To construct a new prediction nomogram to predict the risk of musculoskeletal pain in patients with primary osteoporosis who receive zoledronic acid intravenously for the first time.Clinical data of 368 patients with primary osteoporosis who received the first intravenous injection of zoledronic acid in our hospital from December 2019 to December 2022 were studied. Patients were divided into a musculoskeletal pain group (n = 258) and a non-musculoskeletal pain group (n = 110) based on the presence or absence of musculoskeletal pain 3 days after injection. Statistically significant predictors were screened by logistic regression analysis and the minimum absolute contraction and selection operator (LASSO) to construct a nomogram. The nomogram was evaluated by the receiver operating characteristic (ROC) curve, the calibration curve, the C-index, and the decision curve analysis (DCA) and verified in a validation cohort.The independent predictors of the nomogram were age, serum 25-hydroxyvitamin D, NSAIDs, prior Vitamin D intake, and BMI. The area under the ROC curve (AUC) was 0.980 , showing excellent predictive performance. The nomogram c index was 0.980, and the nomogram c index for internal verification remained high at 0.979. Moreover, calibration curves show that the nomogram has good consistency. Finally, the DCA showed that the net benefit of the nomogram was 0.20–0.49.2. A nomogram constructed from the above predictors can be used to predict musculoskeletal pain after the first zoledronic acid injection.Musculoskeletal pain is a common symptom of APR in OP patients treated with intravenous zoledronic acid. Risk factors for musculoskeletal pain after zoledronic acid injection in OP patients were: non-use of NSAIDs, youth (<80 years old), serum 25 (OH) D<30ng /mL, no prior intake of vitamin D, BMI<24 kg /mThe online version contains supplementary material available at 10.1186/s12891-023-06965-y. The incidence of primary osteoporosis is high in the elderly population around the world. The prevalence of osteoporosis in elderly women over 70 years old in China is 51.3%, and that in elderly men is 12.3% , 5. StudAs the most common adverse event after intravenous injection of zoledronic acid, APR is composed of different symptoms such as musculoskeletal pain, fever, and eye inflammation . StudiesAt present, there are few predictive tools for predicting APR risk after intravenous injection of zoledronic acid. Few studies have focused on predicting the fever symptoms of APR . APR is This study was based on the clinical data of 368 patients diagnosed with primary osteoporosis in the Third Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine from December 2019 to December 2022. These patients were diagnosed with OP and treated with intravenous zoledronic acid. Diagnostic criteria for primary osteoporosis are: bone mineral density less than − 2.5 after excluding other metabolic bone diseases; or bone mineral density is normal or reduced but there is a brittle fracture , 16. ExcPatient data were collected and recorded prior to intravenous therapy: two experienced orthopedic surgeons assessed and recorded symptoms that could cause musculoskeletal pain, such as osteoarthritis, accidental trauma, surgical history, etc. Also, we will measure and record a range of relevant indicators for participants, such as calcium levels, rheumatoid factors, C-reactive protein, etc.The predictors included in the study were: gender, age, BMI, fracture, NSAIDs, serum 25 ( OH ) D, PTH, T index, fluid volume, prior Vitamin D intake, OC. The above variables were converted into dichotomous variables based on previous literature reports , 17–22. P < 0.05. The influencing factors of APR were preliminarily determined through literature research. Variables with univariate analysis P < 0.1 were included in multivariate logistic regression analysis. Multivariate logistic regression analysis P < 0.05 variables as independent predictors.Data were analyzed using R software (version 4.1.0) and SPSS (version 24). Continuous variables are expressed as mean ± standard deviation, and independent sample t test or analysis of variance (ANOVA) is used for comparison between groups. The categorical variables were expressed as ratios, and the chi-square test was used for comparison between groups. The difference was defined as statistically significant at A total of 368 OP patients receiving intravenous zoledronic acid treatment met the inclusion criteria. Among the 258 patients included in the training set, 118 patients had musculoskeletal pain symptoms, and the remaining 140 patients had no musculoskeletal pain symptoms. The average age of the patients in the musculoskeletal pain group was 70.92 ± 7.38 years old, and the average age of the non-musculoskeletal pain group was 82.01 ± 4.24 years old. The validation set included 110 patients: 46 patients in the musculoskeletal pain group and 64 patients in the non-musculoskeletal pain group. The average age of the musculoskeletal pain group in the validation set was 69.01 ± 5.45 years old, and the age of the non-musculoskeletal pain group was 81.77 ± 4.65 years old. The probabilities of musculoskeletal pain in the training set and the validation set were 45.6% and 42.1%, respectively. There was no significant difference in the values of patient characteristics and predictors between the training set and the validation set, as shown in Table After literature research, 11 possible predictors were included in univariate analysis  D < 30nmol /L. The above risk factors should be properly assessed by the clinician before providing zoledronic acid injection therapy.We identified and screened indicators with important predictive value for APR after zoledronic acid injection, and developed a nomogram model as a tool to assist clinical diagnosis. The prediction model can assist clinicians in assessing the risk of musculoskeletal pain in OP patients receiving intravenous zoledronic acid. Therefore, it can solve the clinical difficulties of low compliance with bisphosphonates drugs, maximize the efficacy of anti-osteoporosis treatment, and ultimately reduce the fracture probability of OP patients. Whether in the training set or the validation set, the nomogram provides an excellent ROC curve for risk assessment. Physicians can identify high-risk groups of APR, explain in advance, and give reasonable suggestions. The high risk factors of musculoskeletal pain after zoledronic acid injection in OP patients are: young age (< 80 years old), BMI < 24 kg /mAt present, the potential mechanism of bisphosphonates-induced APR is still unclear. Studies have shown that bisphosphonates induces APR by inhibiting the mevalonate pathway, which can induce peripheral blood γδT cells to produce TNF α, IL6 and other pro-inflammatory cytokines –26. Supp2 was lower than that in patients with lower BMI and a thinner body. We speculate that it is related to the higher metabolic rate of obese patients.We found that patients older than 75 years of age have a lower probability of musculoskeletal pain, which is consistent with the results of Ding, Y . We specIn this study, patients with serum 25 (OH) D less than 30 ng/mLhad a higher risk of musculoskeletal pain, which was consistent with the results of Bertoldo Francesco et al , 22. WheThe results of this study suggest that prophylactic use of NSAIDs can reduce the incidence of musculoskeletal pain symptoms. Wark, J.D et al.found that oral ibuprofen could effectively control the transient influenza-like symptoms caused by 5 mg zoledronic acid, which was consistent with our results . In addiInterestingly, in addition to the predictors included in this study, POPP A W ’s study Our research has some limitations. First, as a retrospective study, there is a certain degree of data loss. Second, the patients we studied were from the same medical institution, and no large multi-center sample study was conducted. Although the model we established has been verified by the validation set, it still cannot ensure the applicability of other races in other countries. In the future, the sensitivity and clinical applicability of the model can be further improved through multi-center retrospective validation studies or prospective randomized controlled studies.Our study found that age, BMI, serum 25 ( OH ) D, NSAIDs, and prior Vitamin D intake were independent risk factors for zoledronic acid-induced musculoskeletal pain. A nomogram containing 5 predictors of appeal can accurately predict the risk of musculoskeletal pain after zoledronic acid infusion.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3Supplementary Material 4Supplementary Material 5Supplementary Material 6Supplementary Material 7Supplementary Material 8Supplementary Material 9Supplementary Material 10Supplementary Material 11Supplementary Material 12Supplementary Material 13Supplementary Material 14Supplementary Material 15Supplementary Material 16Supplementary Material 17Supplementary Material 18Supplementary Material 19Supplementary Material 20


Nurses’ knowledge, expertise, and attitudes significantly impact pain management quality. This study showed that 50% had poor knowledge and attitudes, with a significant association between knowledge and education level, experience caring for cancer patients, and prior pain management training. Low knowledge and attitude pose significant challenges. Adequate training in cancer pain management is crucial to improve pain control and enhance the quality of life for cancer patients.p < 0.05). A low level of knowledge and attitude among nurses in cancer pain management is a significant challenge in providing comprehensive cancer care. Adequate training of nurses in cancer pain management is essential to providing effective pain management and improving the quality of life of cancer patients.Cancer care in the Gulf Cooperation Countries, including Oman, faces challenges due to increasing incidence and late-stage diagnoses. Cancer patients at later stages suffer complex symptoms, pain being a prominent one. Access to adequate pain relief is a global problem, including in the Middle East, where palliative care is lacking. Nurses play a crucial role in pain assessment and management but often lack the necessary training, resulting in inadequate relief and prolonged hospital stays. This study aims to examine the knowledge and attitudes of nurses in a national cancer center toward the management of cancer pain, with the goal of identifying any gaps in their knowledge. This is a cross-sectional descriptive study conducted among nurses at the national cancer center in the Royal Hospital. The Nurses’ Knowledge and Attitudes Survey Regarding Pain (NKASRP) was used to determine the pain-related knowledge and attitudes of the nurses. Out of 150 registered nurses, 118 participated in this study (78% response rate). The mean NKASRP score was 49.6%. Half of the participants (50%) had a poor level of knowledge and attitude, 46% had fair knowledge and attitude, and only five participants (4%) had a good level of knowledge and attitude. A statistically significant association existed between knowledge and education level, years of experience caring for cancer patients, and prior pain management training ( The Gulf Cooperation Countries (GCCs), including Oman, are committed to