The provision of pain management programmes (PMPs) changed substantially in response to the COVID-19 pandemic with virtual delivery implemented in many services. Little is known about patient selection processes for virtual PMPs and how this might differ from in-person programmes. The aim of this audit was to document the patient selection process for PMPs at a speciality pain service prior to and during the pandemic.This retrospective audit used data from consecutive patients attending a multidisciplinary assessment to determine the suitability of a PMP. Anonymized data were extracted from assessment letters and hospital records in the months prior to the pandemic (n =168) and during the start of the pandemic once the service began delivering virtual PMPs (n =171).For the standard pain management pathway, most patients were offered a PMP option within the service before and during the pandemic, although a greater proportion of patients were offered treatment during the pandemic. For the neuromodulation pathway, most patients were offered a pre-neuromodulation PMP option, and this was similar before and during the pandemic. Psychosocial complexities and unwillingness to engage in a pain management approach that does not principally focus on pain reduction were the most common reasons that patients were not offered a programme.This audit points to a pattern of more inclusive assessment outcomes within our service over time and particularly during the pandemic. Offering a range of in-person and virtual PMPs can meet a wider range of patient need. Research is needed to understand how to best assess and match patients with the breadth of treatment delivery formats now available. Rather, multidisciplinary programmes focus on cognitive-behavioural self-management skills enabling participants to engage in valued activities in the face of pain and other challenges. PMPs have been offered in different formats to meet a range of patients’ needs, from intensive residential to less intensive outpatient formats.9 PMPs have also been offered for patients deemed medically suitable for neuromodulation. PMPs prior to neuromodulation provide participants with information about this intervention, so they can make an informed decision about their treatment together with the multidisciplinary team. However, the main aim is to introduce self-management skills to give patients the tools to respond to their pain differently, regardless of the outcome of neuromodulation. Most PMPs have traditionally been group-based and offered in person.Pain Management Programmes (PMPs) have been offered for people with persistent pain for many years and numerous studies support their effectiveness. and better understanding of patterns of exclusion can help to develop more inclusive treatment options. To this end, in 2014 our tertiary pain service conducted an audit of outcomes for 200 patients attending multidisciplinary assessments to judge the suitability of a PMP. Just over half (53%) of the patients assessed were offered treatment, most frequently an intensive residential PMP. Some were offered a shorter outpatient PMP or individual pain management psychology sessions. For those patients who were not offered any of the treatments available within the service, alternative recommendations were frequently made, such as referral for psychological therapy for trauma or other complex psychological issues that were judged as likely to interfere with a person’s capacity to safely engage in a PMP. A sizeable group of patients were not offered a PMP because they were still seeking medical treatments to reduce pain. Some patients were excluded because they did not meet the minimum physical criteria to attend a residential PMP, which typically requires patients to be independently self-caring. On the other end of the spectrum, there was a group of patients who were functioning relatively well and did not need a PMP. This audit highlighted potential gaps in service provision for a number of patients. Notably, this audit did not examine assessment outcomes for patients that are potentially suitable for a PMP to prepare for neuromodulation. Therefore, less is known about assessment outcomes for patients on this pathway.PMPs are not deemed suitable for all people with persistent pain14 Within this context, our service redeveloped a number of previous in-person PMPs for virtual delivery, which included high and low intensity virtual PMPs and a virtual neuromodulation PMP, among other options. These virtual programmes were designed to meet the needs of patients previously recommended our in-person residential, outpatient and neuromodulation PMPs, with the more intensive PMPs designed to support people with more severe or complex pain-related disability and/or distress than the lower intensity PMP. Prior to the pandemic, our service also offered an online PMP which consisted of website-based pre-recorded audio and video content that patients access asynchronously with minimal therapist support, consistent with a growing body of evidence supporting Internet-delivered cognitive-behavioural PMPs.17 While this online programme can increase access given its flexibility, particularly for patients who are working or have caring responsibilities, it may not be suitable for patients needing more intensive support, such as those presenting with greater severity of pain-related disability or distress. To provide more intensive support for patients presenting with more severe pain-related disability and/or distress, such as those who would have been offered a residential or outpatient programme before the pandemic, our service developed virtual PMPs delivered synchronously with clinician facilitation.With the onset of the COVID-19 pandemic in early 2020, practically all pain services in the UK had to stop offering