also patients with the pure motor variant of GBS and pain had low IENFD. At 6-month follow-up, only 3 patients complained of persisting neuropathic pain, whereas 3 patients reported late-onset pain symptoms. IENFD in the acute phase did not predict presence or intensity of pain at 6-month follow-up. IENFD in the acute phase did not correlate with clinical dysautonomia or GBS severity at nadir. However, it correlated with poorer GBS disability score at 6months (P=.04), GBS score at nadir (P=.03), and clinically probable dysautonomia (P=.004). At 6-month follow-up, median IENFD remained significantly low both at the distal leg (P=.024) and lumbar region (P=.005). Double and triple staining confocal microscope studies showed diffuse damage of myelinated dermal nerves along with axonal degeneration, and mononuclear cell infiltration. Unmyelinated and myelinated skin nerves are diffusely affected in GBS and its variants, including the pure motor form. IENFD declines early, remains low over time, correlates with pain severity in the acute phase, and may predict long-term disability.

Purinergic receptor P2Y1 regulates polymodal C-fiber thermal thresholds and sensory neuron phenotypic switching during peripheral inflammation

2011-12-02

Summary: The purinergic receptor P2Y1 modulates the thermal sensitivity of polymodal fibers and the functional phenotype of TRPV1-containing cutaneous fibers following inflammation.Abstract: We have recently found that, following complete Freund’s adjuvant (CFA)-induced inflammation, cutaneous polymodal nociceptors (CPM) lacking the transient receptor potential vanilloid 1 (TRPV1) are sensitized to heat stimuli. In order to determine possible mechanisms playing a role in this change, we examined gene expression in the L2/L3 sensory ganglia following CFA injection into the hairy hind paw skin and found that G-protein-coupled purinoreceptor P2Y1 expression was increased. This receptor is of particular interest, as most CPMs innervating mouse hairy skin bind isolectin B4, which co-localizes with P2Y1. Additionally, our recent findings have shown that cutaneous CPMs in P2Y1−/− mice displayed significantly reduced thermal sensitivity. Together, these findings suggested a possible role for P2Y1 in inflammation-induced heat sensitization in these fibers. To test this hypothesis, we utilized our in vivo small interfering RNA technique to knock down the inflammation-induced increase in P2Y1 expression and then examined the functional effects using ex vivo recording. We found that the normal reduction of heat thresholds in CPM fibers induced by CFA was completely blocked by inhibition of P2Y1. Surprisingly, inhibition of P2Y1 during inflammation also significantly increased the number of CPM neurons expressing TRPV1 without a change in the total number of TRPV1-positive cells in the L2 and L3 dorsal root ganglia. These results show that the inflammation-induced enhanced expression of P2Y1 is required for normal heat sensitization of cutaneous CPM fibers. They also suggest that P2Y1 plays a role in the maintenance of phenotype in cutaneous afferent fibers containing TRPV1.

Experimental characterization of the effects of acute stresslike doses of hydrocortisone in human neurogenic hyperalgesia models

Gilles P.N. Michaux, Walter Magerl, Fernand Anton, Rolf-Detlef Treede — 2011-12-19

Summary: A moderate dose of hydrocortisone reduced capsaicin-induced secondary hyperalgesia, but not pain to pinprick suggesting an antihyperalgesic action of glucocorticoids consistent with protection against maladaptive pain plasticity.Abstract: Relative hypothalamic-pituitary-adrenal axis dysfunction has been described as a common feature of several dysfunctional pain syndromes, and its end hormone cortisol may thus constitute a protective factor against the development of chronic pain. We investigated the potential influence of experimentally induced stresslike hypercortisolism on the induction of neurogenic hyperalgesia using 2 human surrogate models: secondary hyperalgesia after intradermal capsaicin injection into the volar forearm, and perceptual windup in normal skin. In a double-blind, placebo-controlled, randomized, crossover study, a psychophysical study was performed in 10 healthy subjects (median age 23years) examining the effects of 40mg orally administered hydrocortisone. Numeric pain ratings were assessed for punctate pinprick and light touch stimuli applied to the zone of secondary hyperalgesia adjacent to the capsaicin injection and to the contralateral control side. In addition, visual analog ratings were assessed for repetitive pinprick stimulation of the noninjected arm. Hydrocortisone significantly attenuated the late phase of capsaicin-induced pain by nearly 50%, and hyperalgesia to pinprick stimuli by 33% (both P<.05). Baseline mechanical pain and dynamic mechanical allodynia remained unaltered. Temporal summation (windup) to mechanical pain stimuli and electrically induced windup of second pain (tested in an independent cohort of 10 other subjects) were also unchanged. The selective effects of hydrocortisone on pinprick hyperalgesia but not pinprick pain suggest an antihyperalgesic rather than analgesic effect. The findings suggest that hypothalamic-pituitary-adrenal axis reactivity might be an important mechanism in resilience to dysfunctional pain syndromes.

Impact of pain on the course of depressive and anxiety disorders

2011-12-12

Summary: The course of depressive and anxiety disorders in a large, longitudinal cohort study was poorer when pain was present, which was partly mediated by baseline psychiatric characteristics.Abstract: The combination of pain and depression or anxiety is commonly seen in clinical practice. Little is known about the influence of pain on psychopathology over time, as previous studies have been mainly cross-sectional. The objectives of this study are to determine the impact of pain on the course of depressive and/or anxiety disorders, and investigate to what extent the association between pain and course of these mental disorders is mediated by psychiatric characteristics. Data from the Netherlands Study of Depression and Anxiety (NESDA), collected between 2004 and 2009, were used. A total of 1209 participants with a depressive and/or anxiety disorder at baseline were followed up for 2years. Baseline pain was assessed by location, duration, use of pain medication, and severity (based on Chronic Pain Grade). Course of depressive and anxiety disorders was assessed by Composite International Diagnostic Interview (CIDI) and Life Chart Interview. A higher number of pain locations (OR=1.10; P=.008), joint pain (OR=1.64; P<.001), ⩾90days of pain (OR=1.40; P=.009), daily use of pain medication (OR=1.57; P=.047), and a higher Chronic Pain Grade score (OR=1.27; P<.001) were associated with worse course of depressive and anxiety disorders. These associations were largely mediated by baseline severity of the mental disorder. However, joint pain remained associated with a worse course independent of baseline psychiatric characteristics. This study shows that patients with pain are more prone to a chronic course of depressive and anxiety disorders. More attention to pain seems to be necessary when diagnosing and treating these disorders. Future research should focus on treatment modalities for this co-occurrence, with joint pain in particular.

Too sick for school? Parent influences on school functioning among children with chronic pain

Deirdre E. Logan, Laura E. Simons, Elizabeth A. Carpino — 2011-12-12

Summary: Parental protective responses to pain mediated the association between parent pain catastrophizing and child school functioning as assessed by school attendance and subjective report. Promoting adaptive parental responses to pain may enhance success at school.Abstract: Parental responses to children with chronic pain have been shown to influence the extent of the child’s functional disability, but these associations have not been well studied in relation to children’s pain-related school functioning. The current study tests the hypothesis that parental pain catastrophizing and parental protective responses to child pain influence the extent of school impairment in children with chronic pain. A mediational model was tested to determine whether parental protective behaviors serve a mediating role between parental pain catastrophizing and child school impairment. Study participants were a clinical sample of 350 children ages 8–17 years with chronic pain and their parents. Measures of pain characteristics, demographic characteristics, child depressive symptoms, school attendance rates, overall school functioning, parental pain catastrophizing, and parental protective responses to pain were collected. Results show that, controlling for the known influences of pain intensity and child depressive symptoms, parental pain catastrophizing and parental protective responses to child pain each independently predict child school attendance rates and reports of overall school impairment. Parental protectiveness was found to mediate the association between parental cognitions (i.e., parent pain catastrophizing) and child school functioning outcomes. These findings underscore the importance of intervening with parents to foster parental responses to child pain that help children engage and succeed in the school environment despite pain.

Sex similarities and differences in pain-related periaqueductal gray connectivity

Clas Linnman, Jan-Carl Beucke, Karin B. Jensen, Randy L. Gollub, Jian Kong — 2011-12-09

Summary: Pain induces changes in the functional connectivity between the periaqueductal gray and the cingulate, and, in men more than women, connectivity changes to the amygdala.Abstract: This study investigated sex similarities and differences in pain-related functional connectivity in 60 healthy subjects. We used functional magnetic resonance imaging and psychophysiological interaction analysis to investigate how exposure to low vs high experimental pain modulates the functional connectivity of the periaqueductal gray (PAG). We found no sex differences in pain thresholds, and in both men and women, the PAG was more functionally connected with the somatosensory cortex, the supplemental motor area, cerebellum, and thalamus during high pain, consistent with anatomic predictions. Twenty-six men displayed a pain-induced increase in PAG functional connectivity with the amygdala caudate and putamen that was not observed in women. In an extensive literature search, we found that female animals have been largely overlooked when the connections between the PAG and the amygdala have been described, and that women are systematically understudied with regard to endogenous pain inhibition. Our results emphasize the importance of including both male and female subjects when studying basic mechanisms of pain processing, and point toward a possible sex difference in endogenous pain inhibition.

