Journal of Pain最新文献

{"title":"Increased TRPA1 functionality in the skin of rats and cancer patients following oxaliplatin treatment","authors":"Heleen Marynissen ,&nbsp;Sílvia Pinto ,&nbsp;Nele Van Ranst ,&nbsp;Eric Van Cutsem ,&nbsp;Thomas Voets ,&nbsp;Jan de Hoon","doi":"10.1016/j.jpain.2025.104794","DOIUrl":"10.1016/j.jpain.2025.104794","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy is a debilitating pathology affecting a majority of patients who are being treated with specific cytostatic compounds including oxaliplatin. Various <em>in vitro, ex vivo</em> and <em>in vivo</em> preclinical experiments indicate that transient receptor potential ankyrin 1 (TRPA1) plays a crucial role in the symptomatology of chemotherapy-induced peripheral neuropathy. However, it is unclear whether oxaliplatin also modulates the TRPA1 functionality in the skin of rodents or patients. Here, we quantified the vasodilation after topical application of the TRPA1 agonist cinnamaldehyde in a rodent model of chemotherapy-induced peripheral neuropathy (male Sprague Dawley rats, aged 6 weeks) as well as on fingers of patients suffering from chronic chemotherapy-induced peripheral neuropathy after oxaliplatin treatment. Compared to vehicle-treated rats, a cumulative dose of oxaliplatin 32 mg/kg enhanced the vasodilation after cinnamaldehyde application on rat abdominal skin. Likewise, also in patients with chronic chemotherapy-induced peripheral neuropathy after oxaliplatin, the response to cinnamaldehyde was significantly higher compared to sex- and age-matched healthy controls. Thereby, this study is the first to translate the evidence of increased TRPA1 functionality <em>in vitro</em> or <em>ex vivo</em> in rodents to <em>in vivo</em> conditions in human. The increased TRPA1 functionality in patients with chronic chemotherapy-induced peripheral neuropathy does not only confirm the potential of TRPA1 as target to hit to provide efficacious analgesia, it also paves the way for additional patient stratification on a molecular level and possible treatment response prediction.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104794"},"PeriodicalIF":4.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low working memory underpins the association between aberrant functional properties of pain modulation circuitry and chronic back pain severity","authors":"Jennika Veinot ,&nbsp;Douglas Cane ,&nbsp;Javeria Ali Hashmi","doi":"10.1016/j.jpain.2025.104795","DOIUrl":"10.1016/j.jpain.2025.104795","url":null,"abstract":"<div><div>Working memory impairments are common in chronic low back pain and are linked to increased pain severity. Reduced working memory may contribute to chronic pain by disrupting the ability to contextualize threat and modulate pain. These processes involve the dorsolateral prefrontal cortex and its interaction with the periaqueductal gray. However, it is unclear how working memory variability impacts activation and connectivity in this pathway and influences chronic pain. Here, we investigated how working memory variability affected activations in the dorsolateral prefrontal cortex – periaqueductal gray pathway during a pain modulation task (schema task) in individuals with chronic low back pain. This task measures how perceived threat of a strong noxious stimulus biases pain perception, referred to as threat bias. Individuals with worse threat bias experienced more widespread pain and less relief. Lower working memory accuracy was associated with abnormally increased activations in the dorsolateral prefrontal cortex and periaqueductal gray during low-threat conditions. In high-threat conditions, low activation in these regions correlated with greater chronic pain and impaired working memory. Baseline functional connectivity between the dorsolateral prefrontal cortex and periaqueductal gray also predicted working memory variability and pain severity. These findings suggest that working memory and pain modulation converge within the dorsolateral prefrontal cortex-periaqueductal gray pathway, where abnormalities contribute to chronic pain. This highlights cognitive-pain interactions and the potential of targeting working memory and this pathway for therapy.