in-person PMPs because of the public health situation. Considerable effort went into rapidly developing alternatives and soon virtual options for assessment and treatment delivery were trialled.19 Many people with chronic pain struggle using public transport, driving, or walking long distances. Attending from home, therefore, makes programmes available to participants who might previously have been excluded from in-person programmes. Virtual options require less space to run and come with efficiencies that are attractive to commissioners. Staff can run virtual programmes from home or on site, thus increasing flexibility.With this changing landscape of pain management services, it is crucial to consider how virtual options impact on accessibility and patient selection processes. Of course, virtual programmes have advantages. For example, people of lower socio-economic status might not have a computer or Internet access and not everyone has sufficient digital literacy to manage a virtual PMP, which may exclude the very people in most need of support. Lack of stable Internet connections for both patients and clinicians can also pose a problem. In-person programmes offer opportunities to observe participants directly, including their movements, functional abilities, reactions to interventions and body language. This is limited when working virtually, which means clinicians might find it more challenging to connect with patients in a deep and meaningful way. Although functionalities such as ‘breakout rooms’ can enable treatment participants to share their thoughts and feelings, this may disrupt the natural flow of communication and engagement that happens during in-person treatments. Additionally, participants can experience screen fatigue, limiting the length and number of virtual sessions.One obvious drawback of virtual options is their reliance on technology, which not everyone has access to. in the context of programme adaptations that were made during the pandemic. The current audit also builds on the previous one by examining assessment outcomes and exclusion reasons for patients on our neuromodulation pathway before and during the pandemic. Across pathways and time periods, clinician recommendations and reasons for exclusion were identified using information provided in assessment reports. Patient demographics were examined in relation to whether a person was offered treatment or not. Data from this audit will help to inform service provision and options for inclusively delivering PMPs moving forward.The rapid changes to service delivery that occurred because of the pandemic provided a unique opportunity to investigate how the move from in-person to virtual PMPs affected patient selection processes. The aim of the current audit was to repeat the previous audit on patient selection for PMPs by Knight et al.n = 168) and during the pandemic once the service began delivering virtual PMPs . Extracted data were anonymized and stored in a secured database that was only accessed by members of the audit team who were all working clinically in the service. As this was a retrospective audit of routine clinical practice using anonymized data, informed consent was not obtained, as approved by the Trust audit register.This project was an audit based on the Health Research Authority’s decision tool, as it was designed to measure current practices within the service against a previous standard and was not designed to be generalizable. Therefore, research ethics approval was not required. This retrospective audit was registered on the Trust’s audit database (no. 11336) prior to data collection. The audit used data from consecutive patients attending a specialist pain management service in London, UK for a multidisciplinary assessment to determine the suitability of a PMP. Data were extracted from assessment letters and hospital records prior to the COVID-19 pandemic  were considered for a two-week residential neuromodulation PMP or a one day ‘Technology Day’; both of these programmes prepare people to make a fully informed decision about SCS, while the two-week programme also focuses on the development of ACT-based pain management strategies. The choice between the two neuromodulation programmes is predominantly based on clinicians’ judgement of the level of pain-related disability/distress, although patients’ preference and considerations including childcare and work commitments, also influence the recommendation. Patients could also be recommended for ‘case management’ to provide extra support to help them prepare to optimally engage with one of these PMPs as needed . Further details about the nature of and outcomes associated with these programmes have previously been published.15Prior to the pandemic, patients were considered for a three-week residential PMP, a five-session outpatient PMP, or an online self-directed PMP that was completed via a website with asynchronous therapist support. Short-term individual psychology/physiotherapy treatment was offered for people for whom group-based treatment was not suitable, including due to the need for an interpreter or significant interpersonal challenges, such as severe social anxiety, that would impact on their ability to engage with a group-based format. All of these treatment options were based on Acceptance and Commitment Therapy (ACT) and aimed to foster psychological flexibility to help people engage in meaningful life activities in the presence of pain.During the pandemic, patients were also considered for synchronously delivered virtual high and low intensity PMPs, virtual individual psychology/physiotherapy sessions, or a virtual two-week neuromodulation programme or Technology Day . The synchronous virtual programmes were delivered by the BlueJeans/Attend Anywhere platforms approved by the NHS Trust where the