improving the well-being of cancer patients through the implementation of advanced treatments and updated management guidelines. However, the region is witnessing a significant increase in cancer incidence and mortality, with many patients being diagnosed at later stages when treatment options are limited, and survival rates are unfavorable ,2. NotabGenerally, cancer patients diagnosed at a later stage experience various symptoms that significantly impact their quality of life, with pain being one of the most prominent. Unfortunately, access to adequate cancer pain relief remains a substantial problem worldwide. The 2015 Quality of Death Index ranked many Middle Eastern and East African countries at the bottom of the scale in terms of palliative care, including pain management . SeveralNurses, being the largest group within the healthcare team, play a crucial role in cancer care. They often serve as the primary point of contact for patients and families. Nurses are instrumental in evaluating and managing cancer pain, and their level of knowledge, expertise, and attitudes significantly impact the quality of pain control . HoweverThis study aims to assess the general knowledge and attitude of nurses involved in the care of cancer patients in Oman regarding cancer pain assessment, management, and pharmacology. The findings of this study can inform policymakers and guide efforts to incorporate cancer pain management (CPM) education into university curricula and provide pain management workshops for nurses. Ultimately, this will help bridge the knowledge gaps and enhance the quality of care provided to cancer patients.A cross-sectional survey-based study was conducted at the national oncology center of the Royal Hospital, a tertiary hospital that serves the population in Oman. This study was approved by the ethical committee from the Ministry of Health, Oman.In this cancer center, cancer nurses take care of all adult cancer patients regardless of their age. Therefore, all nurses who are currently providing care to adult cancer patients at the national cancer center were invited to participate through institutional email. The survey was distributed to 150 registered cancer nurses, and 118 of them responded to the survey (78% response rate). All participants consented before participating in this study.The “knowledge and attitude survey regarding pain” (KASRP) was used to evaluate nurses’ knowledge in general without specifying the AYA patient population or their needs, as this is a baseline study that will be followed by more customized questionnaires for the AYA group. The questionnaire constitutes of two parts:Part I: Sociodemographic characteristics (6 items), which include gender, age, education levels, years of clinical experience, years of experience caring for patients with cancer, and previous training sessions/workshops in pain management.Part II: The “knowledge and attitude survey regarding pain” (KASRP).The KASRP was created in 1987 by Ferrell and McCaffery and has been revised several times, with the most recent revision completed in 2014 [p < 0.05) was considered significant.The levels of knowledge and attitude were classified as poor (<50), fair (50–70%), and good (≥70%). The ANOVA test was used to determine whether there are any significant associations between levels of knowledge and attitudes toward CPM and nurses’ demographic characteristics. . The items with the highest percentage of accurate answers were: item number 7, “Combining analgesics that work by different mechanisms  may result in better pain control with fewer side effects than using a single analgesic agent” (94.1%); item number 22 “Narcotic/opioid addiction is defined as a chronic neurobiological disease, characterized by behaviors that include one or more of the following: impaired control over drug use compulsive use, continued use despite harm, and craving” (90.7%); item number 16, “After an initial dose of opioid analgesic is given, subsequent doses should be adjusted in accordance with the individual patient’s response” (89.8%); and item number 24, “The recommended route administration of opioid analgesics for patients with brief, severe pain of sudden onset such as trauma or postoperative pain is” (80.5%). These questions were related to analgesics with various mechanisms of action, the concept of opioid addiction, and dose adjustment following the individual patient’s response, respectively. Only six out of the thirty-six questions had a greater than 70% correct answer rate, while the majority of the questions had a low percentage of accurate responses. For instance, 20 items received less than 50% correct answer rate . The questions related to pain assessment and pharmaceutical therapies had the lowest percentage of correct answers.p > 0.05). However, the ANOVA test revealed that the education level, years of experience caring for people with cancer, and participation in previous cancer pain management training significantly impacted the knowledge and attitude levels (p < 0.05). Nurses who have a Master’s degree reported a higher knowledge level (67.78%) than those with diplomas or bachelor’s degrees. Nurses who had attended previous cancer pain management training during their nursing education and employment had a mean KASRP score of 54.27%, which was 10.46% higher than that of nurses who had not received any prior training. Furthermore, nurses with more than five years of experience in managing cancer pain had higher scores (53.55%) than those with less than five years of experience.Inadequate management of cancer pain and the inappropriate use of opioids in cancer patients are significant public health concerns . InsuffiThis study revealed that the average KASPR knowledge score of the participants was 17.86 ± 3.97 (49.6% ± 11.0%), and only 4% of the nurses achieved a good knowledge and attitude score of ≥70%. These findings are consistent with other studies conducted in the Middle East, where knowledge scores ranged from 45.1% to 66% ,21,22,23A recent systematic review identified the lowest mean knowledge and attitude scores reported in KASPR as 28.5% from Iran , while tFurthermore, this study indicated that the nurses’ total score was not influenced by factors such as age, gender, or years of nursing experience. However, it was significantly associated with their level of education, years of experience in caring for cancer patients, and previous participation in training sessions or workshops related to pain management. Previous research has consistently shown that higher scores are linked to longer work experience ,27,28, hThis study’s findings highlighted the presence of disparities in nurses’ knowledge, beliefs, and pain management practices regarding pain management. Although a majority of the nurses acknowledged the subjective nature of pain and the importance of relying on the patient’s self-assessment, a considerable portion of participants expressed a belief in using a placebo to assess the authenticity of pain despite it being considered an unethical practice. Additionally, over two-thirds of the nurses relied on vital signs to determine the severity of pain and mistakenly assumed that stable vital signs indicated the absence of pain. A similar attitude was previously reported in the region ,22.In this study, only a small proportion of nurses (18.6%) demonstrated awareness of the potential risk of increasing morphine IV dosage by 5 mg/h, which could lead to a 1% increase in the incidence of respiratory depression in cancer patients. Furthermore, just 26.3% of nurses demonstrated familiarity with the signs of opioid physical dependency. Moreover, the majority of nurses (55.1%) agreed to withhold opioid analgesia and let the patient suffer, while an even larger majority (73.7%) agreed to prolong the patient’s suffering to identify the cause of pain, which aligns with findings from previous studies ,33. It iThis research underscores the limited understanding among nurses regarding drug pharmacology, dosage adjustment, addiction, and substance abuse. A majority of nurses (61%) hold the belief that patients with a history of substance abuse should be denied opioid analgesia, even when they are experiencing pain. This perspective is ethically unsound and clinically unjust, as all patients deserve access to appropriate pain management, irrespective of their past substance abuse.Given this insufficiency in knowledge and attitude towards cancer pain management, it is essential to provide comprehensive education and training in this subject, tailored to the unique needs of cancer patients. This has become particularly important considering the plans to establish palliative care services in the country, aiming to address the needs of cancer patients in advanced stages, especially when considering the rising number of late-stage cancer diagnoses, particularly among young patients who tend to experience more complex pain, requiring higher doses of opioids compared to older patients with cancer ,35. AddiThe low knowledge score might be due to a shortage of continuing medical education courses on such topics, which necessitates introducing such education . PreviouNumerous cancer centers worldwide have implemented educational initiatives in order to enhance nurses’ understanding of cancer pain management ,41,42,43The present study has several limitations that must be acknowledged. First, the research was conducted at only one hospital in Oman, making it difficult to generalize the findings to all nurses in the country. Second, the sampling strategy employed in this study may have led to selection bias, which could have impacted the results. Thirdly, the survey was distributed to nurses without any restriction on their access to the internet, allowing them to potentially search for or discuss the information before participating. Moreover, while this study primarily focused on nurses’ knowledge and attitudes toward pain treatment, their actual practices were not observed, and thus, more comprehensive monitoring of nursing practices is required. Moreover, this study did not track the frequency with which nurses cared for cancer patients, which could have impacted their pain-related knowledge. Lastly, information about the nurses’ postgraduate pain courses, including their content and duration, was not collected. Future research should address these limitations and assess their influence on pain-related knowledge.In conclusion, the low level of knowledge and attitude among nurses in cancer pain management is a significant challenge in providing comprehensive cancer care. Adequate training of nurses in cancer pain management is essential to provide effective pain management and improve the quality of life of cancer patients. To build a comprehensive cancer care program for adolescents and young adults with cancer, a multidisciplinary team should be established to address their special needs and concerns. The team should consist of experts from different disciplines, including physicians, specialized nurses, social workers, and psychologists, to provide the necessary support and care. By improving the knowledge and skills of nurses and establishing a multidisciplinary team, we can ensure that cancer patients receive the best possible care and support during their treatment and recovery.


The assessment and management of pain and nociception is very challenging in patients unable to communicate functionally such as patients with disorders of consciousness (DoC) or in locked-in syndrome (LIS). In a clinical setting, the detection of signs of pain and nociception by the medical staff is therefore essential for the wellbeing and management of these patients. However, there is still a lot unknown and a lack of clear guidelines regarding the assessment, management and treatment of pain and nociception in these populations. The purpose of this narrative review is to examine the current knowledge regarding this issue by covering different topics such as: the neurophysiology of pain and nociception , the source and impact of nociception and pain in DoC and LIS and, finally, the assessment and treatment of pain and nociception in these populations. In this review we will also give possible research directions that could help to improve the management of this specific population of severely brain damaged patients. In the United States, 2.5 million people suffer from a TBI each year  and some of them will become unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS) patients . In the This manuscript aims at reviewing the current knowledge about the assessment and management of pain and nociception in patients with DoC and LIS. We will first give an overview of the physiology of pain and nociception. We will then look more specifically at the possible sources and impact of pain in these populations. Finally, we will describe the tools and treatments currently in place for the assessment and management of pain and nociception for this patient population. This narrative review is based on systematic reviews, meta-analyses, original articles, and case studies.In order to understand the difference between pain and nociception and to comprehend to what extent severely brain-damaged patients process nociceptive inputs and pain, we must first look at the neurophysiology of these two phenomena. When nociceptive stimulation occurs, following tissue damage for example, a signal will be generated at the endings of the nociceptive Aδ  and C-fibers . These fibers synapse at the level of the dorsal horn with the second nociceptive neuron that continues its path into the spinothalamic tract to the thalamus (for the majority of the fibers). After the thalamus, the signal arrives at several cortical areas . All these cortical and subcortical structures and their connections form a network which is activated following a painful stimulus. In this review, we will use the term “pain-related neuromatrix” to refer to these brain regions activated following a noxious stimulus. However, it is important to note that this network is not only related to pain processing but has been identified more as a salience detection network . This suThe ascending pathways described above activate descending pathways responsible for modulating the transmission of peripheral information. Indeed, the descending pathways (cholinergic and serotonergic) to the dorsal horn of the spinal cord are sensitive to peripheral stimuli and not only to nociceptive stimuli. There are also tonic facilitation and inhibition phenomena that originate in the brainstem and respond to peripheral or non-peripheral stimuli . The actvia painful stimulation of another area (such as the leg) results in a reduction of the fMRI signal in the dorsal reticular nucleus, dorsolateral pons, and spinal trigeminal nucleus  or during daily care . If pain is present after those injuries, it will act as a protective and adaptive signal for the integrity of the body  whereas t input” . Neuropalization . At preslization ], sensorlization . This relization ,b. In adlization , spasticlization . This calization ] items alization . They wilization . A 2022 lization . Nociceplization . This calization . For inslization .The perception of pain can vary according to different factors. Numerous studies carried out over the last few decades have revealed gender differences in terms of prevalence, perception and treatment of pain [for a review see There are many behavioral scales allowing the assessment of pain in non-communicative patients, such as the Neonatal Infant Pain Scales NIPS; , the FacA 2012 study tried to determine an NCS-R cut-off score allowing discrimination between noxious and non-noxious stimulation, but the result was not confirmed in a later study , 2018. CStudies involving nurses working with DoC patients confirm the ease of use and clinical relevance of this scale in assessing signs of pain in this population . NonetheFor appropriate daily management of pain, it appears that the NCS-R is not sufficient alone. The clinical assessment of pain should be based on a multi-modal approach that also considers (neuro)physiological markers wherever possible. Behavioral scales also involving physiological markers have recently been created, such as the Pain Assessment Scale (PAS), devoted to the assessment of patients with acquired brain injuries . It consvia blinking, or alphabetic code) or/and visual analogue scale (VAS) ranging from 0 to 10 . In spite of these systems, some patients in LIS do not communicate about their pain. In a 2022 survey, 52% of the painful patients declare that they do not inform the clinical teams about their pain  technology is possible. Therefore, pain is assessed using communication codes  evaluates the integrity of the central and peripheral sensory pathways within the nervous system . For insvia the neurons of Lamina 1 in the dorsal horn  recording which takes only a few minutes . The calThe GSR  is a biological electrical activity of the skin linked to the activity of the sweat glands which are controlled by the sympathetic system. It is a non-invasive technique allowing the investigation of emotional response following auditory or nociceptive stimulation . StudiesFinally, the pupillary dilatation reflex (PDR), whose variation results from the balance between the ortho- and parasympathetic tone, represents a promising tool to objectify nociception in DoC. The PDR is used to detect pain in brain-injured patients. It is also sensitive to opioids and allows the assessment of the nociception-anti-nociception balance during general anesthesia . In the Pain prevention in patients with DoC still needs improvement. Indeed, a recent pilot clinical trial found that, although the majority of patients showed signs of pain during mobilization, only 33% of them were treated for pain before inclusion in the study . In ordeEven if, in clinical practice, the administration of pharmacological treatment is common, it is very important to pay attention to the nature and the dose of these treatments. There are three levels of analgesics: level 1 corresponds to non-opioid medications , level 2 to weak opioids  and level 3 to strong opioids  . By prevAs explained above, pharmacological treatments often induce side effects that can impact the behavioral responses of patients during evaluations. Therefore, being able to propose non-pharmacological treatments seems essential to manage pain in these patients. The use of invasive brain stimulation techniques such as deep brain stimulation on the PAG and the rostral ventromedial medulla or motor cortex stimulation have proven to be effective in the treatment of chronic pain but remain difficult to implement in patients with DoC . AlthougRegarding the assessment of pain and nociception in patients with DoC or LIS, there are currently no clear guidelines and no clinical consensus. When performing neuroimaging analyses, it is relevant to mention that differences in terms of structures and physiological properties may exist between a severe brain-injured patient and a healthy subject. Therefore, it is essential to perform a multimodal assessment, not only based on neuroimaging but also on pain-related behaviors and physiological changes [physiological and neuroimaging data as complementary measures. It is known that some behavioral UWS patients may show preservation of cortical areas involved in nociceptive signal processing. Then, pain assessment and analgesic treatments should be applied in a more systematic way, and most importantly, independently of patient’s clinical diagnosis. In particular, titration of analgesic agents should be implemented to determine the optimal dose of the medications. The NCS-R and the BINAM represent relevant assessment tools to find a balance between reduced pain and preserved level of consciousness following analgesic treatment. For the moment, the guidelines of the American Academy of Neurology recommend the use of the NCS-R to assess pain in patient with DoC but these guidelines still need to be developed further and refined . RegardiEB: conceptualization, research, references formatting, writing, and editing. AT: conceptualization, supervision, review and editing, visualization, and resources. NL, ES, VB, CM, OG, and SL: review and resources. All authors contributed to the article and approved the submitted version.


Observational studies are valuable for investigating correlations between patient-reported treatment outcomes. In this study, we report a secondary analysis of a published pharmacy-based observational  study on experiences reported by patients who treated their headache with an over-the-counter analgesic.A pharmacy-based exploratory survey was conducted in German community pharmacies. Patients buying a fixed-dose analgesic combination product  to treat their headache were offered a questionnaire that contained—among others—questions about time to onset of pain relief (OPR), assessment of time to onset of pain relief (AOPR), assessment of efficacy and tolerability, and pain intensity 2 h after intake. A correlation analysis of the data was performed. Moreover, perceived treatment effects compared to other acute headache medications used in the past were collected.p < 0.0001). Headache patients assessed the onset of analgesic action within 15 min as “very fast” and within 30 min as “fast”. The other readouts were correlated as well . Compared to previous treatments, most patients (>89%) assessed the speed of analgesic action, efficacy, and tolerability of IbuCaff as equal to or better than for the previous treatment.The correlation between OPR and AOPR was high (Spearman rank correlation r = 0.594, Headache patients assessed the onset of analgesia within 15 min as “very fast” and within 30 min as “fast”. Efficacy assessments for acute headache medication appear to be highly correlated. Acute headache is often treated with over-the counter (OTC) analgesics available in community pharmacies . ObservaEvidence from multiple sources shows that patients expect that acute headache treatments relieve pain as fast and completely as possible. For instance, over 80% of migraine patients ranked complete pain relief and fast onset of action as the most important expectation from their acute pain medication . In a qu®) between February and June 2019 in German community pharmacies were offered participation in a survey. After giving consent, they were handed a questionnaire that was to be filled out by the patients after taking the product to treat an acute pain event. Questionnaires were sent anonymously in envelopes provided to the participants to the institute that collected the data and performed the primary analysis . The identification of participants was therefore not possible . No incentive was given to participants. According to German laws and regulations, ethical committee participation was neither required nor recommended for this kind of investigation.Details of the survey underlying the present analyses have been reported previously . BrieflyThe inclusion criteria were the purchase and use of the respective product, willingness and ability to fill out the questionnaire, usage of the product according to the packaging label, and age of 18 years or older. There were no exclusion criteria. This analysis was restricted to data from patients who reported intake of the product to treat a headache episode. No diagnosis for headache etiology  was performed. The following data on efficacy and tolerability parameters were analyzed: Perceived onset of pain relief , assessment of onset of pain relief , and assessment of efficacy/tolerability (categories: very good/good/not so good/bad). Pain intensities at baseline and 2 h after intake of the medication  were used to calculate the relative pain intensity difference (%PID). Moreover, participants were asked how they assessed onset of action, efficacy, and tolerability in comparison to the last analgesic product they had taken before to treat a similar pain episode .Data management and primary analysis were done by Winicker Norimed using SAS (version 9.2). Additional analyses were conducted by the authors using GraphPad Prism, version 9.3.1. Spearman's rank coefficients were calculated to assess correlations between OPR and AOPR, OPR and %PID, AOPR and %PID, efficacy ratings and %PID, OPR/AOPR and baseline pain intensity, as well as ratings of efficacy and tolerability. Relative and cumulative relative frequencies of OPR categories stratified by AOPR categories were calculated; rate ratios (relative rates) of these cumulated relative frequencies were used to assess which AOPR category steps discriminated between cumulative OPR rates. The relative rate (RR) cutoff for the discrimination between AOPR categories was set to a value of 2.p < 0.0001). Most of the participants experienced OPR as “very fast” (21.8%) or “fast” (58.8%), and only 17.5% and 1.9% assessed it as “moderately fast” or “slow,” respectively , only a small amount of ibuprofen and caffeine from IbuCaff can be expected to be absorbed that fast . A randoInterestingly, other patient-reported efficacy parameters were correlated with OPR and AOPR as well. The earlier the pain was relieved, the higher the %PID was compared to baseline at 2 h. This is not surprising if one assumes a steady increase in pain relief over the time up to 2 h after intake of an analgesic. In consequence, an early onset of pain relief was correlated with the overall impression of treatment efficacy. Correlations of baseline pain with OPR and AOPR were very weak to absent.The strong correlation between the assessment of efficacy of an analgesic and %PID has been shown in a randomized controlled trial before .Somewhat surprising was the correlation between AOPR and assessment of tolerability: Early pain relief and high tolerability went hand in hand. Controlled clinical trial occurrence of untoward effects was correlated with treatment efficacy/pain reduction . OneOne guideline-recommended endpoint for clinical trials investigating migraine headache is the analysis of treatment preference (in comparison to prior treatments) . AlthougIn terms of perceived efficacy, onset of action, and tolerability, IbuCaff was rated worse than previous OTC treatments by only small percentages of patients . On the other hand, large percentages of patients rated IbuCaff better than the comparators. This is not surprising since caffeine-containing analgesics have been shown to be superior to those without caffeine . In compComparisons with historical data bear the risk of bias . If this was the case for our analysis, one should expect random distributions, which was obviously not the case. For the parameters such as “perceived efficacy” and “onset of effect,” the highest percentages reporting superiority were found for paracetamol  and theTaken together, this analysis shows that an abortive headache treatment relieving pain within 15 min after intake can be considered to act “very fast” from the patient's perspective and that within 30 min can be considered to act “fast”. The fast onset of analgesic effects was positively correlated with several other efficacy readouts, suggesting that an early onset of action is a key factor for successfully treating acute headache. This might be an interesting aspect of patient education: when pain relief starts early, chances are high for an overall successful headache treatment.https://www.vivli.org/.Publicly available datasets were analyzed in this study. Qualified researchers may request access to data and related study documents including the study report, study protocol with any amendments, statistical analysis plan, and dataset specifications. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: The manuscript represents a secondary analysis of a published study. Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.CG: Conceptualization, Investigation, Writing—review and editing. SF: Conceptualization, Investigation, Writing—review and editing. WL: Conceptualization, Investigation, Methodology, Writing—review and editing. TW: Conceptualization, Investigation, Methodology, Project administration, Writing—original draft.


Musculoskeletal disorders are among the leading causes of disability and chronic pain worldwide, and their impact is expected to increase in the coming years. Chronic musculoskeletal pain is a disorder that affects millions of people worldwide. It can manifest in various parts of the body, such as the back, knees, or shoulders, and can be caused by various factors including age, intense physical activity, poor posture, and trauma. Chronic pain can limit a person’s ability to perform daily activities and can have a significant impact on quality of life. One of the most common chronic pain conditions is lower back pain, which affects millions of people worldwide. This type of pain is often associated with osteoarthritis of the hips and can lead to a condition known as hip and spine syndrome . Lower bIn this Special Issue, we aim to discuss the current challenges in musculoskeletal rehabilitation and explore new perspectives on how to overcome them.One of the main challenges is to ensure that treatments are evidence-based and patient-centered, taking into account the individual needs and preferences of each patient. In addition, it is essential to improve the integration and coordination of care among different healthcare providers, in order to ensure continuity and quality of care throughout the rehabilitation process.Recent studies have shown the efficacy of non-invasive techniques such as exercise therapy, manual therapy, and modalities such as ultrasound and electrical stimulation in improving musculoskeletal function in conditions such as knee osteoarthritis, rotator cuff tears, and low back pain ,5,6. TheIn addition, the use of minimally invasive techniques such as arthroscopy and percutaneous vertebroplasty has revolutionized the treatment of musculoskeletal conditions, allowing for faster recovery and better outcomes ,8. HowevFurthermore, the importance of rehabilitation after orthopedic surgery or acute events such as stroke or myocardial infarction cannot be overstated. Studies have shown that early and intensive rehabilitation can lead to improved outcomes in terms of functional status, pain management, and overall quality of life ,10,11. RTelemedicine has proven to be an important resource for accessing care, especially for patients with chronic illnesses that require constant medical attention. In particular, rehabilitation through telemedicine has emerged as an innovative solution for the care of patients suffering from chronic musculoskeletal pain. Telemedicine has been adopted as a means to improve access to rehabilitation services for chronic musculoskeletal pain. Tele-rehabilitation allows the patient to be monitored remotely and healthcare services to be delivered effectively and flexibly. Patients can access rehabilitation services more quickly, avoiding long waiting lists in hospitals, and can receive personalized care based on their individual needs .The use of technologies such as videoconferencing, sensors, and smartphones has allowed doctors to provide continuous support to patients in pain management and rehabilitation. Tele-rehabilitation programs include personalized exercises, pain therapies, and relaxation techniques to improve mobility and reduce pain. In addition, tele-rehabilitation also provides psychological support to help patients manage the stress and anxiety associated with chronic pain .Tele-rehabilitation offers numerous advantages over traditional treatments. First, it reduces costs for the patient and the healthcare system as a whole. Furthermore, it offers greater flexibility in scheduling rehabilitation sessions, allowing patients to perform therapies from the comfort of their own home or in any other location they deem appropriate . One proIn conclusion, musculoskeletal rehabilitation is a constantly evolving field that requires innovative approaches and close collaboration between healthcare professionals and patients. Non-invasive techniques, individualized treatment plans, regenerative medicine, and a holistic approach to rehabilitation are all promising new perspectives that can help overcome current challenges and improve patient outcomes. By continuing to explore and develop new approaches, we can ensure that patients receive the best possible care and achieve the highest levels of function and quality of life.


Breast surgery for breast cancer is associated with significant acute and persistent postoperative pain. Surgery is the primary type of treatment, but up to 60% of breast cancer patients experience persistent pain after surgery, and 40% of them develop acute postmastectomy pain syndrome. Preoperative stress, involvement of lymph nodes while dissecting, and the postoperative psychological state of the patients play vital roles in managing the postoperative pain of the patients. The objective of this study is to develop evidence-based guideline on the prevention and management of perioperative pain for breast cancer surgical patients.  An exhaustive literature search was made from PubMed, Cochrane Review, PubMed, Google Scholar, Hinari, and CINAHIL databases that are published from 2012 to 2022 by setting the inclusion and exclusion criteria. After data extraction, filtering was made based on the methodological quality, population data, interventions, and outcome of interest. Finally, one guideline, two meta-analyses, ten systematic reviews, 25 randomized clinical trials and ten observational studies are included in this review, and a conclusion was made based on their level of evidence and grade of recommendation.  A total of 38 studies were considered in this evaluation. The development of this guideline was based on different studies performed on the diagnosis, risk stratification and risk reduction, prevention of postoperative pain, and treatments of postoperative pain.  The management of postoperative pain can be categorized as risk assessment, minimizing risk, early diagnosis, and treatment. Early diagnosis is the mainstay to identify and initiate treatment. The perioperative use of a nonpharmacological approach  as an adjunct to the intraoperative regional anesthetic technique with general anesthesia with proper dosage of the standard pharmacological multimodal regimens is the first-line treatment. For postoperative analgesia, an extended form of intraoperative regional technique, nonpharmacologic technique, and NSAIDs can be used with the opioid-sparing anesthesia technique. Cancer is a condition in which aberrant cells (transformed tumor cells) can infect neighboring tissues and divide out of control . Nearly Breast cancer is the second-most common cause of cancer deaths next to cervical cancer. Women with BC have an 82% 5-year survival rate in Europe, compared to 46% in Uganda, 39% in Algeria, and 12% in Gambia [The incidence of BC varies significantly around the globe with higher incidence in the sub-Saharan countries. A variety of factors such as better healthcare, late marriage, first pregnancies, a decline in breastfeeding, sedentary lifestyle like increased tobacco use and decreased physical activity, and unhealthy diets consisting of fatty fast food may contribute to the continues increments of breast cancer , 7.It may be managed by early diagnosis and the timely initiation of proper treatment including surgery, chemotherapy, radiotherapy, different hormonal therapies, or a combination of treatment modalities. The majority of breast cancer patient present at advanced stages (III and IV) at the time of their initial medical consultation, which makes surgery the main option of management with or without chemotherapy and radiation therapy . This miBreast surgery induces a considerable postoperative pain, whether an acute or chronic pain. It is reported that up to 60% of women experience chronic pain, and 40% experience acute postoperative pain following breast cancer surgery , 10.Hence, inadequate postoperative pain management increases the perils of bad clinical outcomes, such as cardiac impairments, delayed mobilization, extended hospital stays, sleep disruptions, psychological stress, an increase in inflammatory cytokines, and sympathetic nervous system activation. In addition, it may be changed to chronic pain lasting for many years, and greatly affect the quality of life secondary to depression from breast resection, which may affect the physical, psychological, and socio-economic welfare of the patient , 11.Recently, the preventive and management efforts are concentrated on the prevention of postoperative pain and making an early diagnosis and management. Nonpharmacological techniques, pharmaceutical analgesics, oral and intravenously, as well as more invasive procedures using local anesthetics, such as local anesthetic infiltration, intercostal block, thoracic epidural analgesia, and paravertebral block, are useful to control pain , 12.The effective management of postoperative pain depends on the application of proper preoperative preventive complementary medicine and the institution of proper pharmacological techniques. Since the use of prescribed pharmaceuticals might not be adequate to address the pain effectively and decrease the patient's anxiety and distress, the use of nonpharmacological interventions as a multimodal component is strongly advocated. Hence, this needs multidisciplinary team collaboration and the development of comprehensive and integrated practical guidelines to insight the uniform clinical protocol throughout patient management. The current study generate updated evidence and clinical recommendation on the use of nonpharmacological (complementary medicine) including preoperative positive inspirational words and positive expectations, acupuncture, massage, and sleep in combination with the pharmacological approaches for the prevention and management of perioperative pain in breast cancer surgical patients for a low-resource area.Therefore, the objective of this study is to develop an evidence-based practice guideline on the prevention and management of perioperative pain for breast cancer surgical patients in a low-resource area.The review reported according to Reporting Items for practice Guidelines in Healthcare (RIGHT) protocol. The systematic review was sent to clinical study registration.A systematic and exhaustive search of the literature was performed from Cochrane review, PubMed, Google Scholar, and Hinari databases. The search was performed using key words for PubMed, Cochrane, and Hinari , and full-sentence search was carried out for Google Scholar.Observational, interventional studies, guidelines, systematic review and meta-analysis, full articles published from 2009 to August, 2022, and articles written in English language were included in this review.Articles without relevant outcomes, postoperative pain prevention of other types of cancers, nonsurgical interventions of breast cancer, and reconstruction surgeries were excluded.Systematical data extraction was made using the MeSH term and applying PICO  is a simple tool, it has a high sensitivity for identifying treatment effects, and parametric tests can be used to analyze its outcomes. It is a continuous scale, made up of two verbal descriptions, such as “no pain” and “worst imaginable pain,” and a horizontal or vertical line that is typically 100 mm long  Figure .The Numeric Rating Scale (NRS) is a single, 11-point numerical scale that has been thoroughly verified for use with numerous patient types. NRS data are easily documented, comprehensible, and compliant with regulatory criteria for pain assessment and documentation. The pain scores are denoted by the following numbers: 0 = no pain, 1–3 = mild pain, 4–6 = moderate pain, and 7–10 = severe pain  Figure .LOE = 1c and GOR = B.At the first visit of a study conducted by Jessica Quinlan et al., patients who were randomly assigned to the acupuncture group displayed statistically significant improvements in pain. Contrarily, patients who were randomly assigned to the control group did not exhibit any statistically significant variations in pain during the visit between pre- and poststandard care assessments. Postoperative acupuncture treatment (in addition to standard care) reduced pain, nausea, and anxiety while improving coping skills  LOE = 1cLOE = 1a and GOR = A.Postoperative aromatherapy with lavender oil for 20 minutes is believed to decrease pain by decreasing anxiety and stress, but the RCTs included in the systematic review and meta-analysis did not get a significant relationship between postoperative pain and aromatherapy. Further interventional studies with a large sample size are required for strong recommendation  LOE = 1aLOE = 1c and GOR = B.A foot massage (FM), characterized as the manual manipulation of soft tissues with the intention of improving the performance of various bodily systems, is when performed by a skilled therapist , an affordable and secure intervention on appropriately evaluated patients. The quasi-experimental study conducted in 2016 demonstrated that a 20-minute FM intervention dramatically decreased levels of postoperative discomfort within the first and second hours  LOE = 1cLOE = 1a and GOR = A.Exercise, acupuncture, cryotherapy, biofeedback, transcutaneous electrical nerve stimulation, and massage treatment are among the physical therapy methods that have been suggested by Kannan et al. for relieving postmastectomy pain. Exercise group, when compared to control, according to the meta-analysis, could be regarded as a vital part of quality of life and pain management for women with postmastectomy pain syndrome (PMPS) because it is a low cost and safe intervention  LOE = 1aLOE = 1a and GOR = A.Perioperative music therapy, especially with the patient's preference significantly reduced postoperative pain in RCT's included in the review. Music was delivered 5 minutes before surgery; in most studies, it continued intraoperatively and twice a day postoperatively. This decreased patients anxiousness and stress in turn reducing their pain score in comparison with those who did not listen to music throughout  LOE = 1aLOE = 2c.In the last two decades, a growing body of data has confirmed that there is an inverse link between pain and sleep. In a study conducted on 24 women scheduled for breast cancer surgery in New York, USA, it was discovered that poor sleep quality the night before surgery was linked to significantly higher pain intensity and pain interference with everyday activities the week after surgery  LOE = 2cLOE = 2b. A prospective observational study conducted in 2021 found, significant effects between preoperative sleep disruptions in women and more intense peak pain after movement within the first 24 hours after surgery [LOE = 2c, GOR = B, and GOR = C.Women with poor sleep quality who undergone breast cancer