We have been studying different combinations of medications to treat relapsed or refractory multiple myeloma. Among these combinations, one includes daratumumab with pomalidomide and dexamethasone (DPd), and another includes daratumumab with bortezomib and dexamethasone (DVd). So far, there have not been any direct comparisons performed through a clinical trial. In our analysis, we found that the DPd group had more patients with high-risk disease characteristics. Interestingly, the DPd group showed a better response to treatment. However, when we looked at the time until the disease progressed and overall survival, we found that these were similar between the two groups. It is important to note that we should be cautious in drawing conclusions from these findings because there were differences in the characteristics of the patients and lengths and durations of treatment, and the number of patients in both treatment groups was relatively small. Our study highlights the importance of considering factors like the type of patients, the side effects of the medications, and the characteristics of the disease when deciding which treatments to use. It is crucial to personalize the treatment approach for each individual based on these factors. Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma (RRMM) patients. However, no direct comparisons of safety or efficacy of the two regimens have been published to date. We conducted a retrospective study to compare the safety and efficacy of DPd and DVd in daratumumab-naïve RRMM patients. We included 140 daratumumab-naïve patients who had received DPd or DVd for RRMM. Overall, the DPd group had a greater number of patients who had high-risk disease characteristics. Although response was deeper in the DPd group, the median progression-free survival (PFS) and overall survival (OS) were similar between the two groups. The DPd group exhibited a higher incidence of hematologic toxicities, whereas the DVd group had a higher incidence of peripheral neuropathy. The study results showed that while DPd may provide a deeper response, there was no significant difference in PFS or OS compared to DVd. For the high proportion of difficult-to-treat patients, duration of treatment may have contributed to these results, indicating that patient and disease characteristics should be considered when selecting salvage treatments. Daratumumab is a human immunoglobulin G1 kappa monoclonal antibody targeting CD38 originally approved for monotherapy treatment of relapsed refractory multiple myeloma (RRMM) in 2015. Subsequently, the addition of daratumumab to various backbones have yielded exceptional efficacy in RRMM, transplant-eligible, and transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients . HoweverSeveral daratumumab-based triplet regimens are commonly employed for relapsed myeloma, such as daratumumab, carfilzomib, and dexamethasone, (DKd); daratumumab, pomalidomide, and dexamethasone (DPd); daratumumab, bortezomib, and dexamethasone (DVd); or daratumumab lenalidomide and dexamethasone (DRd) . The choThis single center retrospective study was conducted at the Kansas University Medical Center (KUMC) in collaboration with the United States Myeloma Innovations Research Collaborative (USMIRC) after receiving approval from the KUMC Institutional Review Board. For this retrospective analysis, we identified 140 consecutive RRMM patients who had received either DPd or DVd for RRMM at the University of Kansas Cancer Center between January 2015 and June 2022. High-risk MM was defined based on the 2016 International Myeloma Working Group Criteria (IMWG), with the presence of t , del(17/17p), t , t , and gain(1q) by fluorescence in situ hybridization (FISH) at the time of diagnosis [The determination of treatment type was influenced by a range of factors. These factors encompassed various elements such as the timeline of FDA approvals for the specific line of treatment, the patient’s performance status, renal function, comorbidities, and the treating physician’s discretion. 2) on days 1, 4, 8, and 11 every 3 weeks for 8 cycles, and dexamethasone 20 or 40 mg weekly in combination with daratumumab. Responses were evaluated using IMWG criteria [DPd was given as daratumumab at 16 mg/kg IV or 1800 mg SQ weekly for cycles 1 and 2, every 2 weeks for cycles 3–6, and then every 4 weeks afterwards; pomalidomide was dosed at 4 mg orally on days 1–21 of a 28-day cycle; and dexamethasone was given at 20 or 40 mg weekly. The DVd group received daratumumab 16 mg/kg IV or 1800 mg SQ weekly for 3 cycles, every 3 weeks for cycles 4–8, and then every 4 weeks afterwards, bortezomib , overall survival (OS), and duration of response (DOR). PFS was defined as the time from the initiation of treatment (DPd or DVd) to progression or death (regardless of the cause of death), whichever occurred first. OS was defined as the time from initiation of treatment (DPd or DVd) until death or last follow-up. DOR was defined as the time from first observation of partial response (PR) to the time of disease progression, with deaths from causes other than progression censored . t-tests for continuous variables. Unadjusted survival distributions were estimated using the Kaplan–Meier method, and comparisons were performed with the log-rank test. Univariable Cox proportional hazards regression models were used to evaluate the associations between survival outcomes and covariates; multivariable Cox proportional hazards regression models were fitted with pre-specified covariates of the Revised International Staging System (R-ISS) stage, cytogenetic risk, presence of extramedullary disease (EMD), history of autologous stem cell transplantation (ASCT), number of prior regimens, current treatment (DPd vs. DVd), double refractory status (both PI and IMiD), and response to treatment  vs. stringent complete response/complete response (sCR/CR)). A nearest matching analysis was used to compare two treatment groups, specifically matching for high-risk cytogenetics and EMD. We used the software R  v2.15.1 and the survival package for the Kaplan–Meier method. For other statistical calculations, we employed the statistical software IBM SPSS (version 29.0). For the overall cohort, comparisons between subgroups of interest were performed using Fisher’s exact tests for categorical variables and unequal variance p = 0.143). The study population consisted of 140 patients, with 97 treated with DPd, and 43 treated with DVd. Patient and disease characteristics are summarized in The DPd group had more patients with high-risk disease features, such as high-risk cytogenetic abnormalities, EMD, prior ASCT, a higher number of prior regimens, and higher rate of double refractory disease, compared to the DVd group.p = 0.015). Cytogenetic studies by FISH were available for 98% (137/140) of the patients, 60% (83/140) of whom had high-risk cytogenetic abnormalities, with 67% in the DPd and 45% in the DVd groups, respectively (p = 0.022). The median previous LOT was 2 (1–6), and 1 (1–5) in the DPd and DVd groups, respectively (p = 0.02). Of those who received DPd, 61% had double refractory disease, compared to 30% in the DVd group (p < 0.001). The proportion of lenalidomide-refractory patients was 82% in the DPd group compared to 51% in the DVd group (p < 0.001). There was no difference in the bortezomib refractoriness between the two treatment groups, with 53% in the DPd compared to 35% in the DVd group (p = 0.067). The incidence of pomalidomide refractoriness was 0% in DPd compared to 9% in the DVd group (p = 0.008). The incidence of carfilzomib refractoriness was 26% in DPd compared to 9% in the DVd group (p = 0.040).EMD was present in 28% of DPd compared to 9% in the DVd group (p = 0.135).The median duration of therapy was 10 (1–64) months in DPd, compared to 6 (1–42) months in the DVd group (p = 0.736). VGPR or better response was seen in 47% and 28% in the DPd and the DVd groups, respectively (p = 0.041). Similarly, sCR and CR were seen in 37% and 14% in the DPd and the DVd groups, respectively (p = 0.005) (p = 0.5).The overall response rate (ORR) was 74% (103/140) for the entire patient population (74% in DPd group and 72% in DVd group). The median time to best response was 2 (1–9) months in the DPd, compared to 2 (1–6) in the DVd group (= 0.005) . The medThe most common adverse events related to the treatment (DPd vs. DVd) are summarized in p = 0.9; HR = 0.97; 95% CI, 0.62–1.52; p = 0.284; HR = 0.73; 95% CI, 0.41–1.3; The median PFS was 10.3  and 11.7  months for the DPd and the DVd groups, respectively (p = 0.58), indicating no significant difference between the two treatments in terms of PFS in lenalidomide-refractory patients. Similarly, when we analyzed the subgroup of bortezomib-refractory patients, we observed no significant difference in median PFS between the DPd and DVd treatments. The median PFS was 8.8 months for the DPd group and 6.8 months for the DVd group.We performed a subgroup analysis to examine the outcomes of DPd and DVd treatments specifically in lenalidomide-refractory patients. In this subgroup, the median PFS was found to be 10.1 months for the DPd group, and 6.4 months for the DVd group , as shown in Through a 1:1 matching analysis, we decreased the sample size to n = 86 (43 in each group), revealing a median PFS of 20 months for the DPd group and 12 months for the DVd group. However, when comparing the two groups, we obtained a non-significant Cox regression analysis was conducted to identify the predictors of PFS and OS. The variables included in the analysis were R-ISS stage, cytogenetic risk, EMD, history of ASCT, number of prior regimens, current treatment (DPd vs. DVd), double refractory status, and response to treatment (VGPR/PR vs. sCR/CR). p = 0.046; HR = 1.80; 95% CI, 1.01–3.22), R-ISS III , the presence of EMD , higher number of prior regimens , and response of VGPR/PR  emerged as significant predictors of inferior PFS. On multivariate analysis for OS in the entire cohort, R-ISS III , greater number of prior regimens , and response of VGPR/PR  emerged as significant predictors of inferior OS  with or without daratumumab. Of the enrolled subjects, 24% in the DVd group and 33% in the Vd group were lenalidomide refractory, and about a fifth of patients had high risk cytogenetic abnormalities (22% in DVd vs. 21% in Vd group) , suggestp = 0.58), but the difference was not statistically significant. Based on previously published data [In our study, 73% of the population was lenalidomide refractory, with a higher percentage of lenalidomide-refractory patients observed in DPd group (82%) compared to DVd group (51%). We found that the PFS, in the lenalidomide-refractory population was numerically superior in the DPd group . However, after conducting cardinality matching, the DPd group showed a significant improvement in PFS with a 45% reduction in the risk of progression compared to the DVd group . It is important to note that indirect comparisons have limitations and should be interpreted cautiously. In our study, we employed nearest matching analysis, specifically matching for high-risk cytogenetics and EMD, revealing a median PFS of 20 months for DPd compared to 12 months in DVd. However, the nonsignificant p-value (p = 0.62) may be attributed to the limited sample size. Our study has several limitations that are inherent to a single-center retrospective analysis, including selection bias and missing data. However, this is the first study in literature reporting outcomes of the real-world use of DPd vs. DVd for patients with RRMM. Another limitation is the imbalanced distribution of patients between the two treatment groups, with a higher proportion of difficult-to-treat individuals in the DPd group. While the choice of therapy at the time of relapse is affected by several factors, including patient comorbidities, performance status, previous anti-myeloma therapies, as well as efficacy and toxicity profile of the next therapy under consideration, the precise reasons for choice of regimen in our patient population remain unknown due to the retrospective nature of the study. This imbalance in patient characteristics has the potential to bias the efficacy outcomes of the chosen regimen. Therefore, caution should be exercised when extrapolating the findings of our study to other populations or treatment settings. Given the study’s retrospective design, no data are available on the quality-of-life outcomes to determine the impact of DPd and DVd on symptom burden in patients receiving treatment. Multicenter and registry-based retrospective analyses with larger patient populations are needed to confirm the findings of our report and allow for more meaningful and statistically significant subgroup analyses. Similarly, well-designed randomized controlled trials with longer follow-ups are needed to clearly establish the superiority of one salvage regimen over the other. Like our result, the indirect comparison of DPd from APOLLO study with DVd from CASTOR study  showed nIn conclusion, this single-center retrospective analysis found that DPd salvage treatment yielded deeper responses than the DVd regimen, without significant differences in PFS or OS. Both therapies were overall well tolerated. While DPd was associated with more hematological toxicities, DVd showed a higher incidence of peripheral neuropathy. In the treatment landscape of RRMM, the abundance of available therapies underscores the necessity of careful selection and sequencing of various salvage chemotherapy regimens. This study highlights the importance of meticulously considering patient demographics, toxicity profiles, and disease characteristics in selecting salvage treatments for RRMM. Furthermore, assessing patient-reported outcomes and quality of life measures could provide a holistic view of the treatment experience. Additional investigations into potential predictive biomarkers for treatment response and toxicity hold the promise of greatly enhancing treatment selection and customization strategies.