</div><div>Perspective</div><div>This article presents evidence that low working memory is associated with abnormalities in activations and connectivity in the pain modulation pathways in people with chronic low back pain. These changes predict chronic pain severity indicating a potential association between working memory, pain modulation pathways and chronic pain severity.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104795"},"PeriodicalIF":4.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying patient subgroups in the heterogeneous chronic pain population using cluster analysis","authors":"Mienke Rijsdijk ,&nbsp;Hidde M. Smits ,&nbsp;Hazal R. Azizoglu ,&nbsp;Sylvia Brugman ,&nbsp;Yoeri van de Burgt ,&nbsp;Tessa C. van Charldorp ,&nbsp;Dewi J. van Gelder ,&nbsp;Janny C. de Grauw ,&nbsp;Eline A. van Lange ,&nbsp;Frank J. Meye ,&nbsp;Madelijn Strick ,&nbsp;Hedi W.A. Walravens ,&nbsp;Laura H.H. Winkens ,&nbsp;Frank J.P.M. Huygen ,&nbsp;Julia Drylewicz ,&nbsp;Hanneke L.D.M. Willemen","doi":"10.1016/j.jpain.2025.104792","DOIUrl":"10.1016/j.jpain.2025.104792","url":null,"abstract":"<div><div>Chronic pain is an ill-defined disease with complex biopsychosocial aspects, posing treatment challenges. We hypothesized that treatment failure results, at least partly, from limited understanding of diverse patient subgroups. We aimed to identify subgroups using psychological variables, allowing for more tailored interventions. In a retrospective cohort study, we extracted patient-reported data from two Dutch tertiary multidisciplinary outpatient pain clinics (2018–2023) for unsupervised hierarchical clustering. Clusters were defined by anxiety, depression, pain catastrophizing, and kinesiophobia. Sociodemographics, pain characteristics, diagnosis, lifestyle, health-related quality of life and treatment efficacy were compared among clusters. A prediction model was built utilizing a minimum set of questions to reliably assess cluster allocation. Among 5466 patients with chronic pain, three clusters emerged. Cluster 1 (n=750) was characterized by high psychological burden, low health-related quality of life, lower educational levels and employment rates, and more smoking. Cluster 2 (n=1795) showed low psychological burden, intermediate health-related quality of life, higher educational levels and employment rates, and more alcohol consumption. Cluster 3 (n=2909) showed intermediate features. Pain reduction following treatment was least in cluster 1 (28.6% after capsaicin patch, 18.2% after multidisciplinary treatment), compared to &gt;50% for both treatments in clusters 2 and 3. A model incorporating 15 psychometric questions reliably predicted cluster allocation. <strong>In conclusion,</strong> our study identified distinct chronic pain patient clusters through 15 psychological questions, revealing one cluster with notably poorer response to conventional treatment. Our prediction model, integrated in a web-based tool, may help clinicians improve treatment by allowing patient-subgroup targeted therapy according to cluster allocation.</div></div><div><h3>Perspective</h3><div>Hierarchical clustering of chronic pain patients identified three subgroups with similar pain intensity and diagnoses but distinct psychosocial traits. One group with higher psychological burden showed poorer treatment outcomes. A web-based tool using this model could help clinicians tailor therapies by matching interventions to specific patient subgroups for improved outcomes.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104792"},"PeriodicalIF":4.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and age effects on chronic inflammatory pain development, maintenance, and resolution in Wistar rats","authors":"Andrea F. Jones ,&nbsp;Queenie Wang ,&nbsp;Keishla M. Rodríguez-Graciani ,&nbsp;Zaidmara T. Díaz ,&nbsp;Liz Simon ,&nbsp;Nicholas W. Gilpin","doi":"10.1016/j.jpain.2025.104789","DOIUrl":"10.1016/j.jpain.2025.104789","url":null,"abstract":"<div><div>Millions of Americans live with chronic inflammatory pain conditions, and the prevalence of these conditions increases with age and is higher in females. Still, it is poorly understood how sex, age and peripheral gene expression affect the trajectory of chronic inflammatory pain conditions. We used the inflammatory agent, Complete Freund’s Adjuvant (CFA), to systematically test sex and age effects on mechanical and thermal sensitivity in adolescent and adult male and female Wistar rats over 3 