Jan Vollert

The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised, double-blind, placebo-controlled phenotype-stratified study

&NA; The sodium channel blocker oxcarbazepine is efficacious in peripheral neuropathic pain patients, with preserved thermal sensation and some gain of sensory function, that is, the “irritable nociceptor” phenotype. &NA; In neuropathic pain it has been suggested that pain phenotype based on putative pain mechanisms may predict response to treatment. This was a randomised, double‐blind, placebo‐controlled, and phenotype‐stratified study with 2 6‐week treatment periods of oxcarbazepine (1800‐2400 mg) and placebo. The primary efficacy measure was change in median pain intensity between baseline and the last week of treatment measured on an 11‐point numeric rating scale, and the primary objective was to compare the effect of oxcarbazepine in patients with and without the irritable nociceptor phenotype as defined by hypersensitivity and preserved small nerve fibre function determined by detailed quantitative sensory testing. Ninety‐seven patients with peripheral neuropathic pain due to polyneuropathy, surgical or traumatic nerve injury, or postherpetic neuralgia were randomised. The intention‐to‐treat population comprised 83 patients: 31 with the irritable and 52 with the nonirritable nociceptor phenotype. In the total sample, oxcarbazepine relieved pain of 0.7 points (on a numeric rating scale 0‐10; 95% confidence interval [CI] 0.4‐1.4) more than placebo (P = 0.015) and there was a significant interaction between treatment and phenotype of 0.7 (95% CI 0.01‐1.4, P = 0.047). The number needed to treat to obtain one patient with more than 50% pain relief was 6.9 (95% CI 4.2‐22) in the total sample, 3.9 (95% CI 2.3‐12) in the irritable, and 13 (95% CI 5.3‐∞) in the nonirritable nociceptor phenotype. In conclusion, oxcarbazepine is more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype.

Peripheral Neuropathic Pain: A mechanism-related organizing principle based on sensory profiles

Abstract Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype: A randomised, double-blind and placebo-controlled phenotype panel study

Abstract In neuropathic pain with irritable nociceptor (IN) phenotype, upregulation of sodium channels on nociceptors is supposed to be an important pain mechanism that may be targeted by topical sodium channel blockade. This randomised, double-blind, phenotype panel, crossover study with 4-week treatment periods of lidocaine 5% patch and placebo was performed to search for phenotype differences in effect. The primary efficacy measure was the total pain intensity on an 11-point numeric rating scale, and the primary objective was to compare the effect of lidocaine in patients with and without IN phenotype as defined by hypersensitivity and preserved small-fibre function determined by quantitative sensory testing. Forty-six patients with neuropathic pain due to nerve injury or postherpetic neuralgia were randomised. The modified intention-to-treat population comprised 15 patients with irritable nociceptor and 25 patients with nonirritable nociceptor. In the total sample, lidocaine reduced pain by 0.3 numeric rating scale points (95% confidence interval [CI]: 0.1-0.5) and pain-related sleep disturbance by 0.6 points (95% CI: 0.4-0.8) more than placebo (P = 0.007 and P < 0.001) and relieved pain by 0.4 verbal score (−1-5) points more (P = 0.036). For these measures, there was no significant interaction between treatment and phenotype, but there was a significant interaction for pain paroxysms (0.8, 95% CI: 0.4-1.2, P < 0.001) and deep aching pain (0.6, 95% CI: 0.1-1.0, P = 0.013). In conclusion, lidocaine 5% patch had an effect on peripheral neuropathic pain, and it may be most efficacious in patients with IN phenotype. The lack of significant phenotype differences may be caused by too low statistical power.

Quantitative sensory testing using DFNS protocol in Europe: an evaluation of heterogeneity across multiple centers in patients with peripheral neuropathic pain and healthy subjects.

