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ABSTRACT: Pruritus often escapes physicians' attention in patients with peripheral neuropathy (PNP). Here we aimed to characterize neuropathic pruritus in a cohort of 191 patients with PNP (large, mixed, or small fiber) and 57 control subjects with deep phenotyping in a multicenter cross-sectional observational study at 3 German sites. All participants underwent thorough neurological examination, nerve conduction studies, quantitative sensory testing, and skin biopsies to assess intraepidermal nerve fiber density. Patients filled in a set of questionnaires assessing the characteristics of pruritus and pain, the presence of depression and anxiety, and quality of life. Based on the severity of pruritus and pain, patients were grouped into 4 groups: "pruritus," "pain," "pruritus and pain," and "no pruritus/no pain." Although 11% (21/191) of patients reported pruritus as their only symptom, further 34.6% (66/191) reported pruritus and pain. Patients with pain (with or without pruritus) were more affected by anxiety, depression, and reduced quality of life than control subjects. Patients with pruritus (with and without pain) had increases in cold detection threshold, showing Aδ-fiber dysfunction. The pruritus group had lower intraepidermal nerve fiber density at the thigh, concomitant with a more proximal distribution of symptoms compared with the other PNP groups. Stratification of patients with PNP by using cross-sectional datasets and multinominal logistic regression analysis revealed distinct patterns for the patient groups. Together, our study sheds light on the presence of neuropathic pruritus in patients with PNP and its relationship with neuropathic pain, outlines the sensory and structural abnormalities associated with neuropathic pruritus, and highlights its impact on anxiety levels.
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STUDY OBJECTIVE: Regional analgesia following visceral cancer surgery might provide an advantage but evidence for best treatment options related to risk-benefit is unclear. DESIGN: Systematic review of randomized controlled trials (RCT) with meta-analysis and GRADE assessment. SETTING: Postoperative pain treatment. PATIENTS: Adult patients undergoing visceral cancer surgery. INTERVENTIONS: Any kind of peripheral (PRA) or epidural analgesia (EA) with/without systemic analgesia (SA) was compared to SA with or without placebo treatment or any other regional anaesthetic techniques. MEASUREMENTS: Primary outcome measures were postoperative acute pain intensity at rest and during activity 24 h after surgery, the number of patients with block-related adverse events and postoperative paralytic ileus. MAIN RESULTS: 59 RCTs (4345 participants) were included. EA may reduce pain intensity at rest (mean difference (MD) -1.05; 95% confidence interval (CI): -1.35 to -0.75, low certainty evidence) and during activity 24 h after surgery (MD -1.83; 95% CI: -2.34 to -1.33, very low certainty evidence). PRA likely results in little difference in pain intensity at rest (MD -0.75; 95% CI: -1.20 to -0.31, moderate certainty evidence) and pain during activity (MD -0.93; 95% CI: -1.34 to -0.53, moderate certainty evidence) 24 h after surgery compared to SA. There may be no difference in block-related adverse events (very low certainty evidence) and development of paralytic ileus (very low certainty of evidence) between EA, respectively PRA and SA. CONCLUSIONS: Following visceral cancer surgery EA may reduce pain intensity. In contrast, PRA had only limited effects on pain intensity at rest and during activity. However, we are uncertain regarding the effect of both techniques on block-related adverse events and paralytic ileus. Further research is required focusing on regional analgesia techniques especially following laparoscopic visceral cancer surgery.