audit was conducted. The multidisciplinary assessments were conducted by a psychologist and physiotherapist to judge the suitability of an ACT-based pain management programme and, where not suitable, to make recommendations about support needed from other services. Across all programmes , the general inclusion criteria were adults (18 years or older) with pain for at least three months that significantly impacted on daily function and/or mood. The general exclusion criteria across treatment formats included significant ongoing medical investigations or procedures (with the exception of neuromodulation) and psychosocial complexities that would impact safe and effective engagement in a PMP . Additionally, individuals with substance misuse or addiction, including to prescription opioids, that were the overriding focus of the presenting problem were excluded from the programme.For residential programmes, patients had to be able to manage their own self-care and the physical requirements while staying on site. For virtual programmes, patients were required to have Wi-Fi access and a private space to use while completing the programme. The service was able to loan a tablet for the purpose of completing the programme for those with Wi-Fi access but no suitable device. For security purposes, the loaned tablets were configured such that participants could only access the ‘BlueJeans’ video platform which was approved for use for the virtual PMPs by the Trust and pre-downloaded onto the devices. A dedicated courier from the Trust delivered the tablets to ensure participants received them in advance of the programme.Decisions about treatment intensity and format  were made based on patients’ needs. The more intensive programmes  are offered for patients with greater severity/complexity of pain-related disability and/or distress, while the lower intensity treatments  are typically offered for patients with less severe disability and/or distress. The multidisciplinary assessment consists of a semi-structured interview and the clinicians make a judgement about the suitability of a PMP considering the complexity of information from this interview. Standardized pain and psychosocial questionnaires are not administered as part of this assessment and therefore are not captured in the assessment letters. and refined to reflect the changes in service provision that occurred since that audit. Main pain location and pain duration were extracted from the assessment letter where reported. Patient age, gender and ethnicity were extracted from the hospital registration system where this information was recorded. Assessment time period (pre-COVID and during COVID) and pathway (standard PMP or neuromodulation pathway) were recorded on the data extraction form. Assessment outcomes were recorded using the following categories:1) Three-week residential PMP2) High intensity virtual PMP3) Outpatient PMP4) Low intensity virtual PMP5) Online PMP (self-directed with therapist support)6) Individual psychology in-person7) Individual psychology virtual8) Individual physiotherapy in-person9) Individual physiotherapy virtual10) Joint individual psychology and physiotherapy in-person11) Joint individual psychology and physiotherapy virtual12) Two-week residential neuromodulation PMP13) Two-week virtual neuromodulation PMP14) Neuromodulation Technology Day in-person15) Neuromodulation Technology Day virtual16) Referral to internal pain consultant17) Discharge18) Other (specify)Assessment letters were reviewed for each patient that had an assessment during the dates identified above. A standardized data extraction form was developed based on the previous audit1) Does not meet minimum physical criteria2) Psychosocial complexities limiting ability to engage safely and effectively3) Addiction/substance misuse4) Not ready to engage in self-management/seeking further interventions5) Pain is not significantly impacting on functioning/quality of life6) Unable to participate in English7) Other (specify)The data extraction form also captured whether patients were recommended for ‘case management’ through the service’s nursing and/or occupational therapy teams to prepare them to attend one of the recommended programmes. For patients that were discharged, reasons for discharge were recorded using the following categories which reflect key inclusion/exclusion criteria for the programmes, as summarized earlier:The reasons for discharge were not mutually exclusive and multiple reasons could be recorded on the data extraction form if indicated in the assessment letter. If ‘psychosocial complexities’ was selected as a discharge reason, the specific details of this were also recorded . Finally, for discharged patients, recommendations made for onward support in the assessment letter were extracted.The data extraction was split between four individuals working clinically in the service who had experience with the assessment process and understanding of the PMPs offered. Prior to commencing the main data extraction, the four data extractors piloted the extraction form with the same twenty patients for training purposes. The pilot data extraction was compared across the four extractors and discrepancies were discussed to ensure clarity and consistency of coding. Refinements to the data extraction form were made as necessary to further ensure clarity and consistency. For example, there was initial inconsistency in the application of the coding for main pain location with respect to widespread pain. Following discussion amongst the data extraction team, it was agreed to use the code of widespread pain for assessment letters using the terms ‘widespread pain’ or ‘fibromyalgia’, and where the letters described that patients reported three or more pain locations.Descriptive statistics were computed for demographic