Practice, practitioner, or placebo? A multifactorial, mixed-methods randomized controlled trial of acupuncture

2011-12-14

Summary: This multifactorial mixed-methods randomized controlled trial quantified the specific and nonspecific factors of acupuncture, and found that the practitioner, not the treatment, has the strongest effect on outcome.Abstract: The nonspecific effects of acupuncture are well documented; we wished to quantify these factors in osteoarthritic (OA) pain, examining needling, the consultation, and the practitioner. In a prospective randomised, single-blind, placebo-controlled, multifactorial, mixed-methods trial, 221 patients with OA awaiting joint replacement surgery were recruited. Interventions were acupuncture, Streitberger placebo acupuncture, and mock electrical stimulation, each with empathic or nonempathic consultations. Interventions involved eight 30-minute treatments over 4weeks. The primary outcome was pain (VAS) at 1week posttreatment. Face-to-face qualitative interviews were conducted (purposive sample, 27 participants). Improvements occurred from baseline for all interventions with no significant differences between real and placebo acupuncture (mean difference −2.7mm, 95% confidence intervals −9.0 to 3.6; P=.40) or mock stimulation (−3.9, −10.4 to 2.7; P=.25). Empathic consultations did not affect pain (3.0mm, −2.2 to 8.2; P=.26) but practitioner 3 achieved greater analgesia than practitioner 2 (10.9, 3.9 to 18.0; P=.002). Qualitative analysis indicated that patients’ beliefs about treatment veracity and confidence in outcomes were reciprocally linked. The supportive nature of the trial attenuated differences between the different consultation styles. Improvements occurred from baseline, but acupuncture has no specific efficacy over either placebo. The individual practitioner and the patient’s belief had a significant effect on outcome. The 2 placebos were equally as effective and credible as acupuncture. Needle and nonneedle placebos are equivalent. An unknown characteristic of the treating practitioner predicts outcome, as does the patient’s belief (independently). Beliefs about treatment veracity shape how patients self-report outcome, complicating and confounding study interpretation.

Differential effects of experimental central sensitization on the time-course and magnitude of offset analgesia

Katherine T. Martucci, Marc D. Yelle, Robert C. Coghill — 2011-12-08

Summary: Despite observations of thermal hyperalgesia, mechanical allodynia, and temporal alterations of offset analgesia, the magnitude of offset analgesia remains unaltered following capsaicin-heat and heat-only sensitization.Abstract: Pain perception is temporally altered during states of chronic pain and acute central sensitization; however, the mechanisms contributing to temporal processing of nociceptive information remain poorly understood. Offset analgesia is a phenomenon that reflects the presence of temporal contrast mechanisms for nociceptive information and can provide an end point to study temporal aspects of pain processing. In order to investigate whether offset analgesia is disrupted during sensitized states, 23 healthy volunteers provided real-time continuous visual analogue scale responses to noxious heat stimuli that evoke offset analgesia. Responses to these stimuli were evaluated during capsaicin-heat sensitization (45°C stimulus, capsaicin cream 0.1%) and heat-only sensitization (40°C stimulus, placebo cream). Capsaicin-heat sensitization produced significantly larger regions of secondary mechanical allodynia compared to heat-only sensitization. Although areas of mechanical allodynia were positively related to individual differences in heat pain sensitivity, this relationship was altered at later time points after capsaicin-heat sensitization. Heat hyperalgesia was observed in the secondary region following both capsaicin-heat and heat-only sensitization. Increased latencies to maximal offset analgesia and prolonged aftersensations were observed only in the primary regions directly treated by capsaicin-heat or heat alone. However, contrary to the hypothesis that offset analgesia would be reduced following capsaicin-heat sensitization, the magnitude of offset analgesia remained remarkably intact after both capsaicin-heat and heat-only sensitization in zones of both primary and secondary mechanical allodynia. These data indicate that offset analgesia is a robust phenomenon and engages mechanisms that interact minimally with those supporting acute central sensitization.

Menthol pain relief through cumulative inactivation of voltage-gated sodium channels

2011-12-15

Summary: Menthol acts a state-selective blocker of voltage-gated Na+ channels and causes antinociception in mice, providing a molecular basis for its analgesic action.Abstract: Menthol is a natural compound of plant origin known to produce cool sensation via the activation of the TRPM8 channel. It is also frequently part of topical analgesic drugs available in a pharmacy, although its mechanism of action is still unknown. Compelling evidence indicates that voltage-gated Na+ channels are critical for experiencing pain sensation. We tested the hypothesis that menthol may block voltage-gated Na+ channels in dorsal root ganglion (DRG) neurons. By use of a patch clamp, we evaluated the effects of menthol application on tetrodotoxin (TTX)-resistant Nav1.8 and Nav1.9 channel subtypes in DRG neurons, and on TTX-sensitive Na+ channels in immortalized DRG neuron-derived F11 cells. The results indicate that menthol inhibits Na+ channels in a concentration-, voltage-, and frequency-dependent manner. Menthol promoted fast and slow inactivation states, causing use-dependent depression of Na+ channel activity. In current clamp recordings, menthol inhibited firing at high-frequency stimulation with minimal effects on normal neuronal activity. We found that low concentrations of menthol cause analgesia in mice, relieving pain produced by a Na+ channel-targeting toxin. We conclude that menthol is a state-selective blocker of Nav1.8, Nav1.9, and TTX-sensitive Na+ channels, indicating a role for Na+ channel blockade in the efficacy of menthol as topical analgesic compound.