weeks (Experiment 1 [onset]) or 11 weeks (Experiment 2 [recovery]). We report that relative to male CFA rats, CFA females are mechanically hypersensitive at all time points and thermally hypersensitive at later time points (long-term during maintenance and recovery). Also, within CFA rats, more adult males (90%) achieved behavioral recovery at 11 weeks, relative to adolescent males (70%), adult females (70%) and adolescent females (50%). Behavioral recovery was most highly correlated with thermal nociception scores in most groups. Among adult males, significant positive correlations were seen between mechanical and thermal nociception scores and between scores in the CFA-injected and non-injected paws. In paw tissue from a subset of rats from experiment 2, we also report increased transient receptor potential cation channel subfamily V member 1 (TRPV1) gene expression in adult CFA but not adolescent CFA rats, and increased pro- and anti-inflammatory, and triglyceride synthesis-related gene expression in all CFA rats. Our results demonstrate apparent sex and age differences in the trajectory of chronic inflammatory pain-related behavior and gene expression in the affected paw of rats.</div></div><div><h3>Perspective</h3><div>This article highlights sex and age differences in the trajectory of chronic inflammatory pain and possible peripheral mechanisms driving recovery in Wistar rats. This data could be used to better understand recovery patterns in patients with this type of pain and provides a starting point for assessment of novel treatments.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104789"},"PeriodicalIF":4.0,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of centrally acting analgesics on resting-state electroencephalography biomarker candidates of chronic pain","authors":"Paul Theo Zebhauser ,&nbsp;Felix Bott ,&nbsp;Cristina Gil Ávila ,&nbsp;Henrik Heitmann ,&nbsp;Elisabeth S. May ,&nbsp;Laura Tiemann ,&nbsp;Enayatullah Baki ,&nbsp;Thomas R. Tölle ,&nbsp;Markus Ploner","doi":"10.1016/j.jpain.2025.104788","DOIUrl":"10.1016/j.jpain.2025.104788","url":null,"abstract":"<div><div>Resting-state electroencephalography (rsEEG) holds promise as a biomarker of chronic pain. However, the impact of centrally acting analgesics like opioids, antiepileptics, and antidepressants on rsEEG remains unclear. This confounds and limits the interpretability of previous studies and questions the specificity of rsEEG biomarker candidates of chronic pain, especially for potential diagnostic biomarkers. We, therefore, aimed to elucidate the effects of opioids, antiepileptics, and antidepressants on common rsEEG biomarker candidates of chronic pain. To this end, we analyzed two large, independent rsEEG datasets, including 217 people with chronic pain. We performed preregistered multivariate Bayesian analyses to allow for the quantification and interpretation of evidence in favor of as well as against medication effects on EEG. We specifically evaluated the effects of different centrally acting analgesics on rsEEG features and controlled for the potential confounds of age, pain intensity, and depression. Results predominantly provided evidence against effects of centrally acting analgesics on peak alpha frequency, oscillatory power in different frequency bands, and connectivity-based network measures. Although these findings do not rule out any effects of analgesics on rsEEG, they argue against medium to large effects of centrally acting analgesics on rsEEG. These results help to interpret previous and future rsEEG findings in people with chronic pain and strengthen the validity of rsEEG biomarker candidates of chronic pain. Thus, the present findings can help to develop clinically valuable biomarkers of chronic pain.</div></div><div><h3>Perspective</h3><div>This study investigated the effects of centrally acting analgesics on brain-based biomarker candidates of chronic pain, as assessed by electroencephalography. The results predominantly provided evidence against effects on peak alpha frequency, oscillatory power, and connectivity-based network measures. This might help to develop clinically useful biomarkers of chronic pain.</div></div><div><h3>Data availability</h3><div>Datasets are available at <span><span>https://osf.io/uzgxw/files/osfstorage</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104788"},"PeriodicalIF":4.