Fibromyalgia (FM) is a chronic disease characterized by a heterogeneous set of physical and psychological conditions. The chronic experience of disability felt by patients and the impact on quality of life (QoL) of the disease may worsen the cognitive reappraisal ability and contribute to maintaining an altered pain modulation mechanism. This paper presents the study protocol of an INTEGRated psychotherapeutic interventiOn on the management of chronic pain in patients with fibromyalgia (INTEGRO). The aim of the study is to investigate the efficacy of an integrated psychotherapeutic intervention focused on pain management on QoL and pain perception, in a pilot sample of 45 FM patients with idiopathic chronic pain. The contribution of perceived therapeutic relationship  and physiological attunement, in both the patient and therapist, will be considered as possible mediators of intervention efficacy. Attachment dimensions, traumatic experiences, difficulties in emotion regulation, mindfulness attitude and psychophysiological profile will also be considered as covariates. The objectives are to evaluate longitudinally if patients will experience an increase in QoL perception (primary endpoint), pain-managing self-efficacy and emotion-regulation abilities as well as a reduction in pain intensity (secondary endpoints), considering the mediating role of perceived therapeutic alliance and physiological attunement in both the patient and therapist. Fibromyalgia (FM) is a chronic disease with a world prevalence of around 2–6%, according to different epidemiological reports ,2, and 2The etiology of FM is not entirely clear, although several studies describe FM in terms of a central sensitization syndrome, characterized by the alteration of nociceptive process of the central nervous system, distorted pain modulation mechanisms and amplification of pain experience due to stress and psychological factors ,7. For iMoreover, FM patients show a psychological profile characterized by high levels of anxiety, depression, high focus on algic stimuli, catastrophizing and greater sensitivity in the dynamics of interpersonal identification and social comparison ,9. A recFM syndrome requires not only a specialist assessment of pain, disability and co-morbidity, but also a psychosocial assessment. Therefore, the management of FMs should be based on a multimodal method  and should aim to improve health-related quality of life ,14,15, aChronic pain is one of the most relevant symptoms in FM. The literature shows that psychotherapy may be particularly useful for the treatment of chronic pain whose etiology is strongly related to psychological factors ,17,18. ICognitive behavioral therapy (CBT) has been shown to significantly contribute to reducing painful symptoms in patients with chronic pain ,25,26,27Moreover, acceptance and commitment therapy—ACT (CBT third generation intervention)—has been shown to improve the acceptance of pain and the reduce pain catastrophizing, compared to drug therapy only . Most stA rather recent line of research is to study the relationship between the degree of interpersonal attunement and psychophysiological synchronization, expressed as the correlation between continuous measurements of autonomic nervous system activity in two or more people who interact with each other . PsychopThe role of psychophysiological synchronization was underlined by Marci et al. , who shoMore generally, therapeutic alliance is a deep empathy state, connected to limbic area activity, that allows awareness of others’ emotional states . The capPhysiological synchronization in psychotherapy has mainly focused on autonomic nervous system measures, specifically cardiac (ECG) and electrodermal activity (EDA). EDA and ECG are good indicators of sympathetic and parasympathetic nervous system activity and both contribute to describing self-regulation processes and emotional responses. They also contribute to measuring unaware processes that cannot be consciously controlled, or that cannot be evaluated directly by the clinician ,48. HoweAs regards this topic, Thieme et al.  demonstrSimilarly, Finset et al.  showed tGiven the reported evidence of CBT and ACT interventions and the role of interpersonal psychophysiology in therapeutic alliance, we designed a pilot study based on an INTEGRated psychotherapeutic interventiOn devoted to the management of chronic pain in patients with fibromyalgia, named INTEGRO.The main study objective is to evaluate if patients will experience an increase in QoL perception after INTEGRO treatment.there is a reduction in pain intensity;there is an increase in perceived self-efficacy in managing pain;there is an increase in patients’ emotional regulation ability.The secondary objectives are to verify longitudinally if:All these objectives will be longitudinally measured by comparing pre-treatment (T0) to post-treatment (T13) evaluations, considering the mediating role of perceived therapeutic relationship  and physiological attunement, in both the patient and therapist.INTEGRO is an exploratory longitudinal prospective study promoted by the Clinical Psychology Unit in collaboration with the Pain Therapy Unit of the Integrated University Hospital  of Verona, Italy.The Unit of Clinical Psychology will be responsible for the research project management and the psychotherapy intervention. CBT psychotherapists, also trained in the use of relaxion and mindfulness-based techniques, later named as “therapists” will manage the psychotherapy-integrated intervention, together with the pre and post evaluations. The medical staff of the Pain Therapy Unit will be responsible for the recruitment of patients who will satisfy the inclusion criteria provided by the protocol.45 patients with FM diagnosis according to established ACR criteria (American College of Rheumatology ) and idiheart disease ;endocrinological disease;being currently pregnant or lactating;medical condition capable of altering psychophysiological recording , drug and alcohol abuse in the last 3–6 months);psychosis and major depressive disorder;cognitive deterioration, intellectual disability;pharmacological therapy incompatible with physiological recording;currently receiving psychotherapy.Exclusion criteria are:Even the psychotherapists must not have medical conditions that could alter the recording of psychophysiological signals.As a general overview of the study, in SCL-90 (Symptom Checklist-90-R), FIQ-R , MPQ (McGill Pain Questionnaire), BPI (Brief Pain Inventory), DERS , PSEQ (Pain Self-Efficacy Questionnaire), ASQ (Attachment Style Questionnaire), TEC (Traumatic Experience Checklist), FFMQ (Five Facet Mindfulness Questionnaire), VAS-E , SEP , WAI (Working Alliance Inventory). (T0a):All eligible patients under care of the Pain Therapy Unit who agreed to participate to the study will undergo a first set of evaluations to define if they are suitable for the study Socio-demographic data sheet collecting gender, age, education, marital, employment and health status;Sheet for Clinical Data Collection-CRF  completed by the specialist in analgesic therapy  and by a clinical psychologist , who, based both on psychiatric history and current clinical conditions, will deepen psychopathology evaluation using the Structured Clinical Interview-Clinician Version-SCID-CV [-SCID-CV ,57 as a -SCID-CV .Symptom Checklist-90-R . This iWe chose not to apply a standardized but time-consuming clinical evaluation, such as SCID, to all FM patients. This because they already had several tests to complete. We preferred to include a quicker screening test for clinical symptoms such as SCL-90. This seems to be a good compromise between evaluating the presence of psychopathology for each patient and ensuring the feasibility of the study in terms of time assessment.(T0b), by collecting the following measures:A second pre-treatment psychophysiological and psychological evaluation will then be conducted on selected eligible patients at the Clinical Psychology Unit Italian version of the Revised Fibromyalgia Impact Questionnaire . It is e . It evaBrief Pain Inventory . It . It BriePain Self-Efficacy Questionnaire . It evaAttachment Style Questionnaire . The ASTraumatic Experience Checklist . It is Five Facet Mindfulness Questionnaire . It is Psychophysiological evaluation: cardiac activity (ECG), electrodermal activity (EDA), respiratory activity (RESP) and temperature (T) will be collected through the EEG telemetry and polygraphic system “Encephalan-EEGR-19/26”. A tripolar ECG sensor will be applied with proximal disposition at subscapular sites. The EDA sensor  will be placed over the index and ring finger of the non-dominant hand. The respiratory belt will be applied to the abdominal site, and the temperature skin sensor will be placed on left little finger. The sampling rate will be set to 250 Hz. The “Encephalan-EEGR-19/26”, which includes ‘ABP-26’ and ‘Poly-10′ configuration with Rehacor (version 6 Dec 2021) and Encephalan EEG ‘Elite suite’  software, produced by Medicom MTM Ltd.  and distributed by Gea Soluzioni s.r.l (Turin), will be adopted for the acquisition of physiological data.At T0b, a psychophysiological profile  will be recorded according to the observations of Thieme et al.  on FM psT1 to T12, followed by a final post-treatment (T13) evaluation and two follow-up sessions, at one and six months after the conclusion of the intervention. The follow-up will be based on the same psychophysiological assessment performed at T0 (with different versions of the stress task) and the administration of the FIQ-R, BPI, DERS and PSEQ scales. At 6 months, the follow-up will be based on the FIQ-R, BPI, DERS e PSEQ scales.The psychotherapeutic intervention will then take place and will last from T2, T5, T9 and T12, continuous and synchronous recording of physiological variables  of both patient and therapist will be collected during the whole psychotherapy consultation and will be arranged as shown in At The researcher acquiring computer data will stay in an adjacent room to that of the therapist and the patient, which will be connected with a one-way mirror to allow the supervision and the correct detection of physiological parameters.T2 was chosen to allow the creation of a basic relationship between the patient and psychotherapist after the first sessions;T5 was selected because the literature in this field showed evidence for a linear increase in the synchronization of physiological parameters, particularly during the third–fourth session of psychotherapy ,80;T9 was considered as a good intermediate point between T5 and the final session at T12;Lastly, T12 indicates the final quality of therapist–patient interaction.We chose T2-T5-T9-T12 for physiological recording for different reasons:The session will also be video-recorded after the patient’s approval and transcribed to permit a detailed analysis of the patient and therapist interaction.Before starting T2-T5-T9-T12 consultations, the patient will complete the MPQ scale and will undergo a 5 min baseline recording of physiological parameters while remaining in an emotionally neutral condition.At the end of the consultation, the visual analogue scale of empathy (VAS-E), the working alliance inventory short revised (WAI) and the perceived empathy scale (SEP) (only at T2 and T12) will be collected for both the patient and therapist. The patient will also be asked to report which moments of the consultation were felt as more empathic to better understand which moment of the consultation contributed more to empathy perception.Visual Analogue Scale-Empathy(VAS-Empathy), on a 1–10 scale. Both patient and therapist indicate the degree of empathy perceived during the whole consultation and describe the moment in which he/she felt most attuned (referring to the interview that has just ended).Working Alliance Inventory Short Revised . It is  version  of the e version ). It is It is a manualized psychotherapeutic intervention based on CBT, ACT and mindfulness techniques, in line with already published protocols, such as FibroQoL ,35,84 , the objectives of the intervention and the role of cognitive and emotional variables in the perception of pain, together with psychoeducation on chronic pain.Contingencies between pain and contextual patient reactions together with maintenance factors of stress and pain are deeply assessed during the second phase. The protocol sessions will also include: teaching and practice of self-monitoring skills to increase pain awareness, learn relaxation techniques  to manage and reduce pain perception, cognitive restructuring, mindfulness and defusion ACT-based techniques and implementation of effective and assertive communication with doctors and family members to improve performance in the long term.Finally, the third phase consists of a final interview that aims to consolidate all attainments achieved during the whole intervention.The main objective related to INTEGRO intervention is to evaluate QoL perception before pre-treatment (T0) and after post-treatment (T13) intervention, as measured by the FIQ-R scale (primary endpoint).to assess whether INTEGRO intervention contributes to reducing the intensity of pain perception, in terms of median score difference on the BPI scale between T0 and T13;to evaluate patients’ perception of self-efficacy in managing pain by calculating median scores differences in the PSEQ scale between T0 and T13;to assess patients’ emotional regulation abilities in terms of median scores difference on the DERS scale between T0 and T13;Other objectives (secondary endpoints) are:The SEP  and WAI  scales as well as the physiological concordance index  will be considered as mediating variables. For this reason, we will analyze the association between SEP, WAI and physiological concordance index and also their contribution to explain the change in QoL perception, BPI, PSEQ and DERS scales between T0 and T13.Traumatic experiences, attachment style, mindfulness attitude and psychopathology will be considered as covariates.We assume that we have to recruit 45 patients to have a final sample of 38. Sample size was calculated according to the recruitment capacity of the Pain Therapy Unit and on dropout percentages (around 20%) reported in the literature ,85,86.ECG signals will be processed to derive the heart rate variability (HRV) series, which represents the variability of the time distance between two consecutive R peaks . ECG data collection, preparation  and HRV calculation will be performed according the current guidelines . EventuaThe respiratory signal will be pre-processed using bandpass filters between 0.01 Hz and 2 Hz, and the following features will then be derived: respiratory rate , mean variation of the signal, expressed as the average of the first derivative, signal strength. The application of multivariate measures for the estimation of cardiorespiratory coupling by means of phase lock and synchrogram measurements will eventually be evaluated as well.The electrodermal response will be filtered to remove frequency components higher than 2 Hz and will then be decomposed into two signals concerning a basal level (SCL) and a phasic level (SCR). From each of these signals, descriptive measures such as mean and variance will be derived.Time-resolved information about skin temperature will be considered through mean and variance over time.The aforementioned estimates of the autonomic activity derived from the physiological signals  will be derived from both the therapist and patient, and the associated level of agreement will be calculated. In particular, a linear correlation analysis will be performed on such paired data considering different experimental phases. Furthermore, considering HRV series recorded in the patient and in the therapist in sync, synchronization indices such as coherence and phase synchronization indices  will eventually be calculated.To check statistical assumptions before running any analysis, preliminary testing for normality will be assessed group-wise for each psychometric score and for each feature from physiological signals. Parametric or non-parametric tests will then be applied accordingly.For the analysis of all objectives of the study (main and secondary), a paired t-test or a paired Wilcoxon test will be performed.To deal with the multiple measures collected by the mediating variables , generalized mixed models for repeated measures on paired data will be performed.To evaluate the association between mediating variables, the Spearman or Pearson coefficient will be investigated.Finally, appropriate regression models, considering covariates, will be built to evaluate the role of mediating variables on the main and secondary objectives.For all analyses, a 5% significance level will be considered, and a statistical correction for multiple comparison will eventually be applied according to the experimental hypotheses. Appropriate 95% confidence levels or interquartile ranges will be produced.compare themselves with others on “similar health problems” and on contents such as “symptoms”, showing a psychological profile different from findings in other chronic patients (rheumatoid arthritis or cancer patients)”and may be distinguished into those who have a “maladaptive” profile, characterized by higher levels of pain perception, anxiety and depression and more frequent “unfavorable” social comparison strategies and those who show a more “adaptive” profile . It is not yet entirely clear which is the role of these psychological factors in the onset and maintenance of organic pathology.As described in the introductive section, FM patients show a constellation of both somatic  and psychological symptoms  ,9. AmongThe literature on FM psychological interventions tends to support multicomponent or multidisciplinary interventions, which include the management of both psychological and physical symptoms by combining CBT interventions with physical exercise, physical therapy or drug therapy, demonstrating that they are superior to a single pharmacological treatment ,17. NeveBased on these observations, we chose to conduct a pilot study based on an individualized integrated and multicomponent evidence-based intervention ,34,35,84it is important to be mindful that a measure asking clients to rate their attachment in general adult relationships may not find results exactly equivalent to a measure asking clients to rate their relationship with their therapist”. This can be particularly relevant when accounting for difficult therapeutic relationships, where poor alliance and insecure attachment may be present. There is some evidence that the more the patient has secure attachment-based relationships, the better the quality of the alliance with her therapist will be, and on the other side, there is less evidence for patients with an insecure attachment.In addition, the effectiveness of the intervention on QoL, pain-managing self-efficacy, emotion-regulation abilities and pain intensity perception will be related to therapeutic relationship variables , considering individual characteristics as covariates . This is because the recent literature has reported some evidence on the role of patients’ attachment dimensions on the quality of therapeutic alliance ,90,91 suIn our opinion, in order to untangle this complex interaction, the process should be analyzed with different coding and interpretation keys, which include both conscious  and less consciously controllable aspects , togethLifetime traumatic experiences and chronic stress may contribute to the onset and maintenance of chronic pain ,100 becaTrucharte et al.  showed tFinally, mindfulness abilities are strictly related to emotion regulation. Thus, a mindfulness-based intervention, by adopting a nonreactive and nonjudgmental focus, can enhance cognitive flexibility and the ability to regulate emotional reactivity, contributing to reduce pain and to improve overall health and functioning ,105. HowAlthough physiological measures may reflect autonomic phenomena which are not consciously controllable, revealing unaware aspects of the quality of the therapeutic relationship, they do not allow univocal meanings and reflect a non-specific physiological activation, which needs careful interpretation ,95,106.Moreover, the equipment for detecting psychophysiological signals both in the patient and the therapist, albeit managed in such a way to be as noninvasive as possible, may contribute to altering the genuineness of the interaction.Furthermore, the need to set eligibility criteria that consider physiological measure constrains may be a source of bias when selecting patients, reducing sample general representativeness with respect to the FM population. This primarily relates to the most seriously ill patients, who are excluded from psychophysiological detection because of their organic conditions or painkiller drug use.Finally, the preliminary structure of the research and the complexity of the intervention do not allow the study to be carried out in a large sample nor to implement a clinical trial including a control group. Maybe this will be possible after preliminary results coming from the pilot study.To conclude, this protocol will provide a promising individualized and patient-tailored treatment, relating the results to the analysis of the role of the therapeutic relationship together with patient characteristics.The preliminary results of this study may provide a basis for further research in this field, obtaining important results for FM patients, therapists and clinicians involved in chronic pain management.