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Manejo da Dor , Dor Pós-Operatória , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/etiologia , Manejo da Dor/métodos , Analgesia Epidural/métodos , Analgesia Epidural/efeitos adversos , Bloqueio Nervoso/métodos , Bloqueio Nervoso/efeitos adversos , Medição da Dor , Assistência Perioperatória/métodos , Anestesia por Condução/métodos , Anestesia por Condução/efeitos adversosRESUMO
BACKGROUND: Postoperative pain management following laparoscopic, non-oncological visceral surgery in adults is challenging. Regional anaesthesia could be a promising component in multimodal pain management. METHODS: We performed a systematic review and meta-analysis with GRADE assessment. Primary outcomes were postoperative acute pain intensity at rest/during movement after 24 h, the number of patients with block-related adverse events and the number of patients with postoperative paralytic ileus. RESULTS: 82 trials were included. Peripheral regional anaesthesia combined with general anaesthesia versus general anaesthesia may result in a slight reduction of pain intensity at rest at 24 h (mean difference (MD) - 0.72 points; 95% confidence interval (CI) - 0.91 to - 0.54; I2 = 97%; low-certainty evidence), which was not clinically relevant. The evidence is very uncertain regarding the effect on pain intensity during activity at 24 h (MD -0.8 points; 95%CI - 1.17 to - 0.42; I2 = 99%; very low-certainty evidence) and on the incidence of block-related adverse events. In contrast, neuraxial regional analgesia combined with general anaesthesia (versus general anaesthesia) may reduce postoperative pain intensity at rest in a clinical relevant matter (MD - 1.19 points; 95%CI - 1.99 to - 0.39; I2 = 97%; low-certainty evidence), but the effect is uncertain during activity (MD - 1.13 points; 95%CI - 2.31 to 0.06; I2 = 95%; very low-certainty evidence). There is uncertain evidence, that neuraxial regional analgesia combined with general anaesthesia (versus general anaesthesia) increases the risk for block-related adverse events (relative risk (RR) 5.11; 95%CI 1.13 to 23.03; I2 = 0%; very low-certainty evidence). CONCLUSION: This meta-analysis confirms that regional anaesthesia might be an important part of multimodal postoperative analgesia in laparoscopic visceral surgery, e.g. in patients at risk for severe postoperative pain, and with large differences between surgical procedures and settings. Further research is required to evaluate the use of adjuvants and the additional benefit of regional anaesthesia in ERAS programmes. PROTOCOL REGISTRATION: PROSPERO CRD42021258281.
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Anestesia por Condução , Laparoscopia , Dor Pós-Operatória , Humanos , Dor Pós-Operatória/prevenção & controle , Anestesia por Condução/métodos , Laparoscopia/métodos , Laparoscopia/efeitos adversos , Manejo da Dor/métodos , Anestesia Geral/métodos , Medição da Dor , VíscerasRESUMO
BACKGROUND: Chronic postsurgical pain (CPSP) is a clinical problem, and large prospective studies are needed to determine its incidence, characteristics, and risk factors. OBJECTIVE: To find predictive factors for CPSP in an international survey. DESIGN: Observational study. SETTING: Multicentre European prospective observational trial. PATIENTS: Patients undergoing breast cancer surgery, sternotomy, endometriosis surgery, or total knee arthroplasty (TKA). METHOD: Standardised questionnaires were completed by the patients at 1, 3, and 7 days, and at 1, 3, and 6 months after surgery, with follow-up via E-mail, telephone, or interview. MAIN OUTCOME MEASURE: The primary goal of NIT-1 was to propose a scoring system to predict those patient likely to have CPSP at 6 months after surgery. RESULTS: A total of 3297 patients were included from 18 hospitals across Europe and 2494 patients were followed-up for 6 months. The mean incidence of CPSP at 6 months was 10.5%, with variations depending on the type of surgery: sternotomy 6.9%, breast surgery 7.4%, TKA 12.9%, endometriosis 16.2%. At 6 months, neuropathic characteristics were frequent for all types of surgery: sternotomy 33.3%, breast surgery 67.6%, TKA 42.4%, endometriosis 41.4%. One-third of patients experienced CPSP at both 3 and 6 months. Pre-operative pain was frequent for TKA (leg pain) and endometriosis (abdomen) and its frequency and intensity were reduced after surgery. Severe CPSP and a neuropathic pain component decreased psychological and functional wellbeing as well as quality of life. No overarching CPSP risk factors were identified. CONCLUSION: Unfortunately, our findings do not offer a new CPSP predictive score. However, we present reliable new data on the incidence, characteristics, and consequences of CPSP from a large European survey. Interesting new data on the time course of CPSP, its neuropathic pain component, and CPSP after endometriosis surgery generate new hypotheses but need to be confirmed by further research. TRIAL REGISTRATION: clinicaltrials.gov ID: NCT03834922.
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Neoplasias da Mama , Dor Crônica , Endometriose , Neuralgia , Feminino , Humanos , Dor Crônica/diagnóstico , Dor Crônica/epidemiologia , Dor Crônica/etiologia , Endometriose/complicações , Neuralgia/diagnóstico , Neuralgia/epidemiologia , Neuralgia/etiologia , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/etiologia , Qualidade de Vida , Inquéritos e Questionários , MasculinoRESUMO
INTRODUCTION: Co-crystal of tramadol-celecoxib (CTC) is the first analgesic co-crystal for acute pain. This completed phase 3 multicenter, double-blind trial assessed the efficacy and safety/tolerability of CTC in comparison with that of tramadol in the setting of moderate-to-severe pain up to 72 h after elective third molar extraction requiring bone removal. METHODS: Adults (n = 726) were assigned randomly to five groups (2:2:2:2:1): orally administered twice-daily CTC 100 mg (44 mg rac-tramadol hydrochloride/56 mg celecoxib; n = 164), 150 mg (66/84 mg; n = 160) or 200 mg (88/112 mg; n = 160); tramadol 100 mg four times daily (n = 159); or placebo four times daily (n = 83). Participants in CTC groups also received twice-daily placebo. The full analysis set included all participants who underwent randomization. The primary endpoint was the sum of pain intensity differences over 0 to 4 h (SPID0-4; visual analog scale). Key secondary endpoints included 4-h 50% responder and rescue medication use rates. Safety endpoints included adverse events (AEs), laboratory measures, and Opioid-Related Symptom Distress Scale (OR-SDS) score. RESULTS: All CTC doses were superior to placebo (P < 0.001) for primary and key secondary endpoints. All were superior to tramadol for SPID0-4 (analysis of covariance least squares mean differences [95% confidence interval]: - 37.1 [- 56.5, - 17.6], - 40.2 [- 59.7, - 20.6], and - 41.7 [- 61.2, - 22.2] for 100, 150, and 200 mg CTC, respectively; P < 0.001) and 4-h 50% responder rate. Four-hour 50% responder rates were 32.9% (CTC 100 mg), 33.8% (CTC 150 mg), 40.6% (CTC 200 mg), 20.1% (tramadol), and 7.2% (placebo). Rescue medication use was lower in the 100-mg (P = 0.013) and 200-mg (P = 0.003) CTC groups versus tramadol group. AE incidence and OR-SDS scores were highest for tramadol alone. CONCLUSIONS: CTC demonstrated superior pain relief compared with tramadol or placebo, as well as an improved benefit/risk profile versus tramadol. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02982161; EudraCT number, 2016-000592-24.
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Dor Aguda , Tramadol , Adulto , Humanos , Tramadol/efeitos adversos , Celecoxib/uso terapêutico , Celecoxib/efeitos adversos , Dor Aguda/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Extração Dentária/efeitos adversos , Método Duplo-Cego , Dor Pós-Operatória/tratamento farmacológicoRESUMO
BACKGROUND: Despite being a commonly performed surgical procedure, pain management for appendicectomy is often neglected because of insufficient evidence on the most effective treatment options. OBJECTIVE: To provide evidence-based recommendations by assessing the available literature for optimal pain management after appendicectomy. DESIGN AND DATA SOURCES: This systematic review-based guideline was conducted according to the PROSPECT methodology. Relevant randomised controlled trials, systematic reviews and meta-analyses in the English language from January 1999 to October 2022 were retrieved from MEDLINE, Embase and Cochrane Databases using PRISMA search protocols. ELIGIBILITY CRITERIA: We included studies on adults and children. If articles reported combined data from different surgeries, they had to include specific information about appendicectomies. Studies needed to measure pain intensity using a visual analogue scale (VAS) or a numerical rating scale (NRS). Studies that did not report the precise appendicectomy technique were excluded. RESULTS: Out of 1388 studies, 94 met the inclusion criteria. Based on evidence and consensus, the PROSPECT members agreed that basic analgesics [paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] should be administered perioperatively for open and laparoscopic appendicectomies. A laparoscopic approach is preferred because of lower pain scores. Additional recommendations for laparoscopic appendicectomies include a three-port laparoscopic approach and the instillation of intraperitoneal local anaesthetic. For open appendicectomy, a preoperative unilateral transverse abdominis plane (TAP) block is recommended. If not possible, preincisional infiltration with local anaesthetics is an alternative. Opioids should only be used as rescue analgesia. Limited evidence exists for TAP block in laparoscopic appendicectomy, analgesic adjuvants for TAP block, continuous wound infiltration after open appendicectomy and preoperative ketamine and dexamethasone. Recommendations apply to children and adults. CONCLUSION: This review identified an optimal analgesic regimen for open and laparoscopic appendicectomy. Further randomised controlled trials should evaluate the use of regional analgesia and wound infiltrations with adequate baseline analgesia, especially during the recommended conventional three-port approach. REGISTRATION: The protocol for this study was registered with the PROSPERO database (Registration No. CRD42023387994).
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Manejo da Dor , Dor Pós-Operatória , Adulto , Criança , Humanos , Manejo da Dor/métodos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Analgésicos/uso terapêutico , Acetaminofen , Anti-Inflamatórios não Esteroides/uso terapêutico , Anestésicos Locais/uso terapêuticoRESUMO
There is general agreement that acute pain management is an important component of perioperative medicine. However, there is no consensus on the best model of care for perioperative pain management, mainly because evidence is missing in many aspects. Comparing the similarities and differences between countries might reveal some insights into different organisational models and how they work. Here, we performed a narrative review to describe and compare the structures, processes and outcomes of perioperative pain management in the healthcare systems of four European countries using Donabedian's framework as a guide. Our comparison revealed many similarities, differences and gaps. Different structures of acute pain services in the four countries with no common definition and standards of care were found. Protocols have been implemented in all countries and guidelines in some. If outcome is assessed, it is mainly pain intensity, and many patients experiencing more intense pain than others have common risk factors (e.g. preoperative pain, preoperative opioid intake, female sex and young age). Outcome assessment beyond pain intensity (such as pain-related physical function, which is important for early rehabilitation and recovery) is currently not well implemented. Developing common quality indicators, a European guideline for perioperative pain management (e.g. for patients at high risk for experiencing severe pain and other outcome parameters) and common criteria for acute pain services might pave the way forward for improving acute pain management in Europe. Finally, the education of general and specialist staff should be aligned in Europe, for example, by using the curricula of the European Pain Federation (EFIC).
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Analgésicos Opioides , Manejo da Dor , Humanos , Feminino , Europa (Continente) , Analgésicos Opioides/efeitos adversos , DorRESUMO
BACKGROUND: Postsurgical outcome measures are crucial to define the efficacy of perioperative pain management; however, it is unclear which are most appropriate. We conducted a prospective study aiming to assess sensitivity-to-change of patient-reported outcome measures assessing the core outcome set of domains pain intensity (at rest/during activity), physical function, adverse events, and self-efficacy. METHODS: Patient-reported outcome measures were assessed preoperatively, on day 1 (d1), d3, and d7 after four surgical procedures (total knee replacement, breast surgery, endometriosis-related surgery, and sternotomy). Primary outcomes were sensitivity-to-change of patient-reported outcome measures analysed by correlating their changes (d1-d3) with patients' global impression of change and patients' specific impression of change items as anchor criteria. Secondary outcomes included identification of baseline and patient characteristic variables explaining variance in change for each of the scales and descriptive analysis of various patient-reported outcome measures from different domains and after different surgeries. RESULTS: Of 3322 patients included (18 hospitals, 10 countries), data from 2661 patients were analysed. All patient-reported outcome measures improved on average over time; the median calculated sensitivity-to-change for all patient-reported outcome measures (overall surgeries) was 0.22 (range: 0.07-0.31, scale: 0-10); all changes were independent of baseline data or patient characteristics and similar between different procedures. CONCLUSIONS: Pain-related patient-reported outcome measures have low to moderate sensitivity-to-change; those showing higher sensitivity-to-change from the same domain should be considered for inclusion in a core outcome set of patient-reported outcome measures to assess the effectiveness and efficacy of perioperative pain management.
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Dor Aguda , Feminino , Humanos , Estudos Prospectivos , Avaliação de Resultados em Cuidados de Saúde , Dor Pós-Operatória/diagnóstico , Medidas de Resultados Relatados pelo PacienteRESUMO
Background: Pain is the leading cause of disability worldwide among adults and effective treatment options remain elusive. Data harmonization efforts, such as through core outcome sets (COS), could improve care by highlighting cross-cutting pain mechanisms and treatments. Existing pain-related COS often focus on specific conditions, which can hamper data harmonization across various pain states. Methods: Our objective was to develop four overarching COS of domains/subdomains (i.e., what to measure) that transcend pain conditions within different pain categories. We hosted a meeting to assess the need for these four COS in pain research and clinical practice. Potential COS domains/subdomains were identified via a systematic literature review (SLR), meeting attendees, and Delphi participants. We conducted an online, three step Delphi process to reach a consensus on domains to be included in the four final COS. Survey respondents were identified from the SLR and pain-related social networks, including multidisciplinary health care professionals, researchers, and people with lived experience (PWLE) of pain. Advisory boards consisting of COS experts and PWLE provided advice throughout the process. Findings: Domains in final COS were generally related to aspects of pain, quality of life, and physical function/activity limitations, with some differences among pain categories. This effort was the first to generate four separate, overarching COS to encourage international data harmonization within and across different pain categories. Interpretation: The adoption of the COS in research and clinical practice will facilitate comparisons and data integration around the world and across pain studies to optimize resources, expedite therapeutic discovery, and improve pain care. Funding: Innovative Medicines Initiative 2 Join Undertaking; European Union Horizon 2020 research innovation program, European Federation of Pharmaceutical Industries and Associations (EFPIA) provided funding for IMI-PainCare. RDT acknowledges grants from Esteve and TEVA.
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PURPOSE OF REVIEW: Pain is an expected consequence of a surgery, but it is far from being well controlled. One major complication of acute pain is its risk of persistency beyond healing. This so-called chronic post-surgical pain (CPSP) is defined as new or increased pain due to surgery that lasts for at least 3 months after surgery. CPSP is frequent, underlies a complex bio-psycho-social process and constitutes an important socioeconomic challenge with significant impact on patients' quality of life. Its importance has been recognized by its inclusion in the eleventh version of the ICD (International Classification of Diseases). RECENT FINDINGS: Evidence for most pharmacological and non-pharmacological interventions preventing CPSP is inconsistent. Identification of associated patient-related factors, such as psychosocial aspects, comorbidities, surgical factors, pain trajectories, or biomarkers may allow stratification and selection of treatment options based on underlying individual mechanisms. Consequently, the identification of patients at risk and implementation of individually tailored, preventive, multimodal treatment to reduce the risk of transition from acute to chronic pain is facilitated. SUMMARY: This review will give an update on current knowledge on mechanism-based risk, prognostic and predictive factors for CPSP in adults, and preventive and therapeutic approaches, and how to use them for patient stratification in the future.
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Dor Aguda , Dor Crônica , Adulto , Humanos , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Dor Crônica/terapia , Dor Aguda/diagnóstico , Dor Aguda/etiologia , Dor Aguda/terapia , Qualidade de Vida , Prognóstico , Fatores de Risco , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/terapiaRESUMO
PURPOSE OF REVIEW: Prognostic models for chronic postsurgical pain (CPSP) aim to predict the likelihood for development and severity of CPSP in individual patients undergoing surgical procedures. Such models might provide valuable information for healthcare providers, allowing them to identify patients at higher risk and implement targeted interventions to prevent or manage CPSP effectively. This review discusses the latest developments of prognostic models for CPSP, their challenges, limitations, and future directions. RECENT FINDINGS: Numerous studies have been conducted aiming to develop prognostic models for CPSP using various perioperative factors. These include patient-related factors like demographic variables, preexisting pain conditions, psychosocial aspects, procedure-specific characteristics, perioperative analgesic strategies, postoperative complications and, as indicated most recently, biomarkers. Model generation, however, varies and performance and accuracy differ between prognostic models for several reasons and validation of models is rather scarce. SUMMARY: Precise methodology of prognostic model development needs advancements in the field of CPSP. Development of more accurate, validated and refined models in large-scale cohorts is needed to improve reliability and applicability in clinical practice and validation studies are necessary to further refine and improve the performance of prognostic models for CPSP.
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Dor Crônica , Humanos , Prognóstico , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Dor Crônica/terapia , Reprodutibilidade dos Testes , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/terapia , AnalgésicosRESUMO
Cancer-induced bone pain (CIBP) is a common and devastating symptom with limited treatment options in patients, significantly affecting their quality of life. The use of rodent models is the most common approach to uncovering the mechanisms underlying CIBP; however, the translation of results to the clinic may be hindered because the assessment of pain-related behavior is often based exclusively on reflexive-based methods, which are only partially indicative of relevant pain in patients. To improve the accuracy and strength of the preclinical, experimental model of CIBP in rodents, we used a battery of multimodal behavioral tests that were also aimed at identifying rodent-specific behavioral components by using a home-cage monitoring assay (HCM). Rats of all sexes received an injection with either heat-deactivated (sham-group) or potent mammary gland carcinoma Walker 256 cells into the tibia. By integrating multimodal datasets, we assessed pain-related behavioral trajectories of the CIBP-phenotype, including evoked and non-evoked based assays and HCM. Using principal component analysis (PCA), we discovered sex-specific differences in establishing the CIBP-phenotype, which occurred earlier (and differently) in males. Additionally, HCM phenotyping revealed the occurrence of sensory-affective states manifested by mechanical hypersensitivity in sham when housed with a tumor-bearing cagemate (CIBP) of the same sex. This multimodal battery allows for an in-depth characterization of the CIBP-phenotype under social aspects in rats. The detailed, sex-specific, and rat-specific social phenotyping of CIBP enabled by PCA provides the basis for mechanism-driven studies to ensure robustness and generalizability of results and provide information for targeted drug development in the future.
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BACKGROUND: Acute pain after surgery is common and often leads to chronic post-surgical pain, but neither treatment nor prevention is currently sufficient. We hypothesised that specific protein networks (protein-protein interactions) are relevant for pain after surgery in humans and mice. METHODS: Standardised surgical incisions were performed in male human volunteers and male mice. Quantitative and qualitative sensory phenotyping were combined with unbiased quantitative mass spectrometry-based proteomics and protein network theory. The primary outcomes were skin protein signature changes in humans and phenotype-specific protein-protein interaction analysis 24 h after incision. Secondary outcomes were interspecies comparison of protein regulation as well as protein-protein interactions after incision and validation of selected proteins in human skin by immunofluorescence. RESULTS: Skin biopsies in 21 human volunteers revealed 119/1569 regulated proteins 24 h after incision. Protein-protein interaction analysis delineated remarkable differences between subjects with small (low responders, n=12) and large incision-related hyperalgesic areas (high responders, n=7), a phenotype most predictive of developing chronic post-surgical pain. Whereas low responders predominantly showed an anti-inflammatory protein signature, high responders exhibited signatures associated with a distinct proteolytic environment and persistent inflammation. Compared to humans, skin biopsies in mice habored even more regulated proteins (435/1871) 24 h after incision with limited overlap between species as assessed by proteome dynamics and PPI. Immunohistochemistry confirmed the expression of high priority candidates in human skin biopsies. CONCLUSIONS: Proteome profiling of human skin after incision revealed protein-protein interactions correlated with pain and hyperalgesia, which may be of potential significance for preventing chronic post-surgical pain. Importantly, protein-protein interactions were differentially modulated in mice compared to humans opening new avenues for successful translational research.