variables by treatment pathway (standard PMP or neuromodulation) and time period (pre-COVID or during COVID). Frequencies were computed for each assessment outcome according to treatment pathway and time period. Where the assessment outcome was to discharge the patient, frequencies were computed for the discharge reasons, including frequencies of specific psychosocial complexities documented as a reason for discharge. Finally, frequencies were computed for the recommendations made for onward support for discharged patients.Chi-square tests were conducted to compare the proportion of patients discharged before and during the pandemic for the standard PMP and neuromodulation pathways. Chi-square tests were also used to compare whether discharge rates varied by patient ethnicity, coded as ‘white’ or ‘from an ethnically minoritized background’. Mann–Whitney U tests were computed to compare whether people who were and were not discharged differed in terms of age and pain duration, which were not normally distributed. Given the relatively small number of patients that were discharged, patient discharge status was collapsed across treatment pathway and time period for these analyses.Demographic characteristics of patients included in the audit by pathway and time period are presented in Assessment outcomes by treatment pathway and time period are shown in X2 = 4.47, p = 0.03. There was no difference in discharge rates following assessment for the neuromodulation pathway before (4%) and during (5%) the pandemic, X2 = 0.004, p = 0.95. Participants who were discharged did not differ in age compared to those who were not discharged, U = 7339.00, p = 0.62. The pain duration of participants who were discharged did not differ from those who were not discharged, U = 3010.50, p = 0.25. Whether or not a patient was discharged was not significantly associated with their ethnicity  or gender, X2 = 0.02, p = 0.53 and X2 = 0.95, p = 0.42, respectively. The proportion of patients who were discharged from the standard pain management pathway before COVID-19 (31%) was significantly higher than those discharged following assessment for the same pathway during the pandemic (16%), The purpose of this audit was to examine assessment outcomes and reasons for exclusion from a PMP within a speciality care pain service before and during the pandemic. For the standard pain management pathway, the majority of patients were offered one of the PMP options within our service before and during the pandemic, although a greater proportion of patients was offered treatment during the pandemic. For the neuromodulation pathway, the vast majority of patients were offered one of our pre-neuromodulation PMP options, and this was similar before and during the pandemic. Psychosocial complexities and unwillingness to engage in a pain management approach that does not principally focus on pain reduction were the most common reasons that patients were not offered a programme. This audit can inform service provision and future research to optimize patient selection for virtual and in-person PMPs moving forward. In reviewing the literature, we did not identify other audits that have reported on discharge rates following assessments for PMPs from other services. Given challenges around digital poverty and literacy, a minority of patients continued to be offered an in-person PMP option during the pandemic for when treatment was allowed to be offered on site. Therefore, it appears likely that the service’s ability to offer both in-person and virtual delivery formats enabled, at least in part, a greater number of patients to engage with treatment in a manner that suited their needs. From the data available in the current audit, it is not possible to say whether virtual delivery specifically enabled people with higher levels of disability or distress to engage, or if the format was viewed as easier to engage with more generally. Nonetheless, the current findings can support the continued provision of virtual PMPs alongside in-person delivery formats to meet a wider range of needs. A key question for future research is to understand how to match patients with the delivery format that best suits their needs.Immediately prior to the pandemic, 31% of patients were not offered a PMP on the standard pain management pathway. The discharge rates for this pathway reduced to 16% during the pandemic. This is lower than the discharge rate reported in the previous assessment outcome audit in our service conducted in 2014 (45%).In addition to the implementation of virtual PMPs, another plausible explanation for the higher proportion of patients offered treatment in the current audit, particularly during the pandemic, was that more patients were offered a PMP for whom it was not actually suitable. However, this cannot be directly ascertained from the current audit as we were not able to link the data extracted from assessment letters with treatment engagement or outcome data. Anecdotally, clinicians observed that substantial time and effort went into organizing the virtual PMPs and keeping patients engaged with this format relative to what was typically required for the pre-pandemic residential format. Direct investigation of virtual treatment completion rates and outcomes is needed and will help elucidate whether the more inclusive assessment outcomes found in this audit actually contribute to better treatment outcomes. Although the current audit did not collect data on staff turnover, the service has experienced a number of staffing changes from the 2014 audit to the current one. It may be that differences in interpreting and applying the inclusion/exclusion criteria between different staff across these time periods accounted for the more inclusive assessment outcomes observed here.It is also important to consider the role of