To determine specific resting-state network patterns underlying alterations in chronic migraine, we employed oscillatory connectivity and machine learning techniques to distinguish patients with chronic migraine from healthy controls and patients with other pain disorders. This cross-sectional study included 350 participants . We collected resting-state magnetoencephalographic data for analysis. Source-based oscillatory connectivity within each network, including the pain-related network, default mode network, sensorimotor network, visual network, and insula to default mode network, was examined to determine intrinsic connectivity across a frequency range of 1–40 Hz. Features were extracted to establish and validate classification models constructed using machine learning algorithms. The findings indicated that oscillatory connectivity revealed brain network abnormalities in patients with chronic migraine compared with healthy controls, and that oscillatory connectivity exhibited distinct patterns between various pain disorders. After the incorporation of network features, the best classification model demonstrated excellent performance in distinguishing patients with chronic migraine from healthy controls, achieving high accuracy on both training and testing datasets (accuracy > 92.6% and area under the curve > 0.93). Moreover, in validation tests, classification models exhibited high accuracy in discriminating patients with chronic migraine from all other groups of patients (accuracy > 75.7% and area under the curve > 0.8). In conclusion, oscillatory synchrony within the pain-related network and default mode network corresponded to altered neurophysiological processes in patients with chronic migraine. Thus, these networks can serve as pivotal signatures in the model for identifying patients with chronic migraine, providing reliable and generalisable results. This approach may facilitate the objective and individualised diagnosis of migraine. Migraine, a highly prevalent neurological disorder, is a disabling disease that affects over one billion individuals globally, with a global age-standardised prevalence of 14.4% . MigrainWith a strong genetic contribution, migraine is a complex brain network disorder caused by widespread structural and functional abnormalities in the brain regions responsible for multisensory, affective, and cognitive processing –8. Thus,In this study, we employed magnetoencephalography (MEG) to directly record neural activity across a wide frequency range and to analyse resting-state oscillatory connectivity within cortical networks. Compared with conventional scalp electroencephalography and functional MRI, MEG offers superior localisation accuracy and a more detailed understanding of the temporo-spectral dynamics of cortical activities, respectively . To idenAll participants were aged between 20 and 60 years, were right-handed, had no history of systemic or major neurological diseases, had normal physical and neurological examination findings, and were enrolled from the headache clinic of Taipei Veterans General Hospital. HCs did not have personal or family histories of pain disorders and had not experienced any substantial pain condition in the previous year. Participants receiving prophylactic drugs, hormones, or other medications on a daily basis were excluded. This study was approved by the Institutional Review Board of Taipei Veterans General Hospital (VGHTPE: IRB 2015-10-001BC), and all participants provided written informed consent before study commencement.International Classification of Headache Disorders, Third Edition (ICHD-3)  vs. HC [n = 54]) and 84.2% (CM [n = 15] vs. EM [n = 51]). Another study using the functional connections of 33 seeded pain-related regions in the brain reported an accuracy of 86.1% for discriminating patients with migraine (n = 58) from that of HCs (n = 50) [n = 21) from HCs (n = 28) [n = 15] vs. ictal migraine [n = 13]) and 88.7%  for identifying patients with migraine [In functional MRI studies, Schwedt and colleagues  establis(n = 50) . Moreove(n = 28) . One stu(n = 28) . Consistmigraine . These ft test for CM vs. HC) and performing model validation (CM vs. other pain disorders), oscillatory connectivity in the PN and DMN emerged as crucial brain signatures for distinguishing patients with CM from those with other pain disorders and HCs, exhibiting excellent performance . Aberrant activities in the PN have been observed in individuals with pain disorders, which are characterised not only by cortical hyperexcitability and sensory cortex disinhibition [By employing feature selection  or their connections to cortical areas remained unresolved due to the limitations of MEG in recording deep brain activities. Second, the identification of patients with CM by using this model can facilitate individualised clinical decisions. However, whether this model can reveal the severity and progression of diseases or aid in determining the outcomes of treatments or interventions remain unclear. Future studies with longitudinal designs are necessary to explore the further applications of these models. Third, this study investigated oscillatory connectivity within the 1–40 Hz band. Interestingly, prior research has indicated a connection between abnormal high gamma or high-frequency oscillations and migraine patients , 48. TheOscillatory and network patterns provided insights into the distinct brain abnormalities associated with different pain disorders. Functional activities within the PN and DMN corresponded to altered and distributed neurophysiological processes in patients with CM, making them pivotal signatures in the model for identifying patients with CM. With satisfactory reliability and generalisability, this classification model can facilitate the objective and individualised diagnosis of migraine.


Acute sore throat (ST) can occur as part of a common cold of viral origin or caused by pharyngeal bacterial pathogens. The majority of patients with acute ST complain of pain on swallowing and dry scratchiness which can have a negative impact on the quality of life (QoL). This study aimed to evaluate the time to pain relief in patients with acute ST, following a single administration of benzydamine hydrochloride (HCl) 0.3% oromucosal spray or benzydamine HCl 3 mg lozenges.This multicenter, randomized, active-controlled, open label, parallel-group, international phase IV study was conducted at 12 investigational centers in Poland, Hungary, and Russian Federation. The study population consisted of 363 adult patients with recent onset (≤3 days) of ST and a diagnosis of tonsillopharyngitis. The primary endpoint was to assess the efficacy of benzydamine HCl in ST pain relief at 2 minutes after a single-dose administration. Secondary endpoints included, among others, the assessment of a first perceived ST relief at 1 minute after a single-dose administration of benzydamine HCl spray or lozenge.Both the spray and lozenges are effective in providing a ST relief starting already at 2 minutes after a single administration, with an effect lasting up to up to 4 hours. Clinical efficacy after 7 days of treatment and a good safety profile were also demonstrated.Anesthetic and analgesic properties of benzydamine spray and lozenges effectively addressed the patient priority of a rapid relief of symptoms of upper respiratory tract infections (URTI). The majority of patients with acute ST complain of pain on swallowing, dry scratchiness, cough and flu-like symptoms that can have a negative impact on the quality of life (QoL). ST is often caused by an inflammation of the pharynx, tonsils or nasopharynx related to the release of inflammatory mediators, including bradykinin and prostaglandins, following the local responses to cell damage, and that exert their effect on sensory nerves in the airways. In addition, pro-inflammatory cytokines, such as interferon-α, may induce behavioral changes and be associated with sickness symptoms.Acute sore throat (ST) often occurs as part of a common cold of viral origin or caused by pharyngeal bacterial pathogens. In particular, medicated throat lozenges have the advantage over sprays and gargles of being slow-releasing, ensuring continuous delivery of the active ingredients to all affected areas of the throat and over a prolonged period of time, while oral sprays are more effective in coating the oropharynx than oral rinses.Symptomatic relief of pain is the main objective of most over-the-counter treatments available for the self-management of ST, with different formulations and characteristics. Benzydamine HCl is a weak inhibitor of the synthesis of prostaglandins and a strong inhibitor of proinflammatory cytokines, particularly tumor necrosis factor-α, interleukin-1β and monocyte chemoattractant protein-1. Of interest, benzydamine HCl can exert some of its antiinflammatory activities by reducing the vascular changes occurring during inflammation, as well as through the inhibition of neutrophil degranulation with a membrane-stabilizing activity. Locally applied benzydamine HCl also exhibits marked local anesthetic properties, with a rapid effect on pain related to the interaction with cationic channels. Its topical application produces sufficient drug concentrations in the inflamed area with low systemic absorption, thereby limiting unrequired systemic exposure to the drug. In addition, benzydamine HCl revealed the ability to block the neuronal excitability,–17 thus supporting the synergistic and complementary effects of benzydamine HCl in the treatment of local inflammatory symptoms as well as in the painful processes, through a reduction of the inflammation cascade and of the inflammatory-mediated neuronal signaling.Benzydamine hydrochloride (HCl) is an indolic nonsteroidal antiinflammatory drug endowed with some peculiar properties not shared by other NSAIDs, such as local anesthetic and analgesic activities, together with antifungal and antimicrobial properties. proving to be safe and efficient, not only in the symptomatic treatment of pain and irritative/inflammatory conditions of the oropharynx, but also in various conditions ranging from posttonsillectomy pharyngitis or radiomucositis, to throat irritation and/or dysphagia induced by intubation.,19Topical formulations of benzydamine HCl are available for the treatment of several oropharyngeal conditions, Patients with ST often complain of odynophagia, throat swelling, and dysphagia, and may also report a broad range of other functional painful qualities of ST. From the patient perspective, a rapid relief of symptoms is the most important aspect of treating upper respiratory tract infections (URTI). In this setting, we performed a phase IV study  aimed at assessing the speed of pain relief in patients with acute ST, following the administration of benzydamine HCl 0.3% oromucosal spray or benzydamine HCl 3 mg lozenges. Safety and efficacy up to a 7-days treatment period were also evaluated. Finally, any differences between the 2 formulations, in terms of pain relief, duration of the analgesic effect, and effect on other symptoms related to ST were described as well.Acute pharyngitis and tonsillitis are not life-threatening conditions but may have profound negative influence on QoL.A multicenter, randomized, active-controlled, open label, parallel-group, international study was conducted from August 2020 to June 2021 in 12 investigational sites from different sources  located in Hungary, Poland and Russian Federation to evaluate the efficacy and the safety of benzydamine HCl 0.3% oromucosal spray and benzydamine HCl 3 mg lozenges in patients with acute ST.Adult patients (18–75 years) of both sexes, with recent onset of ST (≤3 days), at least 1 symptom of URTI in the previous 24 hours on the URTI questionnaire, a ST pain intensity score ≥ 60 mm on Sore Throat Pain Intensity Scale (STPIS) and an objective diagnosis of tonsillopharyngitis confirmed by a score ≥ 5 on the Tonsillo-Pharyngitis Assessment (TPA) were enrolled in the study. Three visits were scheduled during the study , and activities at each visit were performed as scheduled in Table This was the first study that directly compared the relief provided by benzydamine HCl, using 2 different formats in the same study population. Patients were randomized to treatment according to the order of recruitment either to 1 dose of benzydamine HCl spray oromucosal solution (test product - 4 nebulizations corresponding to 2.04 mg of benzydamine HCl), or to one 3 mg lozenge of benzydamine HCl (reference therapy - corresponding to 2.68 mg of benzydamine HCl), both administered at the investigational site. The efficacy evaluations started immediately after the nebulization or after the complete lozenge dissolution (taking an average time of 9.12 minutes) (Table The primary objective of the study was to assess the efficacy of benzydamine HCl (spray or lozenges) in ST pain relief at 2 minutes (T2min) after a single dose administration.The secondary objectives included the evaluation, after a single-dose administration of benzydamine HCl, of a first perceived ST relief at 1 minute; the meaningful ST relief and the effect on difficult swallowing and sensation of swollen throat at T5min; T10min; T15min; T30min; T60min; T120min; the effect on different characteristics of ST pain and discomfort after 60 minutes and 120 minutes; the ST intensity across the study, the pharyngeal inflammation status and the patient satisfaction at the end of the treatment; safety assessment.The primary endpoint of the study was the percentage of responders defined as patients reporting at least a “slight relief”  at T2min after the first application of benzydamine HCl (spray or lozenges).http://links.lww.com/MD/I709 and were performed as scheduled in Table As secondary endpoints, the comparison between the 2 treatment groups was assessed to determine: the percentage of patients recording a first perceived ST relief (STRRS score ≥1) assessed at T1min; the percentage of patients recording a meaningful ST relief (STRRS score ≥ 3) assessed from T5min to T120minutes after a single dose administration  population, including all randomized patients who took at least 1 dose of the investigational medicinal product (IMP) and performed the T2min efficacy assessment with STRRS, and the per-protocol (PP) population, including all randomized patients who took at least the first dose of the IMP and performed all Day 0 (up to 120 minutes) STRRS evaluations, with no major protocol violations. As this was a noninferiority study, the PP population was used as the primary analysis population. In order to judge the validity of the PP results, the noninferiority analysis was repeated in the m-ITT population. The safety population (SP), comprising all those who took at least 1 dose of the study medication, was used to evaluate safety data and demographic, baseline, and treatment characteristics. All adverse events (AEs) and treatment emergent AEs (TEAEs) were coded according to MedDRA dictionary (version 23.1). For exploratory purposes only, an additional modified-PP (m-PP) population was included to describe secondary efficacy endpoints after 120 minutes. The m-PP population was defined by the PP population with the exclusion of patients who took concomitant treatments or additional doses of IMP during the at-home period or 3 lozenges before V2 on Day 7.Benzydamine HCl spray was considered not inferior to benzydamine HCl lozenges if the lower limit of the 2-sided 95% confidence interval (95% CI) of the difference in responder rates between the benzydamine HCl formulations, defined as % of patients reporting at least a “slight relief” (STRRS score ≥ 1) at T2min, did not exceed the threshold of −10%. Assuming a responder rate, defined as percentage of patients reported at least a slight relief (STRRS score ≥ 1), equal to 90% in the benzydamine HCl lozenges arm at T2min, a sample size of 178 patients per group (with a drop-out rate of 20%) was required to claim the noninferiority between treatment groups, using a 2-tailed confidence level of 95%. In this way, the lower bound of the confidence interval (CI) of the difference in the responder rates between the treatment groups should not exceed the threshold of −10.0% with a power of 80%.The Cochran-Mantel-Haenszel test was applied on percentage of patients with a STRRS score ≥ 1 at 1 minute after the single dose administration and on percentage of patients with a STRRS score ≥ 3 at 5, 10, 15, 30, 60, and 120 minutes after the single dose administration.ANCOVA or ANOVA were applied on: the sum of pain intensity differences (SPID) for DSS and SwoTS, estimated as the area under the pain intensity difference (PID) versus time curve up to 2 hours postdose ; the total pain relief for STRRS, estimated as the area under the pain relief versus time curve by adding the pain relief scores observed 2 to 240 minutes postdose; QuaSTI at 60 and 120 minutes postdose; TPA; STPIS. Covariate used in ANCOVA was the baseline value. Scores were reported as mean ± standard deviation (SD).Descriptive statistics was applied to PSQ at the end of the treatment, to vital signs and their change from V0 and to change from baseline in physical examination presented by treatment group.Confidence intervals and statistical tests for secondary endpoints were of descriptive nature.This phase IV study aimed to generate new clinical data about the speed of relief provided by a single application of Tantum Verde oromucosal spray (benzydamine HCl 0.3%) or Tantum Verde lozenges (benzydamine HCl 3 mg).http://links.lww.com/MD/I710 for size of the 4 populations used for data analysis).A total of 363 adult patients with recent onset of ST (≤3 days) and a confirmed diagnosis of tonsillopharyngitis were randomized to benzydamine HCl 0.3% spray, n = 181) or benzydamine HCl 3mg lozenges (n = 182)  patients entered in the efficacy analysis as PP population and 363 patients as m-ITT population (181 benzydamine HCl 0.3% spray and 182 benzydamine HCl 3 mg lozenges). Based on the results, benzydamine HCl spray resulted not inferior to benzydamine HCl lozenges, as the difference between the percentage of patients reporting at least a “slight relief” (STRRS score ≥ 1) at 2 minutes after the administration of benzydamine HCl spray or benzydamine HCl lozenges, did not exceed the threshold of −10% in both the PP  and m-ITT  populations (Table P = .0041 in m-ITT population and P = .0019 in PP population).A first pain relief (STRRS score ≥ 1) was perceived already at 1 minute after the administration of the benzydamine HCl spray and lozenge: high responder rates were recorded for both the treatment groups , with significantly more responders in benzydamine HCl lozenges arm in comparison with benzydamine HCl spray arm (http://links.lww.com/MD/I711).The prompt relief provided by the application of benzydamine HCl was also confirmed by the high responder percentage of patients reporting a meaningful ST relief (STRRS score ≥ 3). The percentage of patients who experienced a meaningful pain relief was considerable already at T5min after the single dose application and increased at T10min, with a peak at T15min and T30min and a decrease from T60min. However, at T120min, about half of the participants still showed significant pain relief in both the treatment arms. In the benzydamine HCl lozenges arm, the percentage of patients experiencing the ST relief was significantly higher at 5, 30 and 60 minutes post single-administration in comparison to the benzydamine HCl spray arm , showing that both treatments provided a significant reduction of ST up to 1 week of treatment , with no statistically significant difference between the 2 arms. This improvement was confirmed in PP and m-PP population analysis.The TPA assessment in m-ITT population documented an improvement of the score from V0 to V2 by 8.38 ± 2.40 for benzydamine HCl spray arm and 8.47 ± 2.43 for benzydamine HCl lozenges arm  revealed an improvement of the difficulty in swallowing of 49.92 mm ± 41.41 for benzydamine HCl spay and 50.18 mm ± 41.69 mm for benzydamine HCl lozenges in the m-ITT population and an improvement of 46.48 mm ± 39.88 mm for benzydamine HCl spray and 52.11 mm ± 38.98 mm for benzydamine HCl lozenges in the PP population versus the baseline values. The efficacy of the 2 treatments can be considered comparable as no statistically significant difference was found between the 2 treatment arms.The SPID analysis of data from the SwoTS (0–120 minutes postdosing) revealed an improvement of the sensation of swollen throat of 46.15 mm ± 39.21 mm for benzydamine HCl spray and 52.27 mm ± 38.93 mm for benzydamine HCl lozenges in the m-ITT population and an improvement of 46.48 mm ± 39.88 mm for benzydamine HCl spray and 52.11 mm ± 38.98 mm for benzydamine HCl lozenges in the PP population http://links.lww.com/MD/I709), both benzydamine HCl treatments showed a similar and statistically significant effectiveness in reducing symptomatology at T60min and T120min relative to baseline in m-ITT and PP populations (P < .0001). Results also showed the absence of significant differences between the 2 treatment arms, with the exception of QuaSTI agonizing score change at T60min versus V0, showing a significant difference in favor of benzydamine HCl lozenges in m-ITT and PP populations (P = .0199).For all items of the QuaSTI  and clinically improvement in both treatment arms in m-TT, PP and m-PP population and in comparison to baseline assessments, confirming the efficacy of benzydamine HCl in reducing ST pain and inflammation.Moreover, TPA total score demonstrated that all features of pharyngeal inflammation had a statistically ; 9 TEAEs were classified as mild, and all were resolved. None of them was serious or led to withdrawal. Adults have in average 2 to 4 URTI/year, usually occurring during the colder months, rising to 6 to 8 infections/year in children because of their immunological naivety, and are a common reason for primary care consultations. The therapeutic options available for the treatment of ST are aimed not only to eradicate the causal agents and produce a clinical cure, but also to increase patients’ QoL. In particular, local therapies are useful for symptomatic treatment of ST as they allow direct application to the painful area, providing rapid and effective pain relief, with a reduced risk of toxicity when compared with systemic treatments. The local anesthetic activity of benzydamine HCl has been shown to be extremely useful in the treatment of painful throat and mouth conditions, mainly due to rapid pain relief provided. The study results confirm that initial rapid relief from ST pain is perceived by most patients as early as 2 minutes after administration when benzydamine HCl is delivered as either a lozenge or a spray, addressing the patients’ priority of a rapid relief of symptoms of URTI. Evaluation of secondary endpoints showed nearly similar findings for both benzydamine HCl treatment arms. A significant difference in favor of the benzydamine HCl lozenges versus the spray was observed for patients who experienced the first perceived pain relief after 1 minute. This result could be explained considering that efficacy evaluations for lozenges started only when complete dissolution occurs. Consequently, by the time of the first assessment patients had already perceived an initial relief. Conversely, the pain relief assessment carried out for the spray was performed immediately after its administration. A clinical and statistically significant reduction from baseline in pain intensity, pharyngeal inflammation and other pain dimensions was achieved by both formulations every day and also over a period of 1 week.Acute pharyngitis and tonsillitis are not life-threatening conditions but may have a profound negative effect on QoL. In addition, a cross-national survey among pharmacists and general practitioners revealed that benzydamine HCl is largely recognized and recommended as a suitable topical treatment of ST and other inflammatory conditions of the oral cavity.Of note, the appropriate use, and the effectiveness of benzydamine HCl in the treatment of ST has been recently reinforced by a Delphi-based international consensus involving pharmacists and general practitioners.Benzydamine HCl as oromucosal spray 0.3% and 3 mg lozenges confirmed its value providing a rapid relief from symptoms of ST with a high safety profile and product acceptability, thus representing a valuable tool in the clinical practice for the treatment of ST, allowing the patients to choose between 2 equivalent benzydamine HCl formulations according to their own preferences.Medical writing support was provided by Amalia Forte, PhD, on behalf of Menthalia, Naples, Italy.Conceptualization: Carmelina Valerio, Enrica Salvatori.Data curation: Giorgio Di Loreto.Formal analysis: Giorgio Di Loreto.Methodology: Carmelina Valerio, Giorgio Di Loreto.Project administration: Carmelina Valerio.Software: Giorgio Di Loreto.Supervision: Enrica Salvatori, Agnese Cattaneo.Visualization: Carmelina Valerio.Writing – review & editing: Carmelina Valerio, Giorgio Di Loreto, Enrica Salvatori.


Analgesia is a core intervention in emergency medicine. Pain is subjective, so patient-reported experience with pain and analgesia is essential for healthcare professionals.The aim of this study was to evaluate patient-reported side effects and satisfaction associated with pre-hospital analgesia with low-dose esketamine.This is an observational cross-sectional study conducted as part of quality assurance measures of the German Red Cross Emergency Medical Service, Reutlingen, Germany.The survey was administered to all patients who received prehospital esketamine analgesia from paramedics. Addresses were obtained from medical records and mailed 10 days after the event. Patient feedback was anonymous and could not be linked to operational documentation.n=77) being female. The main diagnosis reported was fractures of the extremities in 69.7%. Patients reported initial median pain intensity on a Numeric Rating Scale (NRS) of 10 [8-10]. Pain was unbearable for 96.3% of patients. After administration of analgesia, 95.3% were satisfied or very satisfied. Patients reported no side effects in 78.5%, minor side effects in 10.0%, significant but well tolerable side effects in 11.3%, borderline tolerable side effects in 0.2%, and no unbearable side effects. Borderline tolerable nausea was reported in 2% of patients along with dreams in 0.8%. No nightmares were reported. Further analysis showed that patients older than 80 years reported significantly more side effects (p < 0.001) and were thus less satisfied with the analgesia.A total of 201 patients were contacted, and 119 responses were received via the online questionnaire and postal mail (response rate 59%). The mean age of the patients was 68±13 years, with 64.7% (Both patient perception and analgesia with few side effects were important for both safety and satisfaction. In the present study, low-dose esketamine analgesia was associated with low side effects and high patient satisfaction.The online version contains supplementary material available at 10.1186/s12873-023-00898-4. Analgesia is one of the most significant interventions in emergency medicine. Characteristics such as rapid onset, short-acting effect, good safety profile with few side effects are important from the perspective of patients and professionals , 2. HoweIn addition, analgesia is dependent on the analgesic used. The most common analgesics in German  emergency medicine are fentanyl, morphine, and (es-)ketamine, as well as sufentanil and metamizole , 7. PiriKetamine plays a special role here, as its effect is dose dependent. At low doses, esketamine is an analgesic; at higher doses, it causes dissociative anesthesia to an extent. The transition from analgesia to anesthesia depends on dosage, co-medication, and patient condition, among other factors. For ketamine analgesia, dysphoria, vivid hallucinations, and even "emergence phenomena" (or agitation) are consistently reported as side effects; fewer reports are available for esketamine, the S-enantiomer of ketamine . EsketamThe importance of the pharmacological quality of the drugs on the one hand, but especially the patients' perception of analgesic efficacy with low side effects is crucial for successful analgesia and high patient satisfaction. Particularly for low-dose esketamine, it is unclear how pronounced the side effects are and how much they interfere with patient satisfaction .The aim is to assess the satisfaction and the side effects reported by the patients associated with analgesia with low-dose ketamine in a prehospital setting.This is an observational cross-sectional survey study conducted as part of quality assurance measures of the German Red Cross Emergency Medical Service, Reutlingen, Germany. The reporting structure follows the Checklist for Reporting Of Survey Studies (CROSS) .Since 2005, the Emergency Medical Service (EMS) in Reutlingen qualified and authorized its paramedics in a competence system for the independent administration of esketamine analgesia according to the specifications of the medical director. Indications for esketamine include all moderate to severe pain  –13. This® 50mg/2ml) at an initial dose of 0.125 mg/kg body weight i.v. associated to 1 mg of intravenous midazolam . Midazolam may be given once for dreams, psychomotor agitation, etc. Esketamine may be repeated as needed . Other analgesics have not been used.Low-dose esketamine analgesia in the studied EMS included the administration of esketamine  , 16. GenA good template has already been created by the working group of Sander et al. . HoweverThe following data were collected: age, sex, previous experience with pain, pain assessment, patient-reported indication for analgesia, analgesia success, and incidence of side effects . The catThe pain-experience was measured with an endpoint named scale ranging from 0=no pain experience to 10=subjectively maximum pain experience.Postal addresses were extracted from medical records and mailed 10 days after the event. In addition to the information text, the addressees received a paper questionnaire with a stamped return envelope and the option to complete the questionnaire online via a QR code. Patient feedback was anonymous and could not be linked to the operation or operation documentation or to specific patient data such as age, sex, body weight, or specific drug dosages.All patients who received esketamine with analgesia, administered by paramedics in the German Red Cross Emergency Medical Service of Reutlingen, Germany between June 02, 2022, and November 28, 2022, were included. There were no exclusion criteria given the inclusion criteria. For data collection, patients were contacted per mail 10 days after the event.Questionnaires answered online via QR code were entered using Microsoft Forms. Multiple entries could not be intercepted. Postal returns were scanned using the optical character recognition software FormPro 3.1  and recorded as a dataset, with the correct composition and processing manually checked against the postal returns.This survey was preceded by various analyses of routine and quality assurance data, feedback from emergency physicians, paramedics and emergency department staff, and most importantly, feedback and interviews with patients.p < 0.05 were considered statistically significant. The χ2-test and, for independent samples with normally distributed data, the t-test or single-factor analysis of variance were used to calculate differences, or Mann-Whitney-U-Test when not normally distributed. Statistical analyses were performed with SPSS Statistics 28 .Descriptive statistics were reported with the metric scale for mean ± standard deviation (SD) when normally distributed or medians and interquartile range (IQR) when not normally distributed. Pearson's coefficient was used to describe correlations between metric variables. Frequencies are indicated with absolute and relative numbers. Two-tailed values of n=77) of patients were female. The questionnaire was completed by 68.9% (n=82) of respondents, and 31.1% (n=37) completed by their relatives. When asked about their previous experience with physical pain with the question “How 'experienced' are you with severe physical pain, e.g., major injuries, illnesses, tumors, surgeries, or therapies? Ranked from "no pain experience" to "most severe pain experience" ” the mean response was 5.1 ± 2.5 on an 11-point Likert scale, which is a medium pain experience and interviewed patients obviously have quite painful experiences.A total of 201 patients were contacted, with 119 responses received via online questionnaire and postal mail (response rate 59%). The mean age was 68 ± 13 years (range 12-87 years). 64.7%   Fig. .Fig. 2Pan=6, 5.1%)  answered no. On a four-point pain scale , 6.5% (n=7) of patients reported moderate pain and 93.5% (n=101) of patients reported severe pain. Patients in the "moderate pain" group reported a median pain NRS of 6 [5-7], while patients in the "severe pain" group reported a median pain NRS of 10 [8-10]. A total of 104 patients (92.9%) received additional analgesia in the hospital. Following the administration of analgesia in the prehospital setting, 95.3% of patients were satisfied or very satisfied.Patients reported initial median pain on an NRS of 10 [8-10] (range 5-10). The additional question of whether the pain was considered tolerable prior to treatment was answered in the negative by 96.3%. When asked hypothetically if they could sleep with the pain, 96.6% . A correlation between "pain experience" and initial pain on the NRS could not be shown . When comparing the pain rating in function of the gender, female patients reported a higher NRS compared to the male   in this age group  were significantly more dissatisfied than others, but this is an extremely relevant point for emergency medicine. There are limited data on ketamine in the context of analgesia in geriatric patients. A study comparing an intravenous subdissociative dose of ketamine with morphine for analgesia in geriatric patients showed comparable analgesia with higher rates of psychoperceptual side effects . A sloweThe indication for esketamine, or ketamine, is often associated with prehospital trauma pain or analgesia and anesthesia of polytrauma , 32. Ketn=5), but it is not possible to determine what might have caused the dyspnea, such as thoracic trauma, because there is no link to the case documentation.However, the indications for analgesia in the present study are interpreted by the patients. Injuries, without reference to the diagnoses that are usually not known with certainty in the prehospital setting, are also relatively well reflected as some indications by patients. Some indications are less plausible. For example, the indication of dyspnea was reported by 6%  may have better treatment pathways in the elderly.Additional file 1.


Rest pain, motion pain, and nausea were assessed using NRS scores. Results: Compared with the APAP group, the IV-PCA group experienced significantly greater resting pain and nausea on postoperative day 1. A correlation was found between preoperative and postoperative pain. Postoperative nausea at 8 h was significantly correlated with pain at rest at 4 h (r = 0.193), 8 h (r = 0.194), day 1 (r = 0.245), and day 2 (r = 0.188) after surgery. Early postoperative pain and nausea correlated with subsequent pain and nausea. Conclusions: Intravenous APAP is associated with less pain and nausea and is superior to IV-PCA.Background: Opioids often need to be discontinued because they cause nausea, whereas the administration of intravenous acetaminophen (APAP) causes less nausea and vomiting. This study aimed to compare the effects of fentanyl-based intravenous patient-controlled analgesia (IV-PCA) and intravenous APAP on pain and nausea after total hip arthroplasty (THA). Methods: We prospectively investigated primary THA patients who underwent the anterolateral supine approach at four centers between October 2021 and October 2022. The patients ( Intravenous patient-controlled analgesia (IV-PCA), including opioids, epidural anesthesia, spinal anesthesia, nerve blocks, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen (APAP) is used for analgesia after total hip arthroplasty (THA) ,2. AlthoRecently, the use of multimodal analgesia, which increases analgesic effects and reduces adverse effects through combining analgesics that act at multiple sites in the pain transmission pathway, has increased . APAP caPain is an anxiety factor for patients after undergoing THA; however, if postoperative pain is minimized, early rehabilitation can be performed effectively, leading to an earlier recovery of walking ability and the avoidance of adverse events, such as deep vein thrombosis . FurtherMost THA procedures in our groups are performed using a supine anterolateral approach. This minimally invasive surgery that preserves the muscles and tendons is considered less invasive and painful than conventional THA ,12,13,14Although multimodal analgesia has been shown to increase analgesic effects while decreasing side effects, few studies have compared the efficacy and side-effect profile of IV-PCA with those of opioids and intravenous APAP for pain management after THA. We hypothesized that postoperative pain management based on APAP would be an analgesic method with similar analgesic efficacy but less nausea and vomiting than in IV-PCA treatment. The aim of this study was to compare postoperative analgesia and side effects between intravenous APAP and IV-PCA fentanyl after total hip arthroplasty.We prospectively investigated primary THA patients who underwent the anterolateral supine approach between October 2021 and October 2022 at four centers in Niigata Prefecture, Japan. The participants included male and female patients aged 30–80 years. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Niigata University Ethics Committee (2021-0013). All research was performed in accordance with CONSORT guidelines/regulations, and written informed consent was obtained from the participants according to the study plan. This multicenter randomized controlled trial was registered at the Niigata University Ethics Committee on 20 September 2021 (UMIN-CTR ID: 000045480).2), a gastric ulcer, bronchial asthma, a psychiatric disease, or a research-related drug allergy. In addition, patients with a Crowe grade of 3–4 and intraoperative fractures and patients who had previously undergone hip joint or femur surgery were also excluded.All patients were assigned to the IV-PCA or APAP group using a random-number table. Randomization was performed at each of the four facilities to avoid bias in the number of patients per facility between groups. Patients were excluded if they had liver disease, renal disease  was infused intravenously over 15 min immediately after surgery; the same dose was administered every 6 h until the next day.In both groups, 40 mL of 0.375% ropivacaine (30 mL in patients weighing < 50 kg) was injected topically into the muscle layer and subcutaneous tissues before wound closure. Intravenous flurbiprofen, intramuscular ketoprofen and diclofenac suppositories were used for additional postoperative analgesia. Domperidone and Metoclopramide were used as antiemetics as needed. Celecoxib 400 mg/day and APAP 3000 mg/day were administered orally starting the day after surgery. The administration start times for APAP were adjusted so that APAP and IV-PCA fentanyl did not overlap. Tranexamic acid 1000 mg was administered intravenously at the beginning of the surgery and 6 h postoperatively .The collected survey items included patient age, sex, operative time, and total perioperative blood loss  . RestingBlood tests were performed at each time point (preoperative and postoperative days 1 and 3) to investigate the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. When the levels exceeded thrice the normal upper limit as defined by the respective institution’s standards , APAP administration was promptly discontinued, and the patient was excluded from further evaluation. On postoperative day 7, a lower limb venous echocardiogram was performed by a laboratory technician to search for deep vein thrombosis (DVT). Postoperative therapy was allowed in both groups starting the day after surgery, with early loading according to pain.t-test for continuous variables. With regard to NRS, a Mann–Whitney U-test was conducted, using categorical data to compare APAP and IV-PCA group in each survey period. Pearson’s coefficient was used to evaluate the correlation between each NRS score. A chi-squared test was also conducted with the pain and nausea variables as follows: none/mild and moderate or higher. We have plotted the NRS as a boxplot with medians and interquartile range (IQR). A power analysis determined that the minimum number of cases for which the study could be validated with a power value > 0.8 was 88 cases per group. We also performed a post hoc analysis to evaluate statistical power (type II [β] error). We defined the effect size (d) as 0.5 and type I (α) error as 0.05 for the t-test, and the effect size (d) as 0.3 and type I (α) error as 0.05 in the chi-squared test. Differences were considered statistically significant at p < 0.05.SPSS statistical software  was used to analyze the data. All patients were allocated to either the IV-PCA or APAP group based on a randomly generated number; the researchers generated a random allocation sequence. Each group was compared using the chi-squared test for categorical data and Student’s Overall, 178 patients were included in the study; 88 were assigned randomly to the IV-PCA group and 90 to the APAP group. No significant differences were found in age, sex, body mass index (BMI), operative time, intraoperative blood loss, or total perioperative blood loss between the two groups . Twelve p = 0.043) and nausea on postoperative day 1 (p = 0.047) were significantly greater in the IV-PCA group than in the APAP group (p = 0.009) and 4 (p = 0.030), and nausea on postoperative day 1 (p = 0.041) (Resting pain on postoperative day 1 (AP group . Moreove= 0.041) .A correlation was found between preoperative and postoperative pain in all cases. No other preoperative factors were observed to influence postoperative nausea and pain .Nausea at 8 h postoperatively significantly correlated with rest pain at 4 h (r = 0.193) and 8 h (r = 0.194) and on day 1 (r = 0.245) and day 2 (r = 0.188) after surgery . Other cp = 0.677). AST and ALT levels were abnormal in one patient in each group  . Additionally, the administration of additional antiemetics was similar in the IV-PCA and APAP groups (14 times in the IV-PCA group and 12 times in the APAP group). Additional analgesia and additional antiemetics were more common in the IV-PCA group. DVT occurred in four (4.5%) and three (3.3%) patients in the IV-PCA and APAP groups, respectively, with no significant difference (= 0.987) . The posThe study analysis showed that rest pain on postoperative day 1 and nausea on postoperative day 1 were significantly greater in the IV-PCA group compared to the APAP group. Moreover, moderate or severe resting pain was significantly greater in the IV-PCA group than in the APAP group on postoperative days 1 and 4, and nausea on postoperative day 1. Thus, APAP provided better analgesia for postoperative pain, with less postoperative nausea than IV-PCA. Moreover, APAP is effective in combination with NSAIDs, nerve blocks, and local injections in multimodal analgesia ,19,20,21Roberts et al. found that opioid-induced postoperative nausea and vomiting occurred in 50% and 20% of their patients, respectively . They alIn this study, the NRS score of the IV-PCA group was significantly higher for nausea on postoperative day 1 than that of the APAP group. The NRS score of the IV-PCA group also tended to be higher 4 h postoperatively than that of the APAP group; however, the difference was not significant. Differences between the IV-PCA and APAP groups might have developed as the intraoperative effects decreased and opioid use increased. Furthermore, a significant correlation was found between nausea at 8 h postoperatively and pain at rest for approximately 2 days after surgery, suggesting that nausea may have influenced NRS scores for resting pain. These findings indicate that APAP, which causes less nausea and vomiting than IV-PCA, is preferable for postoperative analgesia.Hepatic dysfunction is a potential side effect of APAP; however, only two liver function abnormalities were observed among all patients. In addition, although overdosage can be a problem, APAP is safe if the dosage is followed  and has This study has some limitations. First, the sample size was small; however, the sample size used was calculated to be the minimum number that a power test could validate. Second, all procedures were performed using an anterolateral supine approach, which preserves the muscles and tendons and may be more beneficial for functional recovery and less painful than the conventional approach ,12,13,14This study could not detect cases for which APAP or IV-PCA was suitable according to sex, BMI, or other factors. Therefore, further research is necessary to select an appropriate analgesic method for each patient.Intravenous acetaminophen decreased the incidence of postoperative pain and nausea as compared to IV-PCA fentanyl and therefore may be the preferred analgesic choice for primary THA surgical patients.