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment expectations and pain-related outcomes in clinical trials of digital cognitive-behavioral therapy for youth with chronic pain","authors":"Rui Li PhD ,&nbsp;Kavin Srinakarin ,&nbsp;Rocío de la Vega ,&nbsp;Caitlin B. Murray ,&nbsp;Tonya M. Palermo","doi":"10.1016/j.jpain.2025.104791","DOIUrl":"10.1016/j.jpain.2025.104791","url":null,"abstract":"<div><div>Treatment expectations (TE) are predictive of patient outcomes in clinical practice and suggested to moderate treatment responses in chronic pain clinical trials. However, evidence is mainly derived from studies conducted with adult populations with musculoskeletal pain, primarily focused on pharmacological treatments and a few alternative intervention modalities (e.g., acupuncture). We examined the role of pretreatment TE in youth participating in two randomized controlled trials of digital cognitive-behavioral therapy (CBT) for chronic pain—the WebMAP2 Trial of youth with chronic primary pain (n = 273) and the iCC-SCD Trial of youth with sickle cell pain (n = 111). Specifically, we tested: 1) whether controlling for TE enhanced the detection of treatment efficacy, 2) the main effect of TE in predicting pain-related outcomes over time (regardless of treatment assignment), and 3) the effect of TE in moderating treatment efficacy (digital CBT vs education control). Findings indicated that adjusting for pretreatment TE did not enhance the ability to detect treatment efficacy. In the WebMAP2 Trial, higher pretreatment TE were associated with greater reductions in anxiety and lower CBT efficacy (relative to education control) in improving depressive and anxiety symptoms. In the iCC-SCD Trial, higher pretreatment TE were associated with greater improvement in mobility and enhanced CBT efficacy (relative to education control) for improving mobility. Overall, higher pretreatment TE were associated with better functioning over time, though the specific domains of improvement and the moderating effects on treatment efficacy somewhat differed between youth with primary and sickle cell-related chronic pain.</div></div><div><h3>Perspective</h3><div>Incorporating TE into clinical assessments and ensuring consistent collection, reporting, and analysis in clinical trials are crucial for identifying potential heterogeneous treatment responses. Standardizing TE measures for youth with chronic pain and considering population characteristics are important for understanding TE's role in treatment responses.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104791"},"PeriodicalIF":4.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and risk factors for the development of chronic postoperative pain after cataract surgery in the Age-related Eye Disease Study (AREDS)","authors":"Rony R. Sayegh MD ,&nbsp;Susan Vitale PhD, MHS ,&nbsp;Elvira Agrón MA ,&nbsp;John T. Farrar MD, PhD ,&nbsp;Penny A. Asbell MD, MBA ,&nbsp;Emily Y. Chew MD ,&nbsp;For the AREDS Research Group","doi":"10.1016/j.jpain.2025.104790","DOIUrl":"10.1016/j.jpain.2025.104790","url":null,"abstract":"<div><div>Chronic ocular pain impacts quality of life and is often linked to ocular surgery. We assessed the prevalence of chronic postoperative pain (CPOP) after cataract surgery and associated risk factors using a secondary cohort post-hoc analysis of data from the Age-Related Eye Disease Study (AREDS), a multicenter, controlled, randomized clinical trial of antioxidant vitamins and minerals. Ocular pain was determined from item 4 of the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), administered between 1997 and 2005. We included participants who underwent cataract surgery during the study and reported no or mild ocular pain before first-eye cataract surgery (n=325). Controls (n=283) reported no or mild ocular pain 3 or more months after first-eye cataract surgery; cases (n=42) reported moderate or severe pain 3 or more months after first-eye cataract surgery. Multivariable logistic regression models assessed associations between potential risk factors (age, sex, body mass index, smoking, diabetes, education level, use of anti-inflammatory agents, use of antacids, general health, AREDS treatment group) and CPOP. Of the 325 participants (mean age, 69.7±4.4 years, 59.4 % female); CPOP developed in 42 (13 %; 95 % CI, 9.3 – 16.6 %). The average time between cataract surgery and the post-surgery VFQ was 18.4±11.8 months (range 3.0 – 65.0 months). Multivariable analysis did not reveal any statistically significant associations with odds of developing CPOP after cataract surgery. As such, in this AREDS cohort who underwent cataract surgery, 13% developed CPOP, consistent with previous reports from cataract and refractive surgery. Our post-hoc analyses did not identify any significant risk factors for CPOP.</div></div><div><h3>Perspective</h3><div>We found a high prevalence of Chronic Postoperative Pain (CPOP) in the AREDS cohort, with 13 % of participants who underwent cataract surgery developing CPOP. Post-hoc analysis did not identify significant risk factors for CPOP. Our study contributes valuable insights into a growing area of interest in pain management within ophthalmology.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104790"},"PeriodicalIF":4.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of complementary health approaches on opioid prescriptions among veterans with musculoskeletal disorders","authors":"Chung-Chu Tung ,&nbsp;Wei-Kai Lee MD ,&nbsp;Wen-Bin Yeh ,&nbsp;Renin Chang","doi":"10.1016/j.jpain.2025.104779","DOIUrl":"10.1016/j.jpain.2025.104779","url":null,"abstract":"","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104779"},"PeriodicalIF":4.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological considerations in chronic pain treatment addressing the impact of mental health and the COVID-19 pandemic","authors":"Chung-Chu Tung ,&nbsp;Wei-Kai Lee MD ,&nbsp;Wen-Bin Yeh ,&nbsp;Renin Chang","doi":"10.1016/j.jpain.2025.104780","DOIUrl":"10.1016/j.jpain.2025.104780","url":null,"abstract":"","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104780"},"PeriodicalIF":4.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placebo nonresponders: An experimental investigation on their unreliability over time","authors":"Fabrizio Benedetti ,&nbsp;Wilma Thoen ,&nbsp;Aziz Shaibani ,&nbsp;Claudia Arduino","doi":"10.1016/j.jpain.2025.104777","DOIUrl":"10.1016/j.jpain.2025.104777","url":null,"abstract":"<div><div>In order to disentangle the effects of drugs from placebo responses, several approaches have been used, such as a placebo run-in phase in which only placebo nonresponders, or poor responders, are considered for further randomization to either placebo or active treatment. This study is aimed at investigating the variability of placebo nonresponders obtained through the classical placebo run-in paradigm (group RUN) and through mismatch conditioning (group MIS), as done in our previous study. To do this, we simulated a real clinical trial in the laboratory, in which the placebo responders of both groups were discarded and the remaining nonresponders of both groups RUN and MIS were randomized to either continuing on placebo (groups RUN-P and MIS-P, respectively) or receiving topical 0.5% lidocaine (groups RUN-L and MIS-L, respectively) applied to the skin. By measuring pain thresholds, we found that the placebo nonresponders selected on the first day of the experiment showed different responses on the following day in both group RUN and MIS. This led to no significant differences between placebo and lidocaine in both groups. Although this is an experimental laboratory situation far from the clinical trial setting, these findings show that placebo nonresponders are not necessarily constant over time, both when a placebo run-in protocol is used and when nonresponders are created in the laboratory. This questions the reliability of selecting placebo nonresponders as a methodological approach in clinical research. Therefore, we suggest reconsidering the validity and usefulness of placebo run-in protocols.</div></div><div><h3>Perspective</h3><div>Placebo nonresponders are sometime selected for further randomization to either placebo or active treatment. In this experimental study, which is a laboratory simulation of a clinical trial, we found that placebo nonresponders vary from day to day, thus questioning their validity as a methodological approach in clinical research.</div></div>","PeriodicalId":51095,"journal":{"name":"Journal of Pain","volume":"28 ","pages":"Article 104777"},"PeriodicalIF":4.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}