Abstract Quantitative sensory testing (QST) in accordance with the DFNS (German Research Network on Neuropathic Pain) protocol assesses the function of afferent nerve fibers on the basis of 13 parameters. Within the consortia IMI (Innovative Medicines Initiative) Europain and Neuropain, QST results from pain research units experienced in QST across Europe can be compared for the first time. Aim of this analysis was to identify possible biases in the QST assessment between 10 centers from 8 different European countries. In total, 188 healthy subjects, 217 patients with painful polyneuropathy, and 150 patients with painful peripheral nerve injury were included in the analysis. Mixed effects models were constructed for each of the 11 normally distributed QST parameters with z-value as the dependent variable, and center as the random effect. The I2 statistic for heterogeneity was calculated, an index ranging from 0% (no heterogeneity) to 100% (perfect heterogeneity). Data from healthy subjects were comparable with the existing reference data base. Patients with polyneuropathy mainly displayed loss of sensory function, whereas patients with peripheral nerve injury often showed sensory loss combined with mechanical hyperalgesia. Heterogeneity was overall low between different centers and parameters. There was no systematic heterogeneity for patients with painful peripheral nerve injury and painful polyneuropathy. For healthy subjects, only blunt pressure pain threshold showed a considerable heterogeneity of 42% (95% confidence interval: 0%-66%). In conclusion, QST of both healthy subjects and patients with peripheral neuropathic pain is largely homogenous within the European centers, an essential prerequisite for performing multicenter QST-based studies.

Quality assurance for Quantitative Sensory Testing laboratories: development and validation of an automated evaluation tool for the analysis of declared healthy samples.

Abstract Quantitative Sensory Testing (QST) is a psychophysical method assessing the somatosensory nervous system. A premise for comparable results between laboratories is standardized testing. Its quality can be proven by analyzing healthy subjects, because their results should lie within confidence intervals estimated from large database samples. However, it is unclear how many abnormal values can be tolerated. Based on a binomial distribution, a tool for assessing samples of healthy subjects was developed to detect inclusion errors (inclusion of nonhealthy subjects) or measuring errors (inaccuracies in single QST parameters). Sensitivity and specificity of detecting inclusion errors were assessed in 431 healthy subjects and 833 patients with neuropathic pain syndromes from the German Research Network on Neuropathic Pain (DFNS) database. Measuring errors were simulated by raising all absolute values in a single parameter by 0.5 SD. We calculated optimal cutoff values for group sizes of 16 healthy subjects, as implemented in the DFNS certification procedures. The algorithm was applied in the certification process of 18 European QST laboratories. With a specificity of 95% and a sensitivity of 60%, inclusion errors can be assumed for ≥4 abnormal values per subject, whereas ≥6 abnormal values per QST parameter and laboratory indicate measuring errors. Subsequently, in the certification process of 5 of 18 centers, inclusion or measuring errors were detected. In most cases, inclusion errors were verified and reasons for measuring errors were illuminated by the centers. This underlines the usefulness and validity of our tool in quality assurance of QST laboratories using the DFNS protocol.

Comparison of muscle and joint pressure-pain thresholds in patients with complex regional pain syndrome and upper limb pain of other origin

Summary Pressure‐pain thresholds measured over distal hand joints are highly specific for complex regional pain syndrome and might be a clinical sign reflecting bone pathophysiology. ABSTRACT Pain localized in the deep tissues occurs frequently in complex regional pain syndrome (CRPS). In addition, hyperalgesia to blunt pressure over muscles is common in CRPS, but it often appears in limb pain of other origin as well. Considering that 3‐phase bone scintigraphy (TPBS) reveals periarticular enhanced bone metabolism in CRPS, joint‐associated hyperalgesia to blunt pressure might be a more specific finding than hyperalgesia over muscles. In 34 patients with upper limb pain (18 CRPS, 16 non‐CRPS; diagnosed in accordance to the Budapest criteria) and in 18 healthy controls, pressure‐pain thresholds (PPT) were assessed bilaterally over the thenar (PPTThenar), the metacarpophalangeal (PPTMCP), and the proximal interphalangeal (PPTPIP) joints using a pressure algometer (Somedic, Sweden). Beforehand, all patients had received TPBS for diagnostic purposes independently of the study. Region‐of‐interest (ROI) ratios (mineralization phase) for the MCP and PIP, excluding fracture sites, were correlated with the PPT. In CRPS, all ROI ratios were significantly increased and all PPT of the affected hand were decreased compared to non‐CRPS (PPTThenar: 243 ± 150 kPa vs 358 ± 197 kPa, PPTMCP: 80 ± 67 kPa vs 159 ± 93 kPa, PPTPIP: 80 ± 56 kPa vs 184 ± 110 kPa; P < .01) and controls (PPTThenar: 478 ± 106 kPa, PPTMCP: 254 ± 50 kPa, PPTPIP: 275 ± 76 kPa; P < .01). A PPTThenar below 293 kPa revealed 77% sensitivity but only 63% specificity, whereas a PPTPIP below 102 kPa had 82% sensitivity and 94% specificity to identify CRPS. Only in CRPS were PPTMCP and PPTPIP correlated significantly inversely with the ROI ratio (MCP: r = −0.439, PIP: r = −0.447). PPTPIP shows higher specificity for CRPS type I than PPTThenar without loss of sensitivity. Therefore, measurement of joint PPT could be a noninvasive diagnostic tool reflecting increased bone metabolism assessed by TPBS as a sign of bone pathophysiology.

Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations

Abstract In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic—ie, a patient can be sorted to more than one phenotype—and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5.

Use of Corneal Confocal Microscopy to Evaluate Small Nerve Fibers in Patients With Human Immunodeficiency Virus

Importance Objective quantification of small fiber neuropathy in patients with human immunodeficiency virus (HIV)–associated sensory neuropathy (HIV-SN) is difficult but needed for diagnosis and monitoring. In vivo corneal confocal microscopy (IVCCM) can quantify small fiber damage. Objective To establish whether IVCCM can identify an abnormality in corneal nerve fibers and Langerhans cells in patients with and without HIV-SN. Design, Setting, and Participants This prospective, cross-sectional cohort study was conducted between July 24, 2015, and September 17, 2015. Twenty patients who were HIV positive were recruited from adult outpatient clinics at Chelsea and Westminster Hospital NHS Foundation Trust in England. These patients underwent IVCCM at Moorfields Eye Hospital NHS Foundation Trust in London, England, and the IVCCM images were analyzed at Weill Cornell Medicine–Qatar in Ar-Rayyan, Qatar. Patients were given a structured clinical examination and completed validated symptom questionnaires and the Clinical HIV-Associated Neuropathy Tool. Results from patients with HIV were compared with the results of the age- and sex-matched healthy control participants (n = 20). All participants were classified into 3 groups: controls, patients with HIV but without SN, and patients with HIV-SN. Main Outcomes and Measures Comparison of corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, corneal nerve fiber tortuosity, and corneal Langerhans cell density between healthy controls and patients with HIV with and without SN. Results All 40 participants were male, and most (≥70%) self-identified as white. Of the 20 patients with HIV, 14 (70%) had HIV-SN. This group was older (mean [SD] age, 57.7 [7.75] years) than the group without HIV-SN (mean [SD] age, 42.3 [7.26] years) and the controls (mean [SD] age, 53.8 [10.5] years). Corneal nerve fiber density was reduced in patients with HIV compared with the controls (26.7/mm2 vs 38.6/mm2; median difference, −10.37; 95.09% CI, −14.27 to −6.25; P < .001) and in patients with HIV-SN compared with those without (25.8/mm2 vs 30.7/mm2; median difference, −4.53; 95.92% CI, −8.85 to −0.26; P = .03). Corneal nerve branch density and corneal nerve fiber length were reduced in patients with HIV, but no differences were identified between those with neuropathy and without neuropathy (corneal nerve branch density: 95.83/mm2 for the controls vs 72.37/mm2 for patients with HIV; median difference, −24.53; 95.32% CI, −50.62 to −3.13; P = .01; and corneal nerve fiber length: 28.4 mm/mm2 for the controls vs 21.9 mm/mm2 for patients with HIV; median difference, −5.24; 95.09% CI, −8.83 to −1.38; P = .001). Tortuosity coefficient was increased in patients with HIV compared with controls (16.44 vs 13.95; median difference, 2.34; 95.09% CI, 0.31 to 4.65; P = .03) and in those with HIV-SN compared with those without (17.84 vs 14.18; median difference, 4.32; 95.92% CI, 0.68-9.23; P = .01). No differences were identified in corneal Langerhans cell density (19.84 cells/mm2 for the controls vs 41.43 cells/mm2 for patients with HIV; median difference, 9.38; 95% CI, −12.51 to 26.34; P = .53). Conclusions and Relevance In vivo corneal confocal microscopy could be used in the assessment of HIV-SN, but larger studies are required to confirm this finding.