Recently, cancer patients have challenges with self-management. This study aims to improve symptoms of chronic pain, and anxiety and depression associated with cancer by PRO-SELF nursing intervention.Sixty-four patients were randomly assigned to an intervention and a control group from Jan 2016 to Dec 2019, 34 usable cases in the intervention group and 30 cases in the control group were collected. The control group received a routine cancer pain nursing intervention, whereas the intervention group received a PRO-SELF based multidisciplinary collaborative cancer pain nursing intervention. After three months of intervention, the Numeric Rating Scale (NRS), Medication Compliance Questionnaire (MCQ), Social Support Rating Scale (SSRS), Self-rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS), Quality of Life Scale (FACT-G Chinese version) and Chronic Pain Self-efficacy Scale were resent to compare the differences in the observation indicators included evaluation of patients’ social support degree, anxiety and depression score, quality of life scores and self-efficacy scores between two groups. The t-test and rank-sum test were used for statistic analysis.No significant differences were found between groups for pain and medication compliance (P > 0.05). However, significant differences were found between groups in social support, life quality, chronic pain self-efficacy, and self-rating anxiety and depression index scores (P < 0.001). The intervention group report more social support, pain self-efficacy and less anxiety and depression (P < 0.001).The PRO-SELF pain symptoms in patients with a cancer pain management programme improved degree of social support, life quality, self-efficacy, anxiety, depression which is worthy of clinical application. Pain is the most common clinical symptom of cancer patients, which seriously affects their quality of life . Along wThe PRO-SELF cancer pain symptom self-management programme was created and developed by Dodd  in 2000.This prospective study takes the pain PRO-SELF strategy as a guide on the continuous nursing intervention for discharged cancer patients. This study intended to evaluate the impact of the pain PRO-SELF strategy on the self-management ability of patients with cancer pain. It subsequently enables the development of an effective pain self-management programme and provides a scientific basis for the effective improvement in patients’ self-management ability.This study aims to investigate the influence of PRO-SELF cancer pain symptom control programme on patients’ self-management ability. Excluding patients who did not meet the inclusion criteria, and patients who did not complete the study due to migration, self-withdrawal, death and other reasons, 64 patients were finally included in this study from Jan 2016 to Dec 2019. The 64 patients were divided into an intervention group (34 cases) and a control group (30 cases).This was a prospective case control study. Patients were recruitment from the outpatient department of cancer centre in our hospital from Jan 2016 to Dec 2019. At the time of enrollment, patients completed a demographic questionnaire, the Karnofsky performance score  and for This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of our hospital. All participants had signed the informed consent. The primary endpoint was the patients pain control, the secondary endpoints were medication compliance, social support, anxiety and depression, quality of life and self-efficacy.The inclusion criteria included (1) older than 18 years old; (2) had cancer with pain diagnosed by histopathology; (3) had Karnofsky Performance Status (KPS) score of ≥50; (4) had average pain intensity scores of ≥2.5; (5) had been aware of their illness and its diagnosis; (6) expected to survive for more than 3 months; (7) have had no language barrier and have had no history of mental illness; (8) be able to read or complete the questionnaire with or without the researchers’ help, understand the study and volunteer to participate in the experiment.The exclusion criteria included (1) bone metastases; (2) taking additional painkillers outside of the prescription; (3) suffer from language communication disorders; (4) unclear consciousness or mental disorders.In our PRO-SELF cancer pain symptom control programme, we formed a multidisciplinary collaborative cancer pain intervention team. The team composed of tumour doctors, pain doctors, psychologists, counsellors, pharmacists, cancer pain nurses and social workers. The pain specialist nurses led a multidisciplinary team. They tried to apply their nursing professional knowledge in the clinical area and strengthen communication and cooperation with the multidisciplinary staff. They also participated in the personalisation and optimisation of the patients’ diagnosis and treatment plans to ensure that all measures were effectively implemented and tracked. They also ensured that the treatments’ effects were fed back to enable them to provide the physicians with complete and accurate clinical information of their patients to ensure successful clinical diagnosis and treatment .The pain specialist nurses contacted with participants or their family caregivers once a week (Every Tuesday or Wednesday from 2:00 to 4:00 p.m) by office phone in Oncology Department. The control group was given a routine cancer pain nursing intervention, while the test group was given a multidisciplinary collaborative cancer pain nursing intervention based on PRO-SELF. During the first visit, we provided patients with written instructions on pain and side effect management, teaching them how to use weekly medication boxes and communicating with doctors about unresolved pain and the need to change pain medication prescriptions. At weeks 4, 8, and 10, the pain specialist nurse contacted the intervention group patients by phone and strengthened the education content of the PRO-SELF, guiding patients on how to modify their pain management plan or how to contact their doctor to improve pain outcomes. PRO-SELF nurses focus on guiding pain management in the following areas: how to evaluate pain and patient response to analgesics; how to improve pain by changing the frequency and frequency of painkillers taken without exceeding the prescribed dosage; how to prevent and manage side effects related to analgesics; and how to communicate with clinical doctors about unresolved pain and the need to change their pain relief prescriptions.Based on the PRO-SELF pain self-management project, this study combined the evidence-based needs of the nursing patients and the multidisciplinary pain control mode to set up a nurse-led multidisciplinary PRO-SELF cancer pain control scheme. To improve the patients’ self-management ability, the intervention was designed in three parts consisting of information, support and skills in six time nodes, including the 2, 4, 6, 8, 10, 12 week after enrollment. The investigators recruited the patients provided the intervention, the content included evaluation of patients’ social support degree, anxiety and depression score, quality of life scores and self-efficacy scores after three months of intervention.Three pain specialist nurses were trained on the PRO-SELF-based multidisciplinary nursing intervention programme for cancer pain and its specific operation methods. The training included the composition and flow of the PRO-SELF pain nursing intervention programme, the working mode and method of the multidisciplinary team, the operation and implementation of specific interventions, such as the contents and methods of pain assessment or tools of pain. In total, the programme consisted of 10 hours to ensure the implementation of the standardised nursing intervention.NRS was used to assessed pain, allowing for pain scores between 0 (no pain) and 10 (worst pain) . Pain waChinese version of Morisky, LL Gen drug compliance Scale was used (MMAS 1:8) . This scSocial Support Rating Scale was developed by Xiao Shuiyuan in 1986 . The sca350 indicates anxiety and the value of SDS353 indicates depress. Their reliability and validity were pretty good in Chinese patients with cancer pain.Self-rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were developed by W.K. Zung and widely used in China . The SASFACT-G was developed by American scholar Cella and translated by Wang Chonghua . MeasuriFor the time of the patients’ admission, we provided the following five scales for the intervention and control groups: NRS, MCQ, SSRS, SAS and SDS FACT-G and Chronic pain self-efficacy scale for the first evaluation , these sAfter three months, the six scales were resent to compare the differences in results between the test and control groups in terms of pain control, medication compliance, social support, anxiety and depression, quality of life and self-efficacy. These results were then used to appraise the impact of the multidisciplinary collaborative cancer pain nursing intervention on patients’ self-management ability.Excel was used to create a database, and the SPSS 17.0 software was employed for statistical analysis. Data conforming to normal distribution were checked by the t-test and variance analysis. Data conforming to non-normal distribution were checked by the rank-sum test. Countable data were checked by the chi-square test.No significant difference was observed between the two groups in terms of gender, marital status, educational level, occupation and monthly income of the family (P > 0.05) see .After a three months’ intervention, no significant difference was seen between the two groups of patients in terms of pain and medication compliance scores. After the intervention, significant differences were observed in the total score of social support, objective support and subjective support between the two groups, and the scores of the intervention group were higher than those of the control group (P < 0.001), as shown in The anxiety and the index of depression severity scores of the two groups after the three months of intervention were significantly different, and the scores of the intervention group were lower than those of the control group (P < 0.001), as shown in After the three months of intervention, significant differences were seen in the total scores of life quality, as well as physiological and emotional statuses between the two groups, and the scores of the intervention group were higher than those of the control group. However, no significant difference was noticed in the social/family and functional statuses (P = 0.037), as shown in Significant differences were observed between the two groups of patients after the intervention in three dimensions: (a) self-efficacy and the overall score of chronic pain self-efficacy, (b) physical function self-efficacy and (c) symptoms coping self-efficacy. And the scores of the intervention group were higher than those of the control group (P < 0.001) see .The results of this study illustrated that the scores of social support, quality of life, self-rating anxiety scale, self-rating depression scale and chronic pain self-efficacy in the patients receving the PRO-SELF cancer symptoms self-management project were significantly better than those in the control group, suggesting that the pain PRO-SELF strategy can improve social support, comprehensive quality of life, self-efficacy, anxiety and depression index of patients with cancer pain.Patients’ self-management included hospital intervention and continuous nursing intervention after discharge. Hospital interventionin included evaluation of the symptoms of patients, providing personalized patient education content in view of the actual situation, pain treatment, relief skills strategy, distribution of pain knowledge manual, emotional support. Continuous nursing intervention after discharge included telephone follow-up or regular home visits, providing emotional support to the patient, medication guidance and cancer pain relief strategies at home.The PRO-SELF cancer pain symptom self-management programme was created and developed by Dodd  in 2000.1416The results illustrated no significant difference in pain and medication compliance scores among patients in the two groups after the three months’ intervention, which is attributed to the defect of the degree of pain, medication compliance and disease, among others. A significant difference was seen in social support, life quality, self-rating anxiety scale, self-rating depression index and chronic pain self-efficacy scores in the two groups of patients before and after the intervention. This finding is consistent with Long Haiyan’s  and He HMultidisciplinary collaboration of pro-self provides personalized support for patients, and ultimately improves patients’ self-management ability by improving patients’ self-management cognition level 21222324.2122232526Limitations. There were several limitations in this study. Firstly, this trial had no blinding. Secondly, this study was only single-center trial and the sample size was limited. Thirdly, the clinical follow-up was short and it was necessary to observe the clinical long term efficacy. Further studies with multicentre randomized controlled trials and larger populations of cancer patients are necessary to evaluate the effect of this PRO-SELF pain symptom control programme.The PRO-SELF pain symptoms in patients with a cancer pain management programme improved degree of social support, life quality, self-efficacy, anxiety, depression and other negative emotions which is worthy of clinical application.The data underlying this article will be shared at reasonable request to the corresponding author.