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Proteoma , Proteômica , Humanos , Masculino , Camundongos , Animais , Hiperalgesia/prevenção & controle , Pele/metabolismo , Dor Pós-OperatóriaRESUMO
BACKGROUND: Conditioned pain modulation (CPM) and offset analgesia quantify impairment of endogenous pain modulation, but magnitude and reliability vary broadly between studies, indicating influencing factors that are not currently controlled for. The aim of this study was to quantify magnitude and retest reliability of CPM and offset analgesia in healthy participants, while investigating the influence of sex and sex hormone levels. METHODS: Sixty-two participants (30 female) completed the study. We tested CPM (heat-cold paradigm) and offset analgesia on 6 days within two menstrual cycles (tests were performed in each phase of two subsequent menstrual cycles, with similar time points for men). RESULTS: Median offset effect was -29.4% in female and - 22.5% in male participants (as change from initial stimulus). Median early CPM effects were - 16.7% for women versus -13.3% for men. Reliability (intra-class correlation coefficient [ICC]) was similar between the main measures, offset effect (female: 0.48, male: 0.47) and early CPM effect (female: 0.49, male: 0.43). There was significant variance between individual experimental parameters within protocols but not between sexes or menstrual phases. While oestradiol and progesterone did not correlate with the magnitude of effect within sexes, we found that testosterone levels explained an estimated 5%-10% of variance within individual responses in all sexes. CONCLUSIONS: Our results show that the reliability of both CPM effect and offset analgesia was independent of sex and menstrual cycle phase. The magnitude of CPM and offset effects was weakly influenced by sex and testosterone levels, indicating an area for future research, rather than clinical significance. SIGNIFICANCE: This study investigated CPM and offset analgesia in parallel, across sexes and during two menstrual cycles while assessing the impact of sex hormones. Reliability seems to depend on experimental parameters rather than participant characteristics, while the magnitude of effect could be weakly linked to sex hormones and sex.
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Analgesia , Limiar da Dor , Condicionamento Psicológico/fisiologia , Feminino , Hormônios Esteroides Gonadais , Voluntários Saudáveis , Humanos , Masculino , Ciclo Menstrual/fisiologia , Dor , Medição da Dor/métodos , Limiar da Dor/fisiologia , Reprodutibilidade dos Testes , TestosteronaRESUMO
STUDY OBJECTIVE: Postoperative pain management in opioid users remains challenging. The perioperative administration of ketamine might lead to favourable pain outcomes in these patients. STUDY DESIGN: A systematic review of randomised controlled trials (RCT) with meta-analysis and assessment of the quality of evidence by GRADE was performed. SETTING: Perioperative pain treatment. PATIENTS: Adult opioid users undergoing surgery. INTERVENTIONS: Perioperative administration of ketamine. MEASUREMENTS: Primary outcomes were postoperative acute pain at rest/during movement after 24 h and number of patients with ketamine-related adverse events. MAIN RESULTS: Nine RCTs (802 patients with at least two weeks opioid-intake) were included. There is low-quality evidence that ketamine may slightly reduce postoperative pain during movement after 24 h (mean difference: -0.79; 95% confidence interval (CI): -1.22 to -0.36). Based on a very low-quality of evidence, we are uncertain on any effect of ketamine on pain at rest after 24 h and incidences of adverse events like hallucinations and confusion within 48 h. However, perioperative ketamine reduced cumulative mean opioid consumption by 97.3 mg (95%CI: -164.8 to -29.7) after 24 h and 186.4 mg (95%CI: -347.6 to -25.2) after 48 h. The relative risks (RR) for opioid-related adverse events were significantly different for sedation within 24 h (RR: 0.54; 95%CI 0.37 to 0.78). CONCLUSIONS: There is currently limited evidence for a reduced postoperative pain intensity using perioperative ketamine in preoperative opioid-consuming patients. However, a clinically relevant opioid-sparing effect was evident associated with a reduced risk for postoperative sedation and without increased harm. Therefore, ketamine might be a useful anti-hyperalgesic adjuvant in these patients. Nevertheless, with clinical heterogeneity being considerable, it's too premature to suggest any specific ketamine protocol. Furthermore, many questions (like ideal dosing, treatment duration and more favourable patient-related outcome measures including long-term effects) remain open and need to be addressed in future studies. PROTOCOL REGISTRATION: Prospero CRD42020185497.