staff turnover in shaping PMP assessment practices and outcomes. A previous study found that high periods of staff turnover predicted poorer outcomes following an intensive group-based PMP. Qualitative work is also needed to understand patients’ experiences at multiple points in the neuromodulation pathway, from referral to post-implantation, and to understand key barriers to and facilitators of successful outcomes from this treatment approach. Research is also needed to understand who is most likely to benefit from neuromodulation to optimize patient selection.It is notable that the majority of patients on the neuromodulation pathway were offered some form of preparatory treatment within our service. The availability of a brief ‘Technology Day’ and a more intensive neuromodulation PMP thus appears to meet a range of patients’ needs. However, this audit did not further explore outcomes on the neuromodulation pathway, such as whether patients went for a trial and full implant of the stimulator. Previous research indicates that, on average, people experience improvements in functioning and mood following completion of a two-week residential neuromodulation PMP and the majority go on to receive a trial implant. while patients assessed on the neuromodulation pathway during the pre-COVID period were predominantly men. It is also notable that most patients with ethnicity data recorded were white, and this was particularly striking for patients attending assessment on the neuromodulation pathway. There was a substantial amount of missing data for ethnicity, which makes interpretation of this finding extremely challenging. Ethnicity data were extracted from the hospital record and these data are obtained centrally, not within our service. Further understanding of the reasons for which ethnicity data are not provided or recorded for a large proportion of patients within our hospital is needed. Consultation with patients, particularly those from ethnically minoritized groups, is needed to understand how to optimize collection and use of these data. When investigating potential disparities in access to pain management services, it is crucial to understand how data can be ‘weaponised against the minoritized’  such that the data further disadvantage or marginalize certain groups. Therefore, clear communication about the use of ethnicity data to monitor and, ultimately improve, the equity of service provision is important. It is also important to consider how demographic factors such as ethnicity might be associated with patients’ likelihood of being referred for assessment at a speciality care pain service in the first place.27The current data indicate that patient discharge status was not associated with demographic factors including gender, ethnicity, or age. Interestingly, though, the standard MDT pathway consisted predominantly of women, which is consistent with the higher prevalence of many persistent pain conditions in women, the presence of complex psychosocial difficulties was one of the most common reasons for exclusion from a PMP in the current audit. Anxiety, depression and trauma-related distress that were judged by the assessing clinicians to be of a severity or complexity that would interfere with a person’s ability to safely and effectively engage in a PMP were the most common psychosocial complexities indicated as a reason for programme exclusion. This is mirrored in randomized-controlled trials of psychological treatments for pain, where people with severe mental health problems are often excluded despite the comorbidity of these problems with chronic pain.29 There is a growing body of research showing the benefits of simultaneously treating post-traumatic stress and chronic pain in particular.35 Given synergies in cognitive-behavioural treatments for pain and mental health, research is needed to better understand how best to integrate treatments for both of these difficulties to further promote inclusion.Consistent with the earlier findings by Knight et al., to understand whether trauma-focused treatment for people with pain is optimally delivered within pain management services, or in mental health services with training in pain-informed trauma therapy. In addition to providing more holistic care for patients, such a combined approach has the potential to reduce referrals between currently siloed services and, ultimately, may reduce costs, although this requires testing.In the current audit, onward recommendations were frequently made for patients who were not offered treatment in our service, including recommendations about engaging in local (trauma-focused) psychological therapy. However, there are barriers to patients accessing these treatments, such as whether an appropriate mental health service is available locally and clinicians’ knowledge of and capacity to refer to such services. Therefore, further work is needed to understand the extent to which such recommendations are actioned and, most importantly, benefit patients. Further collaboration between pain management and mental health services is needed to optimize care for this group. This might include, for example, the provision of pain management training within mental health services or developing more direct referral pathways between services. Effectiveness and implementation research are needed a common reason for discharge was that patients were not yet willing to engage in a pain management approach as they wished to focus on pursuing other investigations or treatments to control the pain. In reviewing the assessment letters, recommendations for discharged patients often indicated the possibility of re-referral to our service in the future. Although challenging, it would be informative to audit the longer-term referral and assessment outcomes of these patients to see the proportion