surgery had a greater frequency of severe postoperative pain, reported higher NRS scores, and required more rescue analgesics in the first postoperative 24 hours which were statistically significant  LOE = 2b surgery  LOE = 2cAn RCT conducted in Buchan, Germany found that psychological techniques that focus on enhancing positive expectations are effective in enhancing patient-reported outcomes for postoperative pain management. This can be achieved with encouraging verbal suggestions combined with other tried-and-true components of doctor-patient communication, including improved empathy, trust, and an upbeat, caring attitude.LOE = 1b. In addition to this, the assessment of coping strategies among breast cancer patients with preoperative pain did not have any predictive value for increased postoperative pain. But, those with greater isolated anxiety ratings for the expectations of higher postoperative pain predict more intense postoperative pain after breast cancer surgery [LOE = 1b, LOE = 2c, GOR = A, and GOR = C.Postoperative pain ratings were lower in women who received positive suggestions compared with neutral verbal comments, irrespective of other interventions  LOE = 1b surgery –25 LOE =LOE = 1a, LOE = 2a, GOR = A, and GOR = B.In a systematic review conducted by Klifto KM regarding women having breast surgery and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), the study discovered evidence that perioperative (preoperative and/or postoperative) NSAIDs may lessen pain severity as well as 30% decrement in opioid use within 24 hours after surgery. However, there was insufficient evidence to support the idea that perioperative NSAIDs would affect the likelihood of breast hematoma within 90 days of breast surgery  and further strong, large-scale RCTs are needed before definite conclusions are made , 26 LOE LOE = 2a.On postoperative day 1 of a prospective cohort study conducted in Washington, USA, the pain levels of opioid free anesthesia (OFA) patients were much lower. Now a day opioids are being replaced by other components of multimodal analgesia regimens and nerve blocks because of their undeniable side effects which has greater impact on the quality of life of the patients after surgery  LOE = 2aLOE = 1b and GOR = A.In a continued opioid free anesthesia regimen, an RCT conducted by Gürkan in 2020 comparing paravertebral and erector spinae block with IV morphine found nearly identical decrement in morphine consumptions were found with both erector spinae and paravertebral block techniques. Such decreased morphine (opioid) consumption could make a clinically significant difference in patient care and opioid free patient's quality of life  LOE = 1b(1) Gabapentin. Anticonvulsant medicine gabapentin is extensively and successfully used to treat chronic neuropathic pain and it has recently been discovered to be helpful for lowering acute postoperative pain when given prior to surgery. Without excessive sedation or other side effects, anticipatory administration of a single oral dosage of 600 mg of gabapentin resulted in a reduction in postoperative analgesic requirements as compared to placebo [LOE = 1b. Patients in the gabapentin group had decreased pain scores at 30 minutes, 1 hour, and 2 hours postoperatively compared to placebo, and intraoperative propofol use was considerably lower [LOE = 1b, 1a, and GOR = A. placebo  LOE = 1bly lower  LOE = 1b(2) Pregabalin. A systematic review and meta-analysis consisting of twelve RCT, pregabalin, which has a higher bioavailability than gabapentin resulting in a superior pharmacokinetic profile, lessens pain during recovery and the need for opioids, but it does not lessen discomfort throughout 24 hours [LOE = 1a and GOR = A.24 hours  LOE = 1a(3) Deluxetine. Duloxetine (a serotonin norepinephrine reuptake inhibitor) has lately been employed as a component of multimodal analgesia in perioperative settings, according to current studies on the effects of perioperative use for treating postoperative pain and opioid intake. The ideal dose for patients undergoing modified radical mastectomy prior to surgery is 60 mg of oral duloxetine, unlike the 90 mg which was associated with an increased level of sedation up to 8 hours postoperatively [LOE = 1b and GOR = A.ratively  LOE = 1b(4) Gabapentin vs. Pregabalin. Pregabalin and gabapentin appear to lessen the use of opioids in the recovery area. Pregabalin does not lessen pain 24 hours after breast cancer surgery; gabapentin does. Neither medication influences the emergence of persistent postsurgical pain [LOE = 1a and GOR = A.cal pain , 32 LOE (5) Pregabalin vs. Ketamine. In a study conducted in Egypt comparing pregabalin with ketamine With a P value of 0.001, it was discovered that preoperative oral 150 mg pregabalin or 0.5 mg/kg ketamine use lowers overall postoperative morphine consumption. The need for opioids was the same in the pregabalin and ketamine groups [LOE = 1b and GOR = A.e groups  LOE = 1bLOE = 2b.Due to its side effects ketamine's, an N-methyl-D-aspartate (NMDA) receptor antagonist, use was formerly restricted. However, a few years ago, this medicine was rescued, and fresh lines of research have shown that it has good analgesic power. In a retrospective cohort study conducted in 2021 comparing ketamine and opioid, the ketamine group had a significantly reduced incidence of acute postoperative pain than the opioid group, as well as a significantly lower pain intensity  LOE = 2bLOE = 1b, GOR = A, and GOR = B.The available data of meta-analysis conducted in China demonstrated that both intravenous ketamine administration and ketamine added to bupivacaine in paravertebral blocks effectively reduces the cumulative consumption of morphine in patients undergoing breast surgery while reducing the risk of either gastrointestinal or CNS adverse events  LOE = 1bLOE = 1b. RCT's conducted in Mexico and Denmark also supports this finding of using 8 mg of dexamethasone to relief acute postoperative pain rather than adding the dosage [LOE = 1b; GOR = A.RCT conducted by Gómez-Hernández et al. with a sample size of 70 breast cancer patients found that preoperative dexamethasone at 8 mg alleviates nausea, vomiting, pain, and decreases the need for analgesics and antiemetics in women right after breast cancer surgery without any discernible side effects  LOE = 1be dosage , 39 LOE LOE = 1a; GOR = A.Despite claims of analgesic advantages for neuropathic pain of abdominal and thoracic procedures, intravenous lidocaine appears to provide when used for breasts, has little benefit for analgesia operation. In one RCT of patients for mastectomy, there was no appreciable difference between patients who received an intraoperative infusion of intravenous lidocaine (3 mg/kg) and those in the placebo group in terms of pain levels or postoperative analgesic use. Further investigation is needed for the conclusion of this finding  LOE = 1aLOE = 1a and GOR = A.For LA wound infiltrations, the most used solutions are ropivacaine, bupivacaine, and lidocaine, which results in a reduction in pain scores and reduced rescue opioid consumption. Although the effect may never last for more than 24 hours and it is most commonly limited up to six hour, the use should be considered in patients with minor to moderate invasive surgeries like lumpectomy and partial lumpectomy since the PPP from these procedures is mild to moderate and the intensity decreases over time  LOE = 1aLOE = 1a and GOR = A.Postoperatively, local anesthesia can be continuously infused by inserting a catheter directly into the wound. Uncertainty exists regarding the analgesic benefits that these catheters offer following breast surgery. Wound catheter infusions with local anesthetic for breast cancer procedures may not provide much in the way of therapeutic benefits, but the subject warrants more research  LOE = 1aLOE = 1b and GOR = A.In an RCT comparing the effect of IV lidocaine (3 mg/kg) and magnesium (50 mg/kg) there was synergistic analgesic effect that was seen in patients who took both lidocaine and magnesium sulfate, both intraoperative and postoperative reduced pain scores throughout the study, and decrement in opioid consumption was observed. This is due to theory that the combined effect of blocking sodium channels and more strongly blocking NMDA receptors should have a more noticeable impact on the sensory system of glutamatergic synapses, resulting in a coordinated synergism. It can serve as effective multimodal component  LOE = 1bLOE = 1b and GOR = A.Women who received intravenous esmolol (0.5 mg/kg) as an adjuvant in a randomized trial study for mastectomy reported much less postoperative pain than those who got a placebo . Esmolol-treated women consumed less morphine and metamizole than placebo-treated women. This finding shows that esmolol, a beta-blocker, is associated with enhanced cardiovascular stability and may significantly minimize the need for intraoperative anesthetics during mastectomy. Further uniform interventions should be conducted to strengthen the result of the study and the recommendation  LOE = 1bPeripheral nerve blocks are become a popular and crucial part of multimodal analgesia as a means of preventing and treating postoperative pain since the sensory nerves of the thoracic wall are primarily responsible for most of the pain experienced during breast surgery.LOE = 1a and GOR = A.The outcomes analyzed by a systematic review and meta-analysis consisting of 79 RCT showed that paravertebral blocks consistently provided the best results, but they also had a higher risk of complications, and SAPB was assessed to have a high likelihood of decreasing 24-hour resting pain . LOE = 1LOE = 2b and LOE = 2b.According to a retrospective cohort studies conducted in Japan and India, thoracic paravertebral block combined with general anesthesia decreased the incidence of postoperative chronic pain for more than a year following breast cancer surgery and postoperative acute pain within the first few hours following surgery , 44 LOE LOE = 1a.A systematic review conducted by Chhabra associated the paravertebral block (PVB) technique with reduced postoperative pain during rest and on motion from 6 to 24 hours, but as the outcomes were assessed by a small number of studies, more large scaled multicentered studies with uniform design are needed to conclude these outcomes. All complications of the paravertebral technique, such as Horner's syndrome, epidural spread of the local anesthetics, bloody tap, or pneumothorax due to pleural injection, are mostly self-limited and does not need any treatment  LOE = 1aLOE = 1b. Because of the amazingly low incidence of postoperative pain, it was not possible to rich conclusion in comparing the efficacy of both PVB with local anesthetics and saline [LOE = 1b, GOR = A, and GOR = B.A multicenter RCT conducted by Albi-Feldzer to validate the long term effect of PVB on chronic postoperative pain comparing it with saline injection in to the paravertebral space which found no significant difference between the two effect on the long run of postoperative pain management  LOE = 1bd saline  LOE = 1bLOE = 1a and GOR = A.When added to a long-acting local anesthetic, clonidine (75 mg) can extend the analgesic block effect for up to 72 hours following administration, similar to how adding fentanyl to a local anesthetic for paravertebral block enhances analgesia for breast surgeries. Despite the fact that there is conflicting evidence about the effects of continuous paravertebral blocks versus single-injection blocks using a continuous paravertebral block is a more reliable technique to extend block duration for more than 12–16 hours after a single-injection paravertebral block can produce analgesia for up to 72 hours according to systematic review of RCTs  LOE = 1aLOE = 1a. For major breast surgeries like a mastectomy with or without axillary node dissection, paravertebral block plus TIVA should be taken into consideration.Total intravenous anesthesia (TIVA), together with paravertebral blocks may boost the benefits of a regional anesthetic technique. Increased postoperative analgesia, reduced opioid needs and reduced recovery room stays have been mentioned in multiple RCTs included in the systematic review of Cheng and Ilfeld  LOE = 1aLOE = 1a and GOR = A.Studies showed that this intervention, when compared to general anesthesia alone, was associated with lower postoperative pain scores, lower systemic analgesia consumption, and a shorter length of hospital stay was noted with addition of TIVA. The effectiveness of this technique for postdischarge pain needs additional multicentered interventional studies. Reference  LOE = 1aLOE = 1b. The results of another RCT included in a systematic review is convincing and shows that a single interscalene block injection may provide analgesic benefits following breast surgery but needs further investigation on a large scale studies [LOE = 1b and GOR = A.Depending on the amount of local anesthetic used, the interscalene block offers a sensory block in the brachial plexus and T1-T2 distribution. However, in an RCT conducted to assess the effectiveness of interscalene brachial plexus block, it could not block the intercostal nerves innervating the skin, and patients needed systemic opioid analgesics in addition to the routine nonsteroid anti-inflammatory analgesics use to provide postoperative analgesia  LOE = 1b studies  LOE = 1bLOE = 1a.Thoracic epidural block after major breast oncologic surgery provides comparable postoperative analgesia when compared with the current data on other available technique, even though there is no direct comparison that currently exists between thoracic and others including continuous paravertebral blocks. Technique-specific limitations include the obligation to stay in the hospital until the epidural is removed, the cautious use of anticoagulants, and the hypotension induced by the sympathectomy  LOE = 1aLOE = 1b and GOR = A.An RCT comparing thoracic epidural with thoracic paravertebral in terms of VAS, there was no statistically significant difference between the examined groups, indicating that the two regional techniques analgesic profiles were comparable in both groups. However, the study group who took thoracic epidural showed instability regarding intraoperative hemodynamic in both HR and BP  LOE = 1bLA infusion (with or without opioid) into the cervical epidural area is a more cephalic epidural alternative. For major breast surgery, this local method may be employed to administer both intraoperative anesthetic and postoperative analgesia. The catheter insertion made between the C7 and T1 vertebrae would provide analgesic benefit because the brachial plexus (C5–C8) is the source of the pectoralis muscle's innervation.LOE = 1a and GOR = A.This is also supported by a previous study that found that a cervical epidural block provides a better sensory block for thoracic procedures than a high thoracic epidural block; however, there are no RCTs that validate or evaluate this strategy in relation to other analgesic methods. Due to their nature, case studies and short patient series that describe the use of this approach cannot accurately assess the procedure's risks. Further, strong interventional studies on a large scale base should be implemented for the standardization of this technique  LOE = 1aLOE = 1b.Thoracic interfascial plane blocks are considered safe and easy superficial nerve blocks for oncologic breast surgery. The medial cutaneous nerve of the arm and forearm, intercosto-brachial, lateral cutaneous branch, long thoracic, and thoracodorsal nerves can all be anesthetized by blocking the pectoral nerves (PECS), which has analgesic effects on the lateral mammary region . A doublLOE = 1a and LOE = 1b.An RCT conducted by Neethu et al. and a meta-analysis conducted by Danielle Lovett both shared common conclusion that, with less restriction to shoulder movement (pain-free mobilization) on the surgical site up to 4 hours and 5 hours after surgery, combined PECS I and PECS II block in adult women undergoing modified radical mastectomy effectively reduces the overall amount of fentanyl required in the intraoperative/postoperative period (up to 24 hours) , 53 LOE LOE = 1b and GOR = A.Another randomized trial from Nigata, Japan, that evaluated the effects of PECS block in combination with general anesthesia on postoperative pain measured by NRS and intraoperative doses of propofol and remifentanil concluded that, PECS block significantly decreased propofol requirement but not that for remifentanil requirement during surgery and POD1. This is due to the blocks adequacy in blocking the lateral cutaneous branches of spinal nerves at the level of T2 to T6, and with a sufficient dose the anterior cutaneous branches might be blocked as the LA may penetrate the external intercostal muscles. If the LA is inadequate, the medial part of the chest wall will not be pain free and the analgesia will be inadequate needing additional systemic analgesia  LOE = 1bnd and 4th hour postoperatively, the severity of acute postoperative pain was noticeably greater in the control group than in the ESP group. In addition, patients' and assessor's ratings of treatment satisfaction in the ESP group were higher than those in the control group [LOE = 1b and GOR = A.Injection of local anesthetics within the erector spinae plane is a relatively easy and secure block for breast surgery procedures that eases pain and help decrease opioid consumption. In an RCT conducted in 2022 with a control group taking general anesthesia in the traditional way, at the 2ol group  LOE = 1bLOE = 1a. An RCT conducted in Turkey by Başak Altıparmak had similar finding while comparing it in regard with tramadol consumption following radical mastectomy surgery, modified PECS block significantly decreased postoperative tramadol use and pain scores compared to ESP block [LOE = 1b and GOR = A.Patients who underwent breast cancer surgery experienced stronger analgesic efficacy from PECS II block and ESP block than from systemic analgesia according to a meta-analysis conducted in 2020 comparing PECS and erector spinae block. Compared to systemic analgesia, PECS II block dramatically reduced opioid use and pain score. While pain scores in patients receiving ESP block did not increase not very different from those with systemic analgesia  LOE = 1aSP block  LOE = 1bLOE = 1b and GOR = A.A novel fascial plane block technique is the SAP block. The anterior and lateral chest walls respond well to analgesia when the second to ninth intercostal nerves (T2–T9) lateral cutaneous branch is blocked. The SAP block methodology is simpler and less fraught with danger than other regional block methods. According to the study's findings, preoperative SAP block can significantly reduce the amount of perioperative opioids consumed during a modified radical mastectomy for breast cancer, as well as the perioperative surgical stress response, perioperative patient satisfaction with postoperative pain management, and the incidence of PMPS. All of these factors are favorable to surgery  LOE = 1bLOE = 1b. Given that the risk-benefit ratio favors PECs block, it should be used as the first-line regional anesthetic method in a multimodal analgesic regimen during breast surgery [LOE = 1a and GOR = A.The PECS 2 block decrease's the rate of moderate to severe PPP after six months of oncologic breast surgeries compared with the serratus plane block  LOE = 1b surgery  LOE = 1aLOE = 1a and GOR = A.A systematic review and meta-analysis with a trial sequential analysis stated that there is no strong evidence that suggests the superiority of PECS block over paravertebral block for breast surgeries  LOE = 1aPostoperative pain is subdivided into acute and chronic. While, acute postoperative pain includes the time immediately after surgery to 3 months postoperatively either at rest or during movement, a postoperative pain is a pain that occurs after 3 months depending on the surgeries involvement and the management of acute PPP. Age, anxiety, depression, pain and genetics may play important role as patient factors while axillary staging and lymph node dissection can be intraoperative factors for developing chronic PPP.LOE = 2c and GOR = C. For postoperative analgesia, an extended form of intraoperative regional technique, nonpharmacologic technique, and NSAIDs can be used with the opioid-sparing anesthesia technique LOE = 1a, 1b GOR = A, and GOR = B  as adjunct to intraoperative regional anesthetic technique with general anesthesia preferably TIVA with calculated appropriate dose of standard pharmacological multimodal regimens. Even though preoperative adequate sleep does not have strong evidence for firm recommendation as an effective nonpharmacological method to reduce postoperative pain, we suggest it with low grade recommendation  GOR = B . The sum GOR = B .


Combination of regional anaesthesia technique that is most effective in analgesia and postoperative functional outcome with the fewest complications needs investigation. Interspace between the popliteal artery and the capsule of the posterior knee block (IPACK) has been introduced clinically. We evaluated the efficacy of IPACK in combination with other nerve blocks after total knee arthroplasty.Data were obtained from PubMed, Cochrane Library, Web of Science, and Sciencedirect. Studies that compared outcomes using IPACK combined with other regional nerve blocks after total knee arthroplasty with other analgesic modalities and those which used pain scores or opioid consumption as primary or secondary outcomes were included.I2 = 94%, p = 0.001), postoperative day 1 , and postoperative day 2 ; there was no significant difference at postoperative day 3 or discharge . Combination treatment resulted in reduced dynamic pain scores at postoperative hours 8–12  and postoperative day 1. There was no difference between postoperative day 2, postoperative day 3 or discharge . In addition, it strongly reduced postoperative opioid consumption within 24 H , 24–48 H , and total opioid use . Although IPACK supplementation improved timed up and go test and walking distance at postoperative day 2, there was no statistically significant difference at other time periods or obvious improvement in knee range of motion and quadriceps strength. IPACK block supplementation could shorten the length of stay (LOS)  and improve patient satisfaction .Seventeen articles  were included. IPACK supplementation significantly reduced rest pain scores after total knee arthroplasty at postoperative hours 8–12(95%CI − 0.85 , Based on these results, IPACK supplementation, in addition to standard postoperative analgesia, can be used effectively and safely to relieve early postoperative pain after total knee arthroplasty.The online version contains supplementary material available at 10.1007/s00402-023-04798-x. Total knee arthroplasty (TKA) is one of the most utilized and successful procedures available to resolve end-stage knee disease and can significantly improve patients’ quality of life and knee function postoperatively. With progressive global aging, the annual worldwide rate of TKA has increased steadily over the past 2 decades . Severe The complex innervation of the knee joint includes the femoral, common peroneal, anterior saphenous, tibial, and posterior obturator nerves; these serve as important targets in postoperative analgesia after TKA . SubsequUltrasound-guided IPACK, a new regional analgesic technique, is believed to relieve posterior knee pain after TKA by targeting the articular branches which innervate the posterior aspect of the knee joint . Hence, This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed a systematic search of various electronic databases  for relevant articles from inception to July 20, 2022, without language and date restrictions. Broad MeSH terms and Boolean operators were selected for each database search; the following search terms were used:  AND  AND (random OR prospective OR blind).Inclusion criteria: All RCTs and prospective studies that compared outcomes using IPACK combined with other regional nerve blocks after TKA compared with other analgesic modalities were included. Studies with pain scores or opioid consumption as primary or secondary outcomes were also included. Exclusion criteria: Non-peer reviewed publications, certain study designs , and non-human trials were excluded. Two authors independently selected abstracts as well as full-text articles from the above listed databases using the aforementioned search strategies, and a third author adjudicated discrepancies. The article selection process is illustrated in Fig. The following data were extracted: (1) demographic and clinical information of the patients visual analog scale (VAS) or numerical rating scale (NRS) scores for rest and dynamic status at PO hours 8–12, POD1, 2, 3, and discharge; (3) opioid consumption at 24 h, 24–48 h, and total opioid consumption; (4) LOS and patient satisfaction; (5) TUG, walking distance, ROM, and quadriceps strength; (6) location of IPACK ; (7) anaesthetic doses for IPACK and other nerve blocks; (8) other nerve blocking methods; and (9) complications. Images and tables in the text were evaluated and analysed in order to extract the required data. For each included study, two reviewers extracted all relevant data independently, and any disagreement was resolved by a third reviewer.The quality of evidence and risk of bias for all RCT trials were assessed for methodological quality using the Cochrane Collaboration's Risk of Bias Tool by two of the researchers. Any disagreements were adjudicated by a third researcher. Risk of bias was graded as low, high, or unclear as represented in Fig. 2 coefficient to assess heterogeneity with the following predetermined limits: low < 50%, moderate 50–74%, and high > 75%; and P ≥ 0.05 and I2 < 50% indicating no statistical heterogeneity between studies. A random-effects model was applied in circumstances of moderate or high heterogeneity; otherwise, a fixed-effects model was employed. If there was significant heterogeneity in the included RCTs, such data were considered unsuitable.All analyses were conducted using the Stata software . The continuous variable median (and interquartile range (IQR)) was estimated by the method described by McGrath et al. , and conA total of 17 publications with 1652 patients were included , 41, 43,n = 1154) reported on the total rest pain scores after TKA with IPACK supplementation [I2 = 94%, p = 0.001) as well as POD1 , and POD2 ;. However, rest pain scores on POD3 or discharge  did not achieve statistical significance  were summarized regarding dynamic pain scores after TKA with IPACK supplementation [I2 = 86%, p = 0.01) and POD1  compared with a control group; however, the results in favour thereof on POD2  and POD3 or discharge  with IPACK supplementation, did not demonstrate a statistically significant difference between studies  characterized postoperative opioid consumption after TKA with IPACK supplementation [I2 = 85%, p < 0.00001) and 24–48 h ; and total opioid use   described the LOS, and 10 studies (n = 747) described patient satisfaction after TKA with IPACK supplementation, respectively [I2 = 70%, p = 0.001) and improve patient satisfaction   Figs.  and 7.FiAlthough IPACK supplementation improved TUG and walking distance at POD2, there was no statistically significant difference at other time points Table , nor an Considering the changing healthcare environment that emphasizes early activity and discharge after TKA, we aimed to determine whether using IPACK combined with other nerve blocks for patients after TKA allows early activity and reduces LOS while providing adequate pain relief. We found that IPACK combined with other nerve blocks could effectively relieve early pain (within 2 days after surgery) in patients after TKA, particularly rest pain at 8–12 h postoperatively, yet there was no statistically significant difference at POD3 or discharge. Dynamic pain scores at 8–12 h PO and POD1 demonstrated statistically significant differences, but none at POD2, POD3 or discharge. There were differences in opioid consumption with IPACK combined with other nerve blocks at 24–48 h PO, especially within 24 h PO. Moreover, total opioid consumption was shown to differ significantly between groups. Additionally, IPACK combined with other nerve blocks could shorten LOS and improve patient satisfaction. Interestingly, the TUG and walking distance were statistically different at POD2 but not at other time points. In our study, the ROM, quadriceps strength and complications did not correlate significantly with the addition of IPACK.Postoperative TKA pain affects patients' functional recovery and can cause patients to refuse surgery due to fear. Therefore, better pain control after TKA is a priority for orthopaedists. Recently, ERAS and multimodal analgesia have contributed greatly to postoperative analgesia after TKA. There is an urgent need for new analgesic models which reduce complications and postoperative analgesia usage without affecting postoperative muscle strength. Compared to epidural analgesia, periarticular injections, and peripheral nerve blocks (PNB), such as the adductor canal (ACB) and saphenous nerve blocks (SNB), are widely accepted and used in multimodal analgesic protocols due to their ability to reduce opioid consumption and motor protection in patients undergoing TKA. These nerve blocks provide similar analgesia to epidural analgesia, with improved mobility and fewer complications, such as lower blood pressure and urinary retention , 34.Femoral and sciatic nerve blocks are considered effective in relieving postoperative pain immediately after primary TKA and have been shown to reduce opioid use , 38. HowUltrasound-guided IPACK targets the branching nerves which innervate the posterior aspect of the knee joint. However, the extent of injection spread and the number of affected branches remains unknown. A cadaveric study showed that latex injections spread to the middle knee artery, which usually accompanies the articular branch of the tibial nerve . AnotherWhen performing posterior capsule release, TKA can cause posterior knee pain due to popliteal soft tissue debridement and cyst excision. As a result, substantial pain occurs, which is usually most intense within 24 h of a TKA and can lead to a variety of complications . This stp = 0.005, POD 0), less intravenous opioid use (p < 0.001), and less need for intravenous self-administered analgesia (p = 0.037) compared with PAI alone [The goal of postoperative rehabilitation after TKA is optimal pain control with minimal opioid requirements, and better motor function preservation. Although opioids can be used for severe pain and are commonly used for analgesia after TKA, long-term opioid use may increase the risk of TKA revision in the first year and predisposes to more complications, such as nausea and vomiting . AdditioAI alone . FurtherAI alone . InteresAI alone ; this maSeveral studies have also shown that IPACK combined with other multimodal analgesic methods can shorten LOS in TKA patients , 9, 41. Our study compared the analgesic effects of proximal and distal IPACK techniques after TKA and showed no visible difference between them. However, it is possible that the effects obtained with proximal and distal IPACKs are different, and there is uncertainty about the clinical outcome due to improper selection of the optimal block site. A cadaver study showed that the dispersion of injectables in cadavers may differ from clinical practice due to differences in tissue structure and the nature of the injectables . Other fAdductor canal block or CACB, combined with IPACK, significantly lowered pain scores within 5 days after surgery compared with ACB or CACB combined with LFA; CACB clearly alleviated pain at 2 weeks and 1 month after surgery . MarianoIn conclusion, it is very important to study the analgesic effect of IPACK after TKA, as it directly affects patient satisfaction and postoperative joint function recovery. The main advantages of IPACK are that it is a promising nerve block method since it provides excellent analgesia and reduces opioid use in combination with other nerve blocks without affecting patient mobility. However, confounding factors in the study must be considered, such as flaws in the study design or analgesic methods that may provide posterior knee coverage. Additionally, other knee surgeries, such as knee cruciate ligament reconstruction and tibial plateau fracture surgery, can be further considered. These studies strongly support the use of IPACK in the multimodal analgesic pathway. Although multimodal analgesia can significantly relieve postoperative pain, preserve motor function, and shorten the LOS, pain reappears with gradual wearing off of the nerve block after discharge, which may increase the probability of readmission analgesia to be required. However, severe rebound pain, hospital readmission due to inadequate pain control, and opioid-related adverse reactions require further development of corresponding protocols, which may lead to the assessment of the feasibility of indwelling catheters in future studies.This study has its limitations. First, the use of IPACK analgesia combined with other analgesic methods, including ACB, FNB, and CACB; will inevitably have different degrees of heterogeneity which may affect the accuracy of the test results. Second, there is a risk of bias when some articles with low level of evidence are merged. Third, the included studies used general or intraspinal anaesthesia for surgical treatment, which would lead to heterogeneity in the combination. Finally, IPACK, as a newer nerve block method, remains in the exploratory phase in some hospitals, causing further heterogeneity.With an increasing need for perioperative services to transition toward an ambulatory model with enhanced recovery, early mobilization, and earlier discharge, IPACK blockade supplementation might be a preferable motor-sparing alternative to TNB with a lower incidence of complications and an increased likelihood of earlier discharge from hospital. Supplementation with IPACK blockade has demonstrated great analgesic effects for early postoperative pain control after TKA, compared to patient-controlled epidural analgesia, and similar to PNB. Moreover, it can significantly reduce postoperative opioid consumption, shorten LOS and improve patient satisfaction. Therefore, IPACK block supplementation as a component of an ERAS protocol for patients undergoing TKA could relieve immediate postoperative pain and encourage a return to daily activities.Supplementary file1 (XLSX 66 kb)Below is the link to the electronic supplementary material.