Symptom profiles in the painDETECT Questionnaire in patients with peripheral neuropathic pain stratified according to sensory loss in quantitative sensory testing.

Abstract The painDETECT Questionnaire (PDQ) is commonly used as a screening tool to discriminate between neuropathic pain (NP) and nociceptive pain, based on the self-report of symptoms, including pain qualities, numbness, and pain to touch, cold, or heat. However, there are minimal data about whether the PDQ is differentially sensitive to different sensory phenotypes in NP. The aim of the study was to analyze whether the overall PDQ score or its items reflect phenotypes of sensory loss in NP as determined by quantitative sensory testing. An exploratory analysis in the Innovative Medicines Initiative Europain and Neuropain database was performed. Data records of 336 patients identified with NP were grouped into sensory profiles characterized by (1) no loss of sensation, (2) loss of thermal sensation, (3) loss of mechanical sensation, and (4) loss of thermal and mechanical sensation. painDETECT Questionnaire profiles were analyzed in a 2-factor analysis of variance. Patients with loss of thermal sensation (2 and 4) significantly more often reported pain evoked by light touch, and patients with loss of mechanical sensation (3 and 4) significantly more often reported numbness and significantly less often burning sensations and pain evoked by light touch. Although the PDQ was not designed to assess sensory loss, single items reflect thermal and/or mechanical sensory loss at group level, but because of substantial variability, the PDQ does not allow for individual allocation of patients into sensory profiles. It will be useful to develop screening tools according to the current definition of NP.

Sleep-disordered breathing decreases after opioid withdrawal: results of a prospective controlled trial.

Abstract An increased cardiovascular event rate in elderly patients under opioid medications was recently reported. One reason for this increase could be the occurrence of nocturnal apnea and hypoxia, as a consequence of sleep-disordered breathing (SDB). Using a controlled study, we prospectively analyzed SDB using polysomnography in a total of 18 patients before and after opioid withdrawal (opioid withdrawal group [OG]) and 14 patients before and after comprehensive pain management (without any strong-acting opioids) who served as the control group (CG). To analyze the differences, unpaired/paired t tests and Mann–Whitney U tests/Wilcoxon rank tests were used. At baseline, the OG presented more nocturnal apneas/hypopneas than the CG with an apnea–hypopnea index (AHI) of 41.4 ± 27.8 vs 21.8 ± 15.9 (P = 0.018). After treatment, the AHI decreased significantly only in the withdrawal group (OG: 16.7 ± 8.9; CG: 20.1 ± 12.9) (P < 0.01). Before treatment, none of the CG but half of the OG patients showed central apnea, which disappeared afterwards. A mean O2 saturation during rapid eye movement sleep lower than 90% was found in 27.5% of the OG patients before opioid withdrawal and in none of the patients after withdrawal (P < 0.01). The AHI was not significantly affected by body mass index, age, or sex. Obviously, nocturnal apnea and O2 desaturation occurred more frequently, as was clinically expected in patients with opioid intake; these findings may explain the opioid-associated cardiovascular morbidity. Thus, SDB may be a risk at lower opioid doses than hitherto described, and particular caution should be exercised in patients with comorbidities that might make them vulnerable to the consequences of SDB.