who return to the service and engage in a PMP at a later date. To increase service efficiency and improve patients’ experience, there remains a need to optimize the referral process to ensure that patients are not referred for a PMP assessment at a time when they are unlikely to be able to engage with and benefit from this approach. Involvement of patients in the design of pre-referral information resources could ensure that they can make a more informed decision about whether and when referral for an assessment for a PMP would be most helpful for them. Research is also needed to understand how to best holistically support patients while they are still seeking medical solutions for pain management.Consistent with the findings of Knight et al.,Several limitations must be considered. As mentioned, there was a substantial amount of missing data on ethnicity. Therefore, it is not possible to determine whether assessment outcomes were associated with ethnicity with certainty. The data represent a snapshot in time immediately before and in the early months of the pandemic. With increasing experience assessing for and delivering virtual programmes, it is plausible that current assessment outcomes and reasons for exclusion changed over the later months of the pandemic. The reasons for exclusion were obtained from the assessment letters. However, a complexity of information is considered when making decisions about treatment that may not be completely documented in the assessment letters. Standardized self-report questionnaire data on pain-related disability and distress were not collected as part of the multidisciplinary assessment. Because of limitations in the data available within the assessment letters, we are not able to speak directly to the important issue of whether patient presentation changed during the pandemic or whether there was a change in clinicians’ willingness to offer a PMP with the availability of a virtual format. Standardized pain and psychosocial questionnaires are collected for participants who go on to complete PMPs within the service and a separate evaluation of participant characteristics based on these data is ongoing. Finally, this audit is also unable to speak to factors that influence whether patients are referred for assessment in the first place.Despite these limitations, the current data point to a pattern of more inclusive assessment outcomes at a specialty pain service over time and particularly during the COVID-19 pandemic. Offering a range of in-person and virtual pain management programmes is likely to enable services to be more inclusive and meet a wider range of patient need. Research is needed to understand how to best assess and match patients with the breadth of treatment delivery formats now available. Outcome data from virtual programmes also need to be scrutinized. Greater understanding of factors that exclude patients from even being referred for assessment is needed. Further research to optimize treatment pathways and outcomes for people with complex mental health problems is needed.


At end of the treatment, significant improvements were observed as a result of the crenotherapy in overweight/obese subjects in terms of pain reduction measured with NRS (p = 0.03) and in terms of function mobility of the lumbar spine measured with ODI (p = 0.006). This study highlights the beneficial effect of sulphurous crenotherapy on the painful symptomatology and disability in both normal weight and overweight/obese patients suffering from chronic low back pain associated with lumbar spine osteoarthritis.Crenotherapy is recognized as being effective in patients with osteoarthritis of the spine, but to date there is no indication if it is effective for patients who are overweight or obese. The aim of this study is to evaluate the efficacy of sulphurous crenotherapy on pain and disability in overweight/obese subjects affected by chronic low back pain from spine osteoarthritis. Forty-three patients (63 ± 8.8 years) affected by chronic low back pain from lumbar spine osteoarthritis were enrolled in this study. Subjects were treated with 2 weeks of sulphurous creno-treatments. Subjective pain was measured by a numerical rating scale score (NRS), and functional mobility of the lumbar spine was measured using the Oswestry Disability Index (ODI) before and after crenotherapy. Both crenotherapy groups  experienced significantly improved NRS and ODI scores (A1:  Lower back pain (LBP) affects 65–80% of the general population worldwide . LBP verSeveral risk factors are described in the literature as causing lower back pain, including a previous episode of back pain, incorrect habits, such as maintaining a certain posture for long periods during day, overweight and obesity ,4,5,6. AChronic low back pain (CLBP) is characterized by the presence of a persistent (more than 12 weeks) discomforting pain localized at the lumbar spine with or without irradiation to the buttocks and lower limbs associated with a functional limitation, considerable psychological stress, and insomnia ,10.Therefore, CLBP and obesity both affect quality of life (QoL), often-causing disability with deleterious social and economic consequences ,13,14,15Analyzing pharmacotherapy, White et al. analyzed the safety and effectiveness of opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and antidepressants for the treatment of CLBP. These authors highlighted that NSAIDs are effective in CLBP but induce side effects with possibly dangerous consequences. They concluded that opioids and antidepressants may be considered but should not be routinely used for the treatment of CLBP . A studyGiven the burden of the CLBP, particularly in subjects with higher BMI, researchers’ interest in possible therapeutic interventions for the treatment of this disease is now increasing. