Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Circadian rhythmicity of pain sensitivity in humans.

Pain intensity has been reported to fluctuate during the day in some experimental and clinical conditions, but the mechanisms underlying these fluctuations are unknown. Although the circadian timing system is known to regulate a wide range of physiological functions, its implication in pain regulation is largely unknown. Using highly controlled laboratory constant-routine conditions, we show that pain sensitivity is rhythmic over the 24 h and strongly controlled by the endogenous circadian timing system. We found that the circadian component of pain sensitivity can be modelled with a sinusoidal function, with a maximum in the middle of the night and a minimum in the afternoon. We also found a weak homeostatic control of pain sensitivity, with a linear increase over the 34 h of prolonged wakefulness, which slowly builds up with sleep pressure. Using mathematical modelling, we describe that the circadian system accounts for ∼80% of the full magnitude of pain sensitivity over the 24 h, and that sleep-related processes account for only ∼20%. Overall, our data reveal the neurobiological mechanisms involved in driving the rhythmicity of pain perception in humans. We show that pain sensitivity is controlled by two superimposed processes: a strong circadian component and a modest homeostatic sleep-related component. Our findings highlight the need to consider time of day in pain assessment, and indicate that personalized circadian medicine may be a promising approach to pain management.

Advances and challenges in neuropathic pain: a narrative review and future directions.

Over the past few decades, substantial advances have been made in neuropathic pain clinical research. An updated definition and classification have been agreed. Validated questionnaires have improved the detection and assessment of acute and chronic neuropathic pain; and newer neuropathic pain syndromes associated with COVID-19 have been described. The management of neuropathic pain has moved from empirical to evidence-based medicine. However, appropriately targeting current medications and the successful clinical development of drugs acting on new targets remain challenging. Innovative approaches to improving therapeutic strategies are required. These mainly encompass rational combination therapy, drug repurposing, non-pharmacological approaches (such as neurostimulation techniques), and personalised therapeutic management. This narrative review reports historical and current perspectives regarding the definitions, classification, assessment, and management of neuropathic pain and explores potential avenues for future research.

Repetitive transcranial magnetic stimulation for neuropathic pain: a randomized multicentre sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI: -0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.

Advances in the treatment of neuropathic pain.

PURPOSE OF REVIEW: Neuropathic pain remains difficult to treat. This review provides an update regarding recent advances in therapeutic management, particularly with regards to newer drugs, neurostimulation techniques and original study designs. RECENT FINDINGS: Although the mainstay of neuropathic pain management is still represented by drug therapy, particularly antidepressants and antiepileptics, the place of nonpharmacological therapy including in particular brain neuromodulation techniques has substantially increased in recent years. Newer study designs are also increasingly implemented, based on in depth phenotypic profiling to achieve more individualized therapy, or on screening strategies to decrease placebo effect and contribute to increase assay sensitivity. These approaches are now considered the most promising to decrease therapeutic failures in neuropathic pain. SUMMARY: Neuropathic pain management should not be restricted to pharmacotherapy but now encompasses multiple approaches including particularly neuromodulation techniques. Multimodal assessment can also help identify predictors of the response in clinical trials in order to ensure appropriate management.

Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial.

LESSONS LEARNED: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo. BACKGROUND: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN. METHODS: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile. RESULTS: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]). CONCLUSION: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.

Validation of the Greek Version of the Fibromyalgia Rapid Screening Tool.

BACKGROUND AND AIM: The Fibromyalgia Rapid Screening Tool (FiRST) is a brief, simple, and straightforward self-administered questionnaire that was developed by Perrot et al. for the detection of fibromyalgia syndrome in patients with diffuse chronic pain. The aim of our study was to develop and validate the Greek version of FiRST. METHODS: The study was set up as a prospective observational study. The original French version of FiRST was adapted into Greek using forward and backward translation. Patients with chronic diffuse pain with a clinical diagnosis of fibromyalgia and osteoarthritis based on the criteria of the American College of Rheumatology were invited to participate to the study. RESULTS: Of the 101 patients who met our inclusion criteria, 42 were diagnosed with fibromyalgia and 59 with osteoarthritis. The 2 groups did not differ significantly regarding gender and pain characteristics (duration, intensity). Cronbach's alpha coefficient was 0.79. Receiver operating characteristic analysis showed an area under the curve of 89% (95% confidence interval = 83 to 95%; SE: 0.032, P < 0.001). At a cutoff score of ≥ 5, FiRST showed a sensitivity of 86%, a specificity of 83%, a positive predictive value of 78%, and a negative predictive value of 89%. The intraclass coefficient for the test-retest reliability was 0.96. CONCLUSION: The Greek version of FiRST is a valid screening tool for fibromyalgia in daily practice.

Does cognitive functioning predict chronic pain? Results from a prospective surgical cohort.

It is well established that chronic pain impairs cognition, particularly memory, attention and mental flexibility. Overlaps have been found between the brain regions involved in pain modulation and cognition, including in particular the prefrontal cortex and the anterior cingulate cortex, which are involved in executive function, attention and memory. However, whether cognitive function may predict chronic pain has not been investigated. We addressed this question in surgical patients, because such patients can be followed prospectively and may have no pain before surgery. In this prospective longitudinal study, we investigated the links between executive function, visual memory and attention, as assessed by clinical measurements and the development of chronic pain, its severity and neuropathic symptoms (based on the 'Douleur Neuropathique 4' questionnaire), 6 and 12 months after surgery (total knee arthroplasty for osteoarthritis or breast surgery for cancer). Neuropsychological tests included the Trail-Making Test A and B, and the Rey-Osterrieth Complex Figure copy and immediate recall, which assess cognitive flexibility, visuospatial processing and visual memory. Anxiety, depression and coping strategies were also evaluated. In total, we investigated 189 patients before surgery: 96% were re-evaluated at 6 months, and 88% at 12 months. Multivariate logistic regression (stepwise selection) for the total group of patients indicated that the presence of clinical meaningful pain at 6 and 12 months (pain intensity ≥ 3/10) was predicted by poorer cognitive performance in the Trail Making Test B (P = 0.0009 and 0.02 for pain at 6 and 12 months, respectively), Rey-Osterrieth Complex Figure copy (P = 0.015 and 0.006 for pain at 6 and 12 months, respectively) and recall (P = 0.016 for pain at 12 months), independently of affective variables. Linear regression analyses indicated that impaired scores on these tests predicted pain intensity (P < 0.01) and neuropathic symptoms in patients with pain (P < 0.05), although the strength of the association was less robust for neuropathic symptoms. These results were not affected by the type of surgery or presurgical pain, similar findings being obtained specifically for patients who initially had no pain. In conclusion, these findings support, for the first time, the notion that premorbid limited cognitive flexibility and memory capacities may be linked to the mechanisms of pain chronicity and probably also to its neuropathic quality. This may imply that patients with deficits in executive functioning or memory because of cerebral conditions have a greater risk of pain chronicity after a painful event.

Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature.

OBJECTIVE: To review the literature on the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) in chronic pain according to different pain syndromes and stimulation parameters. DATA SOURCES: Publications on rTMS and chronic pain were searched in PubMed and Google Scholar using the following key words: chronic pain, analgesia, transcranial magnetic stimulation, neuropathic pain, fibromyalgia, and complex regional pain syndrome. STUDY SELECTION: This review only included double-blind, controlled studies with >10 participants in each arm that were published from 1996 to 2014 and written in English. Studies with relevant information for the understanding of the effects of rTMS were also cited. DATA EXTRACTION: The following data were retained: type of pain syndrome, type of study, coil type, target, stimulation intensity, frequency, number of pulses, orientation of induced current, number of session, and a brief summary of intervention outcomes. DATA SYNTHESIS: A total of 33 randomized trials were found. Many studies reported significant pain relief by rTMS, especially high-frequency stimulation over the primary motor cortex performed in consecutive treatment sessions. Pain relief was frequently >30% compared with control treatment. Neuropathic pain, fibromyalgia, and complex regional pain syndrome were the pain syndromes more frequently studied. However, among all published studies, only a few performed repetitive sessions of rTMS. CONCLUSIONS: rTMS has potential utility in the management of chronic pain; however, studies using maintenance sessions of rTMS and assessing the effects of rTMS on the different aspects of chronic pain are needed to provide a more solid basis for its clinical application for pain relief.

Validation of the Greek Version of the DN4 Diagnostic Questionnaire for Neuropathic Pain.

BACKGROUND: The Douleur Neuropathique 4 questionnaire (DN4) was developed by the French Neuropathic Pain Group and is a simple and objective tool, primarily designed to screen for neuropathic pain. The aim of our study is to validate the DN4 in the Greek language. METHODS: The study was set up as a prospective observational study. Two pain specialists independently examined patients and diagnosed them with neuropathic, nociceptive, or mixed pain, according to the International Association for the Study of Pain (IASP) definitions. A third and a fourth physician administered the DN4 questionnaire to the patients. RESULTS: Out of the 237 patients who met our inclusion criteria and had identical diagnoses regarding the type of pain, 123 were diagnosed with neuropathic, 59 with nociceptive, and 55 with mixed pain. Among patients with identical diagnoses of neuropathic or nociceptive pain, using a receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.92. A cutoff point of equal or greater than 4 resulted in a sensitivity of 93% and a specificity of 78%. Among patients suffering from pain with neuropathic element (neuropathic or mixed pain) or pain with no neuropathic element (nociceptive pain), using a ROC curve analysis, the AUC was 0.89. A cutoff point of equal or greater than 4 resulted in a sensitivity of 89% and a specificity of 78%. CONCLUSION: The Greek version of DN4 is a valid tool for discriminating between neuropathic and nociceptive pain conditions in daily practice.

ARIZONA study: is the risk of post-herpetic neuralgia and its burden increased in the most elderly patients?

BACKGROUND: In a context of change in the demographic profile of the older population, to identify an age threshold for increased risk and burden of herpes zoster (HZ) in 70+ patients. METHODS: Post hoc analysis of the 12-month French nationwide prospective observational ARIZONA cohort study. HZ was assessed by means of the following validated questionnaires: Neuropathic Pain Symptom Inventory (NPSI), Zoster Brief Pain Inventory (ZBPI), Short-Form health survey (SF-12), and Hospital Anxiety and Depression Scale (HADS). RESULTS: 644 general practitioners included 1,358 volunteer patients with acute HZ in the ARIZONA study; 609 patients (45%) were 70+. In 70+ patients, age did not increase rash severity or HZ-related pain intensity at diagnosis, but increased by 64% the frequency of ophthalmic zoster (from 5.5% in 70-74 years age-group to 9.0% in 85+ patients, p = NS). Age was significantly associated with low physical health as assessed by the SF-12 Physical Component Summary (SF-12 PCS) score and bad mood as assessed by the HADS depression score (p < 0.001). Within the year following HZ, post-herpetic neuralgia (PHN) was systematically but not significantly more frequent in 85+ patients than in the 70-74, 75-79, or 80-84 years age-groups (19.0% vs. 13.3%/15.3%/11.6% at month 3; 15.1% vs. 7.3%/11.0%/12.2% at month 6; 15.2% vs. 6.0%/8.0%/6.0% at month12, respectively). SF-12 PCS and HADS depression scores improved from day 0 to month 12 in all patients (p < 0.001). 85+ patients were more impaired than younger patients (p < 0.001), but without clear difference according to PHN. CONCLUSIONS: This study did not show in 70+ patients a clear and significant age threshold at which disease burden increased, although for some domains the impact seemed higher among the oldest patients; the cut-off of 70 years remains thus relevant for clinical and epidemiological studies. However, at individual level, assessment of the burden of HZ and HZ-related pain appears necessary to improve management and prevent functional decline in the most vulnerable 70+ patients.

Validity and reliability of the persian (Farsi) version of the DN4 (Douleur Neuropathique 4 Questions) questionnaire for differential diagnosis of neuropathic from non-neuropathic pains.

The aim of our study was translation and assessment of validity and reliability of the Persian version of DN4 questionnaire. The goal was to fill the gap caused by the absence of a validated instrument in Persian to facilitate discrimination of neuropathic pain. In this study, the adaptation and validation of the questionnaire was carried out in 4 steps, including translation, retranslation, semantic, and literal assessments, and a pilot study for practicability and potential perception difficulties of the final Persian version on 45 patient samples. The questionnaire validation performed on 175 patients, 112 (64%) females with the mean age of 52.53 (SD = 14.98) ranging from 22 to 87 years of age with neuropathic (N = 86) and non-neuropathic pain (NNP) (N = 89). Sensitivity, specificity, and Youden Index in cut-off point ≥ 4 were 90%, 95%, and 0.85, respectively, which are noteworthy findings among other validation studies. The Cronbach's alpha coefficient of the whole questionnaire was 0.852. Inter-rater agreement and test-retest reliability were significant intraclass coefficient (ICC = 0.957 and ICC = 0.918, respectively). The Persian version of DN4 questionnaire is a reliable, valid, feasible, and easily administered tool for precise discrimination neuropathic pain from NNP in Farsi. The characteristics of this test can assist practitioner to diagnose neuropathic pain accurately for both clinical and research purposes.

Prediction of the response to repetitive transcranial magnetic stimulation of the motor cortex in peripheral neuropathic pain and validation of a new algorithm.

CLINICAL TRIAL REGISTRATION: NCT02010281.

Efficacy and safety of eliapixant in diabetic neuropathic pain and prediction of placebo responders with an exploratory novel algorithm: results from the randomized controlled phase 2a PUCCINI study.

ABSTRACT: Phase 2a of the PUCCINI study was a placebo-controlled, double-blind, parallel-group, multicenter, proof-of-concept study evaluating the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with diabetic neuropathic pain (DNP) ( ClinicalTrials.gov NCT04641273). Adults with type 1 or type 2 diabetes mellitus with painful distal symmetric sensorimotor neuropathy of >6 months' duration and neuropathic pain were enrolled and randomized 1:1 to 150 mg oral eliapixant twice daily or placebo for 8 weeks. The primary endpoint was change from baseline in weekly mean 24-hour average pain intensity score at week 8. In total, 135 participants completed treatment, 67 in the eliapixant group and 68 in the placebo group. At week 8, the change from baseline in posterior mean 24-hour average pain intensity score (90% credible interval) in the eliapixant group was -1.56 (-1.95, -1.18) compared with -2.17 (-2.54, -1.80) for the placebo group. The mean treatment difference was 0.60 (0.06, 1.14) in favor of placebo. The use of a model-based framework suggests that various factors may contribute to the placebo-responder profile. Adverse events were mostly mild or moderate in severity and occurred in 51% of the eliapixant group and 48% of the placebo group. As the primary endpoint was not met, the PUCCINI study was terminated after completion of phase 2a and did not proceed to phase 2b. In conclusion, selective P2X3 antagonism in patients with DNP did not translate to any relevant improvement in different pain intensity outcomes compared with placebo. Funding: Bayer AG.

Comparison of the analgesic effects of "superficial" and "deep" repetitive transcranial magnetic stimulation in patients with central neuropathic pain: a randomized sham-controlled multicenter international crossover study.

ABSTRACT: We directly compared the analgesic effects of "superficial" and 'deep" repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex in patients with central neuropathic pain. Fifty-nine consecutive patients were randomly assigned to active or sham "superficial" (using a figure-of-8 [F8]-coil) or "deep" (using a Hesed [H]-coil) stimulation according to a double-blind crossover design. Each treatment period consisted of 5 daily stimulation sessions and 2 follow-up visits at 1 and 3 weeks after the last stimulation session. The primary outcome was the comparison of the mean change in average pain intensity over the course of the treatment (group × time interaction). Secondary outcomes included neuropathic symptoms (NPSI), pain interference, patient global impression of change (PGIC), anxiety, depression, and catastrophizing. In total, 51 patients participated in at least one session of both treatments. There was a significant interaction between "treatment" and "time" (F = 2.7; P = 0.0024), indicating that both figure-8 (F8-coil) and H-coil active stimulation induced significantly higher analgesic effects than sham stimulation. The analgesic effects of both types of coils had a similar magnitude but were only moderately correlated ( r = 0.39, P = 0.02). The effects of F8-coil stimulation appeared earlier, whereas the effects of H-coil stimulation were delayed, but tended to last longer (up to 3 weeks) as regards to several secondary outcomes (PGIC and total NPSI score). In conclusion, "deep" and "superficial" rTMS induced analgesic effects of similar magnitude in patients with central pain, which may involve different mechanisms of action.

A systematic literature review on patient-reported outcome domains and measures in nonsurgical efficacy trials related to chronic pain associated with endometriosis: an urgent call to action.

ABSTRACT: Endometriosis, a common cause for chronic pelvic pain, significantly affects quality of life, fertility, and overall productivity of those affected. Therapeutic options remain limited, and collating evidence on treatment efficacy is complicated. One reason could be the heterogeneity of assessed outcomes in nonsurgical clinical trials, impeding meaningful result comparisons. This systematic literature review examines outcome domains and patient-reported outcome measures (PROMs) used in clinical trials. Through comprehensive search of Embase, MEDLINE, and CENTRAL up until July 2022, we screened 1286 records, of which 191 were included in our analyses. Methodological quality (GRADE criteria), information about publication, patient population, and intervention were assessed, and domains as well as PROMs were extracted and analyzed. In accordance with IMMPACT domain framework, the domain pain was assessed in almost all studies (98.4%), followed by adverse events (73.8%). By contrast, assessment of physical functioning (29.8%), improvement and satisfaction (14.1%), and emotional functioning (6.8%) occurred less frequently. Studies of a better methodological quality tended to use more different domains. Nevertheless, combinations of more than 2 domains were rare, failing to comprehensively capture the bio-psycho-social aspects of endometriosis-associated pain. The PROMs used showed an even broader heterogeneity across all studies. Our findings underscore the large heterogeneity of assessed domains and PROMs in clinical pain-related endometriosis trials. This highlights the urgent need for a standardized approach to both, assessed domains and high-quality PROMs ideally realized through development and implementation of a core outcome set, encompassing the most pivotal domains and PROMs for both, stakeholders and patients.

Paradoxical heat sensation as a manifestation of thermal hypesthesia: a study of 1090 patients with lesions of the somatosensory system.

ABSTRACT: Paradoxical heat sensation (PHS) is the perception of warmth when the skin is cooled. Paradoxical heat sensation rarely occurs in healthy individuals but more frequently in patients suffering from lesions or disease of the peripheral or central nervous system. To further understand mechanisms and epidemiology of PHS, we evaluated the occurrence of PHS in relation to disease aetiology, pain levels, quantitative sensory testing parameters, and Neuropathic Pain Symptom Inventory (NPSI) items in patients with nervous system lesions. Data of 1090 patients, including NPSI scores from 404 patients, were included in the analysis. We tested 11 quantitative sensory testing parameters for thermal and mechanical detection and pain thresholds, and 10 NPSI items in a multivariate generalised linear model with PHS, aetiology, and pain (yes or no) as fixed effects. In total, 30% of the neuropathic patients reported PHS in contrast to 2% of healthy individuals. The frequency of PHS was not linked to the presence or intensity of pain. Paradoxical heat sensation was more frequent in patients living with polyneuropathy compared with central or unilateral peripheral nerve lesions. Patients who reported PHS demonstrated significantly lower sensitivity to thermal perception, with lower sensitivity to normally painful heat and cold stimuli. Neuropathic Pain Symptom Inventory scores were lower for burning and electric shock-like pain quality for patients with PHS. Our findings suggest that PHS is associated with loss of small thermosensory fibre function normally involved in cold and warm perception. Clinically, presence of PHS could help screening for loss of small fibre function as it is straightforward to measure or self-reported by patients.