Pain screening in youth with sickle cell disease: A quality improvement study.

BACKGROUND: Youth with sickle cell disease (SCD) face several challenges as they age, including increased pain frequency, duration, and interference. The purpose of this study was to (i) determine the feasibility of routine pain screening; (ii) identify and describe various clinical pain presentations; and (iii) understand preferences/resources related to engaging in integrative health and medicine (IHM) modalities within an outpatient pediatric SCD clinic. METHODS: During routine outpatient visits, patients aged 8-18 completed measures of pain frequency, duration, and chronic pain risk (Pediatric Pain Screening Tool [PPST]). Participants screening positive for (i) persistent or chronic pain or (ii) medium or high risk for persistent symptoms and disability on the PPST were asked to complete measures of pain interference, pain catastrophizing, and interest in/resources for engaging in IHM modalities. RESULTS: Between March 2022 and May 2023, 104/141 (73.8%) patients who attended at least one outpatient visit were screened. Of these 104 (mean age 12.46, 53.8% female, 63.5% HbSS), 34 (32.7%) reported persistent or chronic pain, and 48 (46.2%) reported medium or high risk for persistent symptoms and disability. Patients completing subsequent pain screening measures reported a mean pain interference T-score of 53.2 ± 8.8 and a mean pain catastrophizing total score of 24.3 ± 10.2. Patients expressed highest interest in music (55.6%) and art therapy (51.9%) and preferred in-person (81.5%) over virtual programming (22.2%). CONCLUSIONS: Comprehensive pain screening is feasible within pediatric SCD care. Classifying patients by PPST risk may provide a means of triaging patients to appropriate services to address pain-related psychosocial factors.

Characterizing Extreme Phenotypes for Perceived Improvement From Treatment in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To define and characterize extreme phenotypes based on perceived improvement in pain for persons with chronic pain following traumatic brain injury (TBI). SETTING: Eighteen Traumatic Brain Injury Model System (TBIMS) Centers. PARTICIPANTS: A total of 1762 TBIMS participants 1 to 30 years post-injury reporting chronic pain at their most recent follow-up interview. PRIMARY MEASURES: The Patient's Global Impression of Change (PGIC) related to pain treatment. Sociodemographic, injury, functional outcome, pain, and pain treatment characteristics. RESULTS: Participants were mostly male (73%), White (75%), middle-aged (mean 46 years), injured in motor vehicle accidents (53%), or falls (20%). Extreme phenotypes were created for an extreme improvement phenotype ( n = 512, 29.8%) defined as "moderately better" or above on the PGIC and an extreme no-change group ( n = 290, 16.9%) defined as no change or worse. Least absolute shrinkage and selection operator (LASSO) regression combined with logistic regression identified multivariable predictors of improvement versus no-change extreme phenotypes. Higher odds of extreme improvement phenotype were significantly associated with being female (odds ratio [OR] = 1.85), married versus single (OR = 2.02), better motor function (OR = 1.03), lower pain intensity (OR = 0.78), and less frequent pain, especially chest pain (OR = 0.36). Several pain treatments were associated with higher odds of being in the extreme improvement versus no-change phenotypes including pain medication (OR = 1.85), physical therapy (OR = 1.51), yoga (OR = 1.61), home exercise program (OR = 1.07), and massage (OR = 1.69). CONCLUSION: Investigation of extreme phenotypes based on perceived improvement with pain treatment highlights the ability to identify characteristics of individuals based on pain treatment responsiveness. A better understanding of the biopsychosocial characteristics of those who respond and do not respond to pain treatments received may help inform better surveillance, monitoring, and treatment. With further research, the identification of risk factors (such as pain intensity and frequency) for treatment response/nonresponse may provide indicators to prompt changes in care for individuals with chronic pain after TBI.

Case report: Dorsal root ganglion stimulator lead fracture.

BACKGROUND: One of the unique advances in neuromodulation for chronic pain has been spinal cord stimulators (SCS) and dorsal root ganglion stimulators (DRG-S). These devices have aided in conditions such as neuropathic pain, complex regional pain syndromes, failed back surgery, and peripheral neuropathies. With these benefits, however, complications from implantable stimulators have included lead fractures and migration. The authors reviewed a lead migration, kinking, and subsequent fracture event involving a patient with complex regional pain syndrome (CRPS) II, who was treated with a DRG-S. CASE PRESENTATION: The case report follows this patient, from their past medical history to assessment of appropriate qualifications for neuromodulation, to successful surgical placement, to follow-up care. The authors further monitored assessment of inefficacy of pain relief, and identification of lead migration and kinking through imaging. In the process of removal, due to lead stress, lead fracturing occurred. After lead removal, the leads were fully replaced, and the patient was followed up and experienced improved pain relief. CONCLUSION: The case report assesses probable mechanisms of lead fracture and considerations for physicians for future assessment and triage of neuromodulation efficacy.

Management of chronic pain associated with temporomandibular disorders: a clinical practice guideline.

CLINICAL QUESTION: What is the comparative effectiveness of available therapies for chronic pain associated with temporomandibular disorders (TMD)? CURRENT PRACTICE: TMD are the second most common musculoskeletal chronic pain disorder after low back pain, affecting 6-9% of adults globally. TMD are associated with pain affecting the jaw and associated structures and may present with headaches, earache, clicking, popping, or crackling sounds in the temporomandibular joint, and impaired mandibular function. Current clinical practice guidelines are largely consensus-based and provide inconsistent recommendations. RECOMMENDATIONS: For patients living with chronic pain (≥3 months) associated with TMD, and compared with placebo or sham procedures, the guideline panel issued: (1) strong recommendations in favour of cognitive behavioural therapy (CBT) with or without biofeedback or relaxation therapy, therapist-assisted mobilisation, manual trigger point therapy, supervised postural exercise, supervised jaw exercise and stretching with or without manual trigger point therapy, and usual care (such as home exercises, stretching, reassurance, and education); (2) conditional recommendations in favour of manipulation, supervised jaw exercise with mobilisation, CBT with non-steroidal anti-inflammatory drugs (NSAIDS), manipulation with postural exercise, and acupuncture; (3) conditional recommendations against reversible occlusal splints (alone or in combination with other interventions), arthrocentesis (alone or in combination with other interventions), cartilage supplement with or without hyaluronic acid injection, low level laser therapy (alone or in combination with other interventions), transcutaneous electrical nerve stimulation, gabapentin, botulinum toxin injection, hyaluronic acid injection, relaxation therapy, trigger point injection, acetaminophen (with or without muscle relaxants or NSAIDS), topical capsaicin, biofeedback, corticosteroid injection (with or without NSAIDS), benzodiazepines, and ß blockers; and (4) strong recommendations against irreversible oral splints, discectomy, and NSAIDS with opioids. HOW THIS GUIDELINE WAS CREATED: An international guideline development panel including patients, clinicians with content expertise, and methodologists produced these recommendations in adherence with standards for trustworthy guidelines using the GRADE approach. The MAGIC Evidence Ecosystem Foundation (MAGIC) provided methodological support. The panel approached the formulation of recommendations from the perspective of patients, rather than a population or health system perspective. THE EVIDENCE: Recommendations are informed by a linked systematic review and network meta-analysis summarising the current body of evidence for benefits and harms of conservative, pharmacologic, and invasive interventions for chronic pain secondary to TMD. UNDERSTANDING THE RECOMMENDATION: These recommendations apply to patients living with chronic pain (≥3 months duration) associated with TMD as a group of conditions, and do not apply to the management of acute TMD pain. When considering management options, clinicians and patients should first consider strongly recommended interventions, then those conditionally recommended in favour, then conditionally against. In doing so, shared decision making is essential to ensure patients make choices that reflect their values and preference, availability of interventions, and what they may have already tried. Further research is warranted and may alter recommendations in the future.

The Impact and Correlation of Anxiety and Depression on Pressure Pain Threshold of Acupoints in Patients with Chronic Pelvic Inflammatory Disease.

Background: Chronic pelvic inflammatory disease (CPID) is a clinically common gynecological disease. Patients experience chronic pelvic pain and often accompany with emotional dysfunction. However, the impact and correlation of anxiety and depression on pain sensitization is not completely known. Objective: To explore the differences and correlations among anxiety, depression, and pressure pain threshold (PPT) of acupoints in patients with CPID. Methods: One hundred and forty-seven patients with CPID were recruited. The Visual Analog Scale (VAS) and short-form McGill Pain Questionnaire (SF-MPQ) were used to assess pain. Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were used to evaluate the emotional state of patients. The PPT of acupoints was collected using an electronic Von Frey by two licensed acupuncturists. Results: The CPID patients were divided into anxiety-depression group (group A) or nonanxiety-depression group (group B), according to the SAS and SDS scores. Finally, there were 73 patients in group A and 74 patients in group B. Group A had significantly higher SAS, SDS, VAS, and SF-MPQ scores than group B (P < 0.05). In addition, significant differences were observed in the PPTs of ST28 (R), ST29 (R), SP10 (R), SP9 (R), SP9 (L), ST36 (R), and LR3 (L) between the two groups (P < 0.05). No considerable differences in PPTs at the other acupoints were observed between the two groups. SAS scores showed a positive correlation with PPTs of ST29 (R), SP10 (R), SP9 (L), ST36 (R), and LR3 (L). No remarkable correlation was observed between the SDS scores and PPTs. Conclusion: Anxiety and depression can affect the PPT of some acupoints in CPID patients, which may provide a reference for acupoint selection for acupuncture treatment of CPID with emotional disorders. This trial is registered with ChiCTR2100052632.

Comparing the effectiveness of extracorporeal shockwave therapy and myofascial release therapy in chronic pelvic pain syndrome: study protocol for a randomized controlled trial.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome is a highly prevalent syndrome. Previous studies showed that extracorporeal shockwave therapy and myofascial release therapy could improve the quality of life in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Theoretically, combined therapy with extracorporeal shockwave therapy and myofascial release therapy will likely have significant advantages in treating CP/CPPS. We, therefore, present a protocol for conducting a well-designed randomized controlled trial to compare the efficacy and safety of each therapy. METHODS: The proposed study will be a three-group randomized control trial (RCT) design that includes 150 participants from Zhongda Hospital Affiliated to Southeast University, with equal allocation of participants to the three intervention groups. The study duration will be 8 weeks, which includes a 4-week treatment period and a 4-week follow-up period. The primary outcome will be the changes in surface electromyography (sEMG) assessment and National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI). The secondary outcomes will include the changes in three-dimensional quantification, shear wave elastography (SWE), and sympathetic skin response (SSR) testing. Assessments will be conducted before the intervention (T0), before the 5th intervention (T1), immediately after the 8th intervention (T2), and the 4th week after the end of the 8th intervention (T3). DISCUSSION: This trial will compare the differences in efficacy between single extracorporeal shockwave therapy, single myofascial release therapy, and combined therapy to select the most appropriate treatment option for patients with CP/CPPS. The possible pathogenesis of CP/CPPS would also be analyzed by comparing the intercorrelation between each objective and subjective measurement (NIH-CPSI score, sEMG, SWE, SSR). TRIAL REGISTRATION: The name of the registry: Extracorporeal Shockwave and Myofascial Release Therapy in Chronic Pelvic Pain Syndrome. REGISTRATION NUMBER: NCT05659199. Date of registration: December 2022.

Sacral neuromodulation in endometriosis - A promising treatment option for chronic pelvic pain.

INTRODUCTION: Chronic pelvic pain (CPP) affects over one fifth of women worldwide, and endometriosis is one of the most common causes. In the present study, we examined whether sacral neuromodulation (SNM) is effective in the treatment of refractory chronic pelvic pain in women with endometriosis. MATERIAL AND METHODS: This multicenter prospective pilot study was started in 2017 and includes patients with chronic pelvic pain with no other obvious pathology than endometriosis. Other treatment options have been tried or they are unsuitable. Patients underwent SNM implantation. The main outcome was postoperative pain reduction and secondary outcome was quality of life. The following questionnaires were used to assess the outcomes: Brief pain inventory (BPI), clinical global impression - improvement (CGI-I), 15D-measure of health-related quality of life, and Biberoglu and Behrman (B&B) score. RESULTS: A total of 35 patients underwent the SNM procedure and, at the time of analysis, 15 patients had returned one-year questionnaires. The patients had a history of endometriosis for a median of 5.5 (interquartile range 2-9) years, with no correlation between the severity of symptoms and the duration of the disease (p = 0.158). A total of 31 patients (89%) were implanted with the internal pulse generator. There were statistically significant changes in BPI pain-related items. Worst experienced daily pain decreased among those who returned 12-month questionnaires from median 9 to 5 (p = 0.006), average daily pain from 6 to 3.5 (p = 0.004), and least daily pain from 3 to 1 (p = 0.004). Based on the CGI questionnaire (n = 14), at 12 months nine patients (60%) experienced great improvement in their symptoms, three patients (20%) much improvement and two patients (13%) minimal improvement. None of the patients experienced worsening of their symptoms. There was a statistically significant change in overall 15D score at 1 month (p < 0.001), 6 months (p = 0.001) and 12 months (p = 0.018), when the results were compared to baseline values. Median B&B score also improved significantly and decreased from a baseline value of 8 (4-12) to 4.5 (0-6), p = 0.002. CONCLUSIONS: Based on the preliminary findings of our study, SNM might be a promising treatment of CPP in endometriosis patients.

Biopsychosocial approach to male chronic pelvic pain syndrome: recent treatments and trials.

INTRODUCTION: Chronic pelvic pain syndrome (CPPS) is a common urologic condition that can cause significant disability in affected individuals. Physiologic explanations of chronic pain are often incomplete; appropriate management of CPPS includes recognition of biological, psychological, and social elements, known as the biopsychosocial model. OBJECTIVE: The aim of this narrative review is to investigate treatments for men with CPPS, with a special focus on those utilizing the biopsychosocial model of care. METHODS: A comprehensive literature search was conducted on the electronic databases PubMed, Embase, and Cochrane Library, using relevant Medical Subject Heading terms and keywords related to CPPS treatments. The search was limited to studies published in English from inception to January 2023. Additionally, reference lists of selected studies were manually reviewed to find studies not identified by the initial search. Studies were included if they investigated pharmacologic or nonpharmacologic treatments for men with CPPS. RESULTS: A total of 30 studies met the inclusion criteria. Antibiotics, α-blockers, nonsteroidal anti-inflammatory drugs, gabapentinoids, antidepressants, and phosphodiesterase type 5 inhibitors were among the pharmacologic agents included in trials attempting to reduce symptoms of male CPPS. Studies that focused on treating CPPS without medication included interventions such as shockwave therapy, acupuncture, physical therapy, botulinum toxin, cryotherapy, electrotherapy, exercise, and cognitive behavioral therapy. CONCLUSION: α-Blockers and nonsteroidal anti-inflammatory drugs have shown promising results in treating CPPS in men, while the effectiveness of antibiotics remains controversial. Antidepressants and phosphodiesterase type 5 inhibitors may also be useful in decreasing symptoms in patients with CPPS. Treatments such as pelvic floor muscle therapy, acupuncture, shockwave therapy, and cognitive behavioral therapy must be considered effective complements to medical management in men with CPPS. While these interventions demonstrate benefits as monotherapies, the individualization and combination of treatment modalities are likely to result in reduced pain and improved quality of life.

Feasibility and outcomes of Desarda vs Lichtenstein hernioplasty by local anesthesia for inguinal hernia: a noninferiority randomized clinical trial.

INTRODUCTION: The Desarda autologous tissue repair is comparable to the Lichtenstein hernioplasty for inguinal hernia regarding recurrence, chronic groin pain, and return to work activities. This study was designed to establish the outcomes of Desarda's repair versus Lichtenstein's hernioplasty concerning post-operative recovery to normal gait and its feasibility under local anesthesia (LA). MATERIALS AND METHODS: This study was a single-center, prospective, double-blinded, non-inferiority, randomized trial. Patients undergoing open hernia repair for primary inguinal hernia were included. Patients were randomly assigned and followed up for 2 years. The primary endpoint was the time to return to normal gait post-surgery with comfort (non-inferiority margin fixed as 0.5 days). The secondary outcomes studied were post-operative pain score, the time required to return to work (all previously performed activities), and surgical-site occurrences (SSO). RESULTS: One hundred ten eligible patients were randomly assigned [56 patients (50.9%) in the Desarda group and 54 patients (49.1%) in the Lichtenstein group]. All the procedures were safely performed under LA. The median (interquartile range) time for resuming gait post-surgery with comfort was 5 days in the Desarda vs 4 days in Lichtenstein's arm (P = 0.16), thereby failing to demonstrate non-inferiority of Desarda against Lichtenstein hernioplasty. However, there were no significant differences in days to return to work, SSO, chronic groin pain, and recurrence within two years of surgery. CONCLUSIONS AND RELEVANCE: This study could not demonstrate the non-inferiority of the Desarda repair versus Lichtenstein hernioplasty regarding the time taken to return to normal gait. Comparing the days to return to work, pain score, SSO, and chronic groin pain, including recurrence rate, Desarda repair faired equally with Lichtenstein hernioplasty, thereby highlighting its feasibility and efficacy under LA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03512366.

[Influence of chronic pain in osteoarthritis on the risk of cardiovascular diseases and modern methods of drug prevention]. / Vliyanie khronicheskoi boli pri osteoartrite na risk razvitiya serdechno-sosudistykh zabolevanii i sovremennye sposoby ikh lekarstvennoi profilaktiki.

The purpose of the review of scientific medical literature was to evaluate the data of the epidemiology of osteoarthritis (OA) and cardiovascular diseases (CVD) with the analysis of risk factors, pathophysiological and pathobiochemical mechanisms of the relationship between OA and the risk of developing CVD in the presence of chronic pain, modern strategies for screening and management of this cohort of patients, the mechanism of action and pharmacological effects of chondroitin sulfate (CS). Conclusions were drawn about the need for additional clinical and observational studies of the efficacy and safety of the parenteral form of CS (Chondroguard) in patients with chronic pain in OA and CVD, improvement of clinical recommendations for the treatment of chronic pain in patients with OA and cardiovascular risk, with special attention to interventions that eliminate mobility restrictions in patients and the inclusion of basic and adjuvant therapy with DMOADs to achieve the goals of multipurpose monotherapy in patients with contraindications to standard therapy drugs.

Chronic Primary Pelvic Pain Syndrome in Men.

BACKGROUND: Chronic primary pelvic pain syndrome in men (CPPPSm) can be associated with urogenital pain, urinary symptoms, sexual dysfunction, and emotional disturbance. Its clinical heterogeneity and incompletely understood pathogenesis make it more difficult to treat. This article is intended to familiarize the reader with basic aspects of the manifestations, pathophysiology, diagnostic evaluation, differential diagnosis, and treatment of this condition. METHODS: This article is based on relevant publications retrieved by a selective search of the literature, including the current guidelines of the European Association of Urology. The features of this disease pertaining to urology, psychosomatic medicine, and pain medicine are illuminated from an interdisciplinary perspective. RESULTS: Chronic pelvic pain appears to arise through a complex interaction of inflammatory, infectious, neurological, musculoskeletal, and psychosomatic factors. A comprehensive diagnostic work-up should be carried out to evaluate and exclude the numerous differential diagnoses. Treatment strategies are based on the clinical phenotype. Randomized controlled trials have shown that significant relief can be achieved with a variety of drugs and non-pharmacological treatments, selected according to the manifestations of the condition in the individual case. Attention must be paid to treatment-specific adverse effects. CONCLUSION: The management of patients with CPPPSm should consist of a comprehensive differential diagnostic evaluation and an individually oriented treatment strategy.

Acupuncture for Chronic Prostatitis or Chronic Pelvic Pain Syndrome: An Updated Systematic Review and Meta-Analysis.

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex male dysfunction, mostly seen in young and middle-aged men with a history of more than 3 months. As a traditional therapy of Traditional Chinese Medicine, acupuncture has been proven an effective method to treat CP/CPPS in recent years. Though some meta-analyses on acupuncture for chronic prostatitis were published in 2018 and 2019, most of the included studies were low in quality according to the JADAD score (JADAD < 4). The conclusions of acupuncture for CP/CPPS remain indefinite. Purpose: This review aims to evaluate the efficacy of acupuncture for CP/CPPS by including high-quality literature only (JADAD ≥ 4) to provide a reliable basis for clinical applications and research. Method: Nine electronic databases were searched from inception to March 1, 2022, and only randomized controlled trials (RCT) with high-quality (JADAD ≥ 4) were included. Data were analyzed using Review Manager 5.3. and was verified through trial sequential analysis (TSA). We carried out a sensitivity analysis for the heterogeneity (I 2 ≥ 50%). Publication bias was explored using a funnel plot. Result: Ten RCTs (11 trials) of high-quality methodology involving 798 patients were included. Meta-analysis showed that compared to sham acupuncture (SAT) and western medicine (WM), acupuncture (AT) played superior roles for CP/CPPS patients in pain score, NIH-CPSI score, quality of life score, urinary symptom, and efficacy rate. As for the adverse effects, 4 RCTs described mild hematoma and pain in AT and SAT groups, while specific symptoms including nausea, abdominal pain, dizziness, and low blood pressure were reported in WM groups. Conclusion: This meta-analysis indicated that acupuncture has measurable benefits on CP/CPPS, and security has also been ensured. However, this meta-analysis only included 10 RCTs; thus, RCTs with a larger sample size and longer-term observation are required to verify the effectiveness of acupuncture further in the future.

Acupuncture use for pain after traumatic brain injury: a NIDILRR Traumatic Brain Injury Model Systems cohort study.

BACKGROUND: Pain after traumatic brain injury (TBI) is common and can become chronic. Acupuncture is an increasingly popular non-pharmacologic option in the United States and is commonly used for pain. OBJECTIVE: We explored demographics, injury characteristics, and pain characteristics of individuals who reported using acupuncture for chronic pain after TBI. METHODS: We analyzed a subset of data collected as part of the Pain After Traumatic Brain Injury collaborative study and identified individuals reporting a history of acupuncture as part of management for chronic pain after TBI. We characterized and compared basic demographic data, pain treatment engagements, pain severity, pain interference, functional independence, and pain locations using descriptive and inferential statistics. RESULTS: Our sample included 1,064 individuals. Acupuncture use (n = 208) was lower proportionally among females, Blacks/African Americans, Asians, less educated, and nonmilitary service members. Insurance type varied between acupuncture and non-acupuncture users. Functional and pain outcomes were similar, but acupuncture users reported a higher number of pain sites. DISCUSSION: Acupuncture is one treatment utilized by individuals with TBI and chronic pain. Further investigation would be helpful to understand the barriers and facilitators of acupuncture use to inform clinical trials to examine the potential benefit of acupuncture on pain outcomes after TBI.

Mechanisms of chiropractic spinal manipulative therapy for patients with chronic primary low back pain: protocol for a mechanistic randomised placebo-controlled trial.

INTRODUCTION: Chronic low back pain (CLBP) is a highly prevalent and disabling condition. Identifying subgroups of patients afflicted with CLBP is a current research priority, for which a classification system based on pain mechanisms was proposed. Spinal manipulative therapy (SMT) is recommended for the management of CLBP. Yet, little data are available regarding its mechanisms of action, making it difficult to match this intervention to the patients who may benefit the most. It was suggested that SMT may influence mechanisms associated with central sensitisation. Therefore, classifying patients with CLBP according to central sensitisation mechanisms may help predict their response to SMT. METHODS AND ANALYSIS: This protocol describes a randomised placebo-controlled trial aiming to examine which variables linked to central sensitisation may help predict the clinical response to SMT in a cohort of patients with CLBP. One hundred patients with chronic primary low back pain will be randomised to receive 12 sessions of SMT or placebo SMT over a 4-week period. Pain intensity and disability will be assessed as primary outcomes after completing the 4-week treatment (primary endpoint), and at 4-week and 12-week follow-ups. Baseline values of two pain questionnaires, lumbar pressure pain thresholds, concentrations of an inflammatory cytokine and expectations of pain relief will be entered as predictors of the response to SMT in a multiple regression model. Changes in these variables after treatment will be used in a second multiple regression model. The reference values of these predictors will be measured from 50 age and sex-matched healthy controls to allow interpretation of values in patients. Mixed analyses of variance will also be conducted to compare the primary outcomes and the predictors between groups (SMT vs placebo) over time (baseline vs post-treatment). ETHICS AND DISSEMINATION: Ethical approval was granted by the Fundación Jiménez Díaz Clinical Research Ethics Committee. TRIAL REGISTRATION NUMBER: NCT05162924.