Immune conditions associated with CD4+ T effector-induced opioid release and analgesia

2011-12-22

Summary: Endogenous analgesia is a delta opioid-mediated CD4+ T effector function, dependent on recognition of the antigen within the inflammatory site.Abstract: Effector CD4+ T lymphocytes generated in response to antigens produce endogenous opioids. Thus, in addition to their critical role in host defenses against pathogens, effector CD4+ T lymphocytes contribute to relieving inflammatory pain. In this study, we investigated mechanisms of opioid release by antigen-experienced effector CD4+ T cells that leave draining lymph nodes and come back into the inflammatory site. Effector antigen-primed CD4+ T lymphocytes generated in vitro were intravenously injected into nude mice previously immunized with either cognate or irrelevant antigens in complete Freund adjuvant (CFA). CFA-induced mechanical hyperalgesia was only reduced in mice immunized with cognate antigen. Thus, antinociceptive activity of effector CD4+ T cells requires the presence of the antigen for which they are specific within the inflammatory site. Accordingly, analgesia was inhibited by neutralizing cognate T cell receptor-mediated interaction between effector CD4+ T lymphocytes and antigen-presenting cells at the site of inflammation. Analgesia was observed by transferring effector CD4+ T lymphocytes with Th1 or Th2 phenotype, suggesting that antinociceptive activity is a fundamental property of effector CD4+ T lymphocytes irrespective of their effector functions. Based on the use of agonists and antagonists selective for each of the opioid receptor subclasses, we showed that analgesia induced by T cell-derived opioids is elicited via activation of δ-type opioid receptors in the periphery. Thus, the antinociceptive activity is a fundamental property associated with the effector phase of adaptive immunity, which is driven by recognition of the cognate antigen by effector CD4+ T lymphocytes at the inflammatory site.

Group cognitive behavioural interventions for low back pain in primary care: Extended follow-up of the Back Skills Training Trial (ISRCTN54717854)

2012-01-09

Summary: Long-term follow-up of a randomised controlled trial of a cognitive behavioural intervention for low back pain indicates that effects on disability and pain are maintained to at least 34 months.Abstract: Group cognitive behavioural intervention (CBI) is effective in reducing low back pain and disability over a 12-month period, in comparison to best practice advice in primary care. The aim was to study the effects of this CBI beyond 12 months. We undertook an extended follow-up of our original randomised, controlled trial of a group CBI and best practice advice in primary care, in comparison to best practice advice alone. Participants were mailed a questionnaire including measures of disability, pain, health services resource use, and health-related quality of life. The time of extended follow-up ranged between 20 and 50 months (mean 34 months). Fifty-six percent (395 of 701) of the original cohort provided extended follow-up. Those who responded were older and had less disability and pain at baseline than did the original trial cohort. After 12 months, the improvements in pain and disability observed with CBI were sustained. For disability measures, the treatment difference in favour of CBI persisted (mean difference 1.3 Roland and Morris Disability Questionnaire points, 95% confidence interval 0.27 to 2.26; 5.5 Modified von Korff Scale disability points, 95% confidence interval 0.27 to 10.64). There was no between-group difference in Modified von Korff Scale pain outcomes. The results suggest that the effects of a group CBI are maintained up to an average of 34 months. Although pain improves in response to best practice advice, longer-term recovery of disability remains substantially less.

Noppers et al., Drug-induced liver injury following a reported course of ketamine treatment for chronic pain in CRPS type I patients. A report on 3 cases. Pain 2011;152:2173–8

Dagmar Westerling, Peter Lindblom — 2011-12-09

We have read with great interest the article by Noppers et al. , as well as the accompanying editorial , on liver injury following repeated intravenous ketamine treatment of complex regional pain syndrome (CRPS) type I. Ketamine may be a useful alternative in the treatment of neuropathic pain and CRPS . In the perioperative period or following trauma, patients in severe pain may benefit from subanesthetic ketamine infusions as part of a balanced analgesia .

S(+)-Ketamine analgesic drug dose

2011-12-12

We thank Drs. Westerling and Lindblom for their careful reading of our paper on drug-induced liver injury following a repeated course of S(+)-ketamine treatment for chronic pain in patients with complex regional pain syndrome type I (CRPS-I) . We agree with the authors that the increase in liver enzymes in 3 out of 6 patients treated with a repeated intravenous infusion is a serious issue and, as we conclude in our paper, indicates the need to monitor all patients receiving long-term or repeated ketamine infusions for any treatment.