Test-Retest and Inter-Examiner Reliability of a Novel Bedside Quantitative Sensory Testing Battery in Postherpetic Neuralgia Patients.

In health and disease, the somatosensory system has been interrogated with standardized research techniques, collectively referred to as quantitative sensory testing (QST). In neuropathic pain, QST has been used to characterize multiple sensory derangements. However, the use of QST outside the lab has been limited by several factors, including a lack of standardization, variability in procedural technique, and duration of testing that would be unacceptable for clinic. To address these shortcomings, the Neuropathic Pain Research Consortium designed an easy and low-cost "bedside" QST procedure. To test the hypothesis that this procedure would be clinically reliable over time and across different examiners, a multisite, blinded study was performed in subjects with postherpetic neuralgia. Generally, agreement between 2 examiners and over 2 study visits with 1 examiner was high. Additionally, intraclass correlation coefficients and Kappa statistics calculated showed that the battery of QST tests included were highly reliable. Interestingly, mechanical modalities (light brush, pinprick, pressure, and vibration) showed the highest reliability. The least reliable modalities were cool (room temperature) and warmth (38°C). These data demonstrate that the Neuropathic Pain Research Consortium beside QST protocol is reliable across examiner and over time, providing a validated QST tool for use in clinical practice and clinical trials. PERSPECTIVE: This blinded, multicenter trial in 32 patients with postherpetic neuralgia demonstrates bedside QST is reliable and suitable as a clinical trial outcome. The novel bedside battery could be used in clinical trials or in clinical practice over time given the reliability data presented in this article.

Relationships Among Pain Quality, Pain Impact, and Overall Improvement in Patients with Postherpetic Neuralgia Treated with Gastroretentive Gabapentin.

OBJECTIVE: To determine the effect of gastroretentive gabapentin (G-GR) and describe relationships among pain quality, pain impact, and overall-improvement scores in patients with postherpetic neuralgia (PHN). METHODS: Analyses of integrated data from two Phase 3 studies in which PHN patients received once-daily G-GR 1,800 mg (n = 356) or placebo (n = 363). Neuropathic pain scale (NPS) and brief pain inventory (BPI) were completed at baseline and Week 10; patients' global impression of change (PGIC) at Week 10. Regression analyses described relationships among changes in the NPS, BPI, and PGIC scores. RESULTS: Compared with placebo, G-GR patients had significant reductions from baseline in individual NPS measures except cold pain (P < 0.05); composite NPS scores (P ≤ 0.003); BPI pain scores (P < 0.05); three individual (mood, sleep, and enjoyment of life) and the average of BPI interference scores (P < 0.05). Clinically significant improvements in BPI interference scores (except walking ability) were positively correlated with reductions in BPI and NPS pain (except dull and cold pain), and with improvements on the PGIC. Reductions in pain qualities at Week 2, especially in NPS pain intensity, were significant (P ≤ 0.0001) predictors of improvements in three BPI interference scores, total NPS score, and PGIC. CONCLUSIONS: For patients with PHN, G-GR provided significant improvements in multiple measures of pain quality and pain-related functional impairment. There was a positive correlation between pain relief and improvement in patient function, with reduction in pain intensity among predictors of improvements in patients' lives. Such comprehensive analyses give an insight into numerous factors that may contribute to better management of PHN.

Refractory Chronic Pain Screening Tool (RCPST): a feasibility study to assess practicality and validity of identifying potential neurostimulation candidates.

OBJECTIVE: An international panel of pain specialists (anesthesiology, neurology, neurosurgery, and psychology) and research methodologists developed a screening tool to identify patients who may be suitable for spinal cord stimulation (SCS)--the Refractory Chronic Pain Screening Tool (RCPST) prototype. We describe a feasibility study to explore practicality and validity of this prototype. DESIGN: Consecutive outpatients were screened in two centers (United Kingdom and United States). Sixty chronic pain adults without satisfactory pain relief despite treatment were assessed using RCPST (by pain specialist without expertise in neurostimulation) and then evaluated by two pain specialists experienced in SCS implantation and management to determine whether the patient should be referred for SCS. To maintain blinding, the participating physicians did not inform each other or the patient of assessment outcome. Sensitivity and specificity of the RCPST prototype were calculated using implanters' judgment as "gold standard." RESULTS: The average age of patients was 47.7 years; 53% were female. Fifty-seven patients completed the study (one withdrew consent, two lost to follow-up). The pain specialists agreed the prototype was easy to use and took <10 minutes to complete. Implanter agreement was moderate (Kappa: 0.63, 95% confidence interval: 0.35-0.91). The prototype had low sensitivity (40%, 19-61%) and moderate specificity (78%, 65-92%). Using the same questionnaire with a modified decision algorithm, new prototypes were generated with range of high sensitivity (80-100%) and specificity (89-97%) values. CONCLUSIONS: The RCPST aims to identify patients that should be referred for consideration for neurostimulation. The final implant decision requires appropriate neurological diagnostic workup, psychological assessment, and trial stimulation. RCPST was considered practical for routine clinical practice and contained appropriate questions. Sensitivity needs to be improved. A future study should select and validate the ideal RCPST prototype.

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.

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

NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension.

OBJECTIVES: To assess the efficacy, tolerability, and safety of NGX-4010, a high-concentration capsaicin dermal patch (capsaicin 640 microg/cm(2), 8%) in patients with postherpetic neuralgia (PHN). METHODS: Patients were randomized to receive NGX-4010 or control patch in a 4-week, double-blind study. This was followed by an open-label extension phase (up to 48 weeks total) where patients could receive up to three additional treatments no sooner than 12 weeks after initial treatment. The primary efficacy variable was mean change from baseline in mean morning and evening numerical pain rating scale (NPRS) scores. RESULTS: During days 8-28 after the double-blind treatment, NGX-4010 patients had a mean change in NPRS scores from baseline of -32.7% compared with -4.4% for control patients (P = 0.003). Mean NPRS scores decreased from baseline during week 1 in both treatment groups, remained relatively stable through week 12 in NXG-4010 patients, but returned to near baseline during weeks 2-4 in controls. Mean change in NPRS scores from baseline during weeks 2-12 was -33.8% for NGX-4010 and +4.9% for control recipients. A similar decrease in NPRS scores from baseline was maintained with subsequent NGX-4010 treatments, regardless of the number of treatments received. Transient increases in application site pain were adequately managed with analgesics. No increases in application site reactions or adverse events were observed with repeated treatments. No patients discontinued the study due to an adverse event. CONCLUSION: NGX-4010 is a promising topical treatment for PHN patients, which appears to be tolerable, generally safe, and effective.

Assessment of neuropathic pain in primary care.

Management of patients presenting with chronic pain is a common problem in primary care. Essentially, the classification of chronic pain falls into 3 broad categories: (1) pain owing to tissue disease or damage (nociceptive pain), (2) pain caused by somatosensory system disease or damage (neuropathic pain), and (3) pain without a known somatic background. Key challenges in developing a targeted holistic approach to treatment include appropriate diagnosis of the cause or causes of pain; identifying the type of pain and assessing the relative importance of its various components; and determining appropriate treatment. In clinical examination, sensory abnormalities are the crucial findings leading to a diagnosis of neuropathic pain, for which pharmacotherapy with antidepressants and anticonvulsants represents the cornerstone of medical treatment. Chronic neuropathic pain is underrecognized and undertreated, yet primary care physicians are uniquely placed on the frontlines of patient management, where they can play a pivotal role in treatment and prevention through diagnosis, therapy, follow-up, and referral. This review provides guidance in understanding and identifying the neuropathic contribution to pain presenting in primary care; assessing its severity through patient history, physical examination, and appropriate diagnostic tests; and establishing a rational treatment plan.

Quantitative sensory testing and mapping: a review of nonautomated quantitative methods for examination of the patient with neuropathic pain.

OBJECTIVES: Despite a growing interest in neuropathic pain, neurologists and pain specialists do not have a standard, validated, office examination for the evaluation of neuropathic pain signs to complement the neurologic, musculoskeletal, and general physical examinations. An office neuropathic pain examination focused on quantifying sensory features of neuropathic pain, ranging from deficits to allodynia and hyperalgesia, and evoked by a physiologically representative array of stimuli, will be an essential tool to monitor treatment effectiveness and for clinical investigation into the mechanisms and management of neuropathic pain. Such an examination should include mapping of areas of stimulus-evoked neuropathic pain and standardized, reproducible quantitative sensory testing (QST) of tactile, punctuate, pressure, and thermal modalities. METHODS: We review quantitative sensory testing methodology in general and specific tests for the evaluation of neuropathic pain phenomena. RESULTS: Numerous quantitative sensory testing techniques for dynamic mechanical, pressure, vibration, and thermal sensory testing and mapping have been described. We propose a comprehensive neuropathic pain evaluation protocol that is based upon these available techniques. CONCLUSIONS: A comprehensive neuropathic pain evaluation protocol is essential for further advancement of clinical research in neuropathic pain. A protocol that uses tools readily available in clinical practice, when established and validated, can be used widely and thus accelerate data collection for clinical research and increase clinical awareness of the features of neuropathic pain.

Pulsed electromagnetic fields to reduce diabetic neuropathic pain and stimulate neuronal repair: a randomized controlled trial.

OBJECTIVE: To determine whether repetitive and cumulative exposure to low-frequency pulsed electromagnetic fields (PEMF) targeting painful feet can reduce neuropathic pain (NP), influence sleep in symptomatic diabetic peripheral neuropathy (DPN), and influence nerve regeneration. DESIGN: Randomized, double-blind, placebo-controlled parallel study. SETTING: Sixteen academic and clinical sites in 13 states. PARTICIPANTS: Subjects (N=225) with DPN stage II or III were randomly assigned to use identical devices generating PEMF or sham (placebo) 2 h/d to feet for 3 months. INTERVENTIONS: Nerve conduction testing was performed serially. MAIN OUTCOME MEASURES: Pain reduction scores using a visual analog scale (VAS), the Neuropathy Pain Scale (NPS), and the Patient's Global Impression of Change (PGIC). A subset of subjects underwent serial 3-mm punch skin biopsies from 3 standard lower limb sites for epidermal nerve fiber density (ENFD) quantification. RESULTS: Subjects (N=225) were randomized with a dropout rate of 13.8%. There was a trend toward reductions in DPN symptoms on the PGIC, favoring the PEMF group (44% vs 31%; P=.04). There were no significant differences between PEMF and sham groups in the NP intensity on NPS or VAS. Twenty-seven subjects completed serial biopsies. Twenty-nine percent of PEMF subjects had an increase in distal leg ENFD of at least 0.5 SDs, while none did in the sham group (P=.04). Increases in distal thigh ENFD were significantly correlated with decreases in pain scores. CONCLUSIONS: PEMF at this dosimetry was noneffective in reducing NP. However neurobiological effects on ENFD, PGIC and reduced itching scores suggest future studies are indicated with higher dosimetry (3000-5000 G), longer duration of exposure, and larger biopsy cohort.

A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain.

ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 microg BID, ABT-594 225 microg BID, or ABT-594 300 microg BID. Patients were titrated to a fixed-dose of ABT-594 over 7 days and remained at this dose for another 6 weeks. Compared to placebo, all three ABT-594 treatment groups showed significantly greater decreases on the average diary-based 0-10 Pain Rating Scale (PRS) score from baseline to final evaluation, the primary efficacy measure (placebo, -1.1; 150 microg BID, -1.9; 225 microg BID, -1.9; 300 microg BID, -2.0). The proportion of patients achieving at least a 50% improvement in the average diary-based PRS was greater in all three ABT-594 treatment groups. However, adverse event (AE) dropout rates were significantly higher in all three ABT-594 treatment groups (28% for 150 microg BID, 46% for 225 microg BID, and 66% for 300 microg BID) than for the placebo group (9%). Consistent with the expected side-effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain.

Voluntary facial displays of pain increase suffering in response to nociceptive stimulation.

UNLABELLED: Facial expressions of pain are an important part of the pain response, signaling distress to others and eliciting social support. To evaluate how voluntary modulation of this response contributes to the pain experience, 29 subjects were exposed to thermal stimulation while making standardized pain, control, or relaxed faces. Dependent measures were self-reported negative effect (valence and arousal) as well as the intensity of nociceptive stimulation required to reach a given subjective level of pain. No direct social feedback was given by the experimenter. Although the amount of nociceptive stimulation did not differ across face conditions, subjects reported more negative effects in response to painful stimulation while holding the pain face. Subsequent analyses suggested the effects were not due to preexisting differences in the difficulty or unpleasantness of making the pain face. These results suggest that voluntary pain expressions have no positively reinforcing (pain attenuating) qualities, at least in the absence of external contingencies such as social reinforcement, and that such expressions may indeed be associated with higher levels of negative affect in response to similar nociceptive input. PERSPECTIVE: This study demonstrates that making a standardized pain face increases negative affect in response to nociceptive stimulation, even in the absence of social feedback. This suggests that exaggerated facial displays of pain, although often socially reinforced, may also have unintended aversive consequences.

Individual differences in the effects of perceived controllability on pain perception: critical role of the prefrontal cortex.

The degree to which perceived controllability alters the way a stressor is experienced varies greatly among individuals. We used functional magnetic resonance imaging to examine the neural activation associated with individual differences in the impact of perceived controllability on self-reported pain perception. Subjects with greater activation in response to uncontrollable (UC) rather than controllable (C) pain in the pregenual anterior cingulate cortex (pACC), periaqueductal gray (PAG), and posterior insula/SII reported higher levels of pain during the UC versus C conditions. Conversely, subjects with greater activation in the ventral lateral prefrontal cortex (VLPFC) in anticipation of pain in the UC versus C conditions reported less pain in response to UC versus C pain. Activation in the VLPFC was significantly correlated with the acceptance and denial subscales of the COPE inventory [Carver, C. S., Scheier, M. F., & Weintraub, J. K. Assessing coping strategies: A theoretically based approach. Journal of Personality and Social Psychology, 56, 267-283, 1989], supporting the interpretation that this anticipatory activation was associated with an attempt to cope with the emotional impact of uncontrollable pain. A regression model containing the two prefrontal clusters (VLPFC and pACC) predicted 64% of the variance in pain rating difference, with activation in the two additional regions (PAG and insula/SII) predicting almost no additional variance. In addition to supporting the conclusion that the impact of perceived controllability on pain perception varies highly between individuals, these findings suggest that these effects are primarily top-down, driven by processes in regions of the prefrontal cortex previously associated with cognitive modulation of pain and emotion regulation.

Long-term use of controlled-release oxycodone for noncancer pain: results of a 3-year registry study.

OBJECTIVE: To evaluate the outcomes associated with the use of controlled-release (CR) oxycodone for up to 3 years in the treatment of noncancer pain. METHODS: Adult patients who previously participated in controlled trials of CR oxycodone for osteoarthritis pain, diabetic neuropathy pain, or low back pain, and who continued to require opioid analgesia for moderate or severe pain, were enrolled in an open-label, uncontrolled, registry study. Data collected over time included dose, pain severity on a numeric scale, treatment acceptability, adverse events, and descriptions of problematic drug-related behavior. RESULTS: Two hundred thirty-three patients were enrolled. When the study closed, 141, 86, and 39 patients had taken CR oxycodone for at least 1, 2, and 3 years, respectively; mean duration of treatment was 541.5 days. Among the 219 intent-to-treat patients (received at least 1 dose and provided at least 1 postdose study observation), the mean (SD, range) daily dose was 52.5 (+/-38.5, 10.0 to 293.5) mg. Before the end of month 3, 44% required an increase in total daily dose; this dropped to 23% during months 4 to 6, to 17% during months 10 to 12, and remained at approximately 10% for each time interval thereafter (range 8% to 13%). Among the large majority of patients with stable or lower dose requirements after the initial 3 months of treatment, the average pain intensity ratings were unchanged or improved for approximately 70% to 80% of patients at all subsequent time points through month 33, and for 54% (7/13 patients) at month 36. A decrease in pain was initially seen by the end of month 3, and for the majority of patients, the Average Pain Intensity score remained the same, better, or minimally worse (<3 points) for the remainder of the 3-year study period. The most common adverse events were constipation and nausea, and the incidence of these events declined over time on treatment. Investigators reported 6 cases (2.6%) of possible drug misuse but no evidence of de novo addiction was observed. DISCUSSION: These registry data demonstrate that a subgroup of patients with noncancer pain experienced prolonged relief with tolerable side effects and modest need for dose escalation during long-term therapy with CR oxycodone.

Assessment: use of epidural steroid injections to treat radicular lumbosacral pain: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

Based on the available evidence, the Therapeutics and Technology Assessment subcommittee concluded that 1) epidural steroid injections may result in some improvement in radicular lumbosacral pain when assessed between 2 and 6 weeks following the injection, compared to control treatments (Level C, Class I-III evidence). The average magnitude of effect is small and generalizability of the observation is limited by the small number of studies, highly selected patient populations, few techniques and doses, and variable comparison treatments; 2) in general, epidural steroid injection for radicular lumbosacral pain does not impact average impairment of function, need for surgery, or provide long-term pain relief beyond 3 months. Their routine use for these indications is not recommended (Level B, Class I-III evidence); 3) there is insufficient evidence to make any recommendation for the use of epidural steroid injections to treat radicular cervical pain (Level U).

Depression, night terrors, and insomnia associated with long-term intrathecal clonidine therapy.

Intraspinal clonidine is an effective adjunct to intrathecal/epidural opioid administration. We report a case of neuropathic pain treated with intraspinal analgesics in which depression, insomnia, and night terrors developed in association with intraspinal clonidine.

Duloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studies.

OBJECTIVE: This post hoc analysis was aimed to summarize the efficacy and tolerability of duloxetine as represented by number needed to treat (NNT) and number needed to harm (NNH) to provide a clinically useful assessment of the position of duloxetine among current agents used to treat diabetic peripheral neuropathic pain (DPNP). METHODS: Data were pooled from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which patients received 60 mg duloxetine either QD or BID or placebo. NNT was calculated based on rates of response (defined as >or=30% and >or=50% reductions from baseline in the weekly mean of the 24-hour average pain severity scores); NNH was calculated based on rates of discontinuation due to adverse events (AEs). RESULTS: Patients receiving duloxetine 60 mg QD and 60 mg BID had NNTs (95% CI) of 5.2 (3.8-8.3) and 4.9 (3.6-7.6), respectively, based on last observation carried forward; NNTs of 5.3 (3.8-8.3) for 60 mg QD and 5.7 (4.1-9.7) for 60 mg BID were obtained based on baseline observations carried forward. The NNHs (95% CI) based on discontinuation due to AEs were 17.5 (10.2-58.8) in the duloxetine 60-mg QD group and 8.8 (6.3-14.7) in the 60-mg BID group. CONCLUSION: These post hoc results suggest that duloxetine was effective and well tolerated for the management of DPNP and further support the importance of duloxetine as a treatment option for clinicians and patients to assist with the management of DPNP.

Classification of patients with pain based on neuropathic pain symptoms: comparison of an artificial neural network against an established scoring system.

Wider use of pain assessment tools that are specifically designed for certain types of pain--such as neuropathic pain--contribute an increasing amount of information which in turn offers the opportunity to employ advanced methods of data analysis. In this manuscript, we present the results of a study where we employed artificial neural networks (ANNs) in an analysis of pain descriptors with the goal of determining how an approach that uses a specific symptoms-based tool would perform with data from the real world of clinical practice. We also used traditional statistics approaches in the form of established scoring systems as well as logistic regression analysis for the purpose of comparison. Our results confirm the clinical experience that groups of pain descriptors rather than single items differentiate between patients with neuropathic and non-neuropathic pain. The accuracy obtained by ANN analysis was only slightly higher than that of the traditional approaches, indicating the absence of nonlinear relationships in this dataset. Data analysis with ANNs provides a framework that extends what current approaches offer, especially for dynamic data, such as the rating of pain descriptors over time.

Quantitative sensory testing for spinal cord stimulation in patients with chronic neuropathic pain.

OBJECTIVE: A prospective pilot study was conducted, attempting to identify objective tests that would help clinicians to assess the efficacy of spinal cord stimulation (SCS) trial preceding permanent device implantation. SETTING: Four university hospitals in the United States and Israel. PARTICIPANTS: Thirteen patients with radicular leg pain due to failed back surgery syndrome (FBSS) or leg pain due to complex regional pain syndrome (CRPS) who were candidates for SCS. METHODS: PARTICIPANTS underwent a series of quantitative sensory tests prior to, and seven days after the initiation of SCS trial. These tests included: vibration threshold (conducted using the VSA 3000; Medoc Inc., Ramat Ishay, Israel), cold threshold, warm threshold, heat pain threshold, phasic heat pain threshold, tonic heat pain threshold (conducted using the TSA 2001; Medoc Inc.), and electrical pain tolerance at 5, 250 and 2000 Hz (administered using the NerveScan 2000; Neurotron, Inc., Baltimore, MD, USA). RESULTS: Useful data were obtained from 12 patients. The results of the vibration threshold and the tolerance to electrical stimulation at 5 and 250 Hz changed with an SCS trial. These results also correlated with the decision regarding the permanent implantation, which was made independently of them. In contrast, the results of thermal thresholds and tolerance to electrical stimulation at 2000 Hz tests did not change with the SCS trial. CONCLUSIONS: Our findings, which agree with those of a few other studies, suggest that the vibration threshold and the tolerance to electrical stimulation at 5 and 250 Hz tests can assist the clinician to select the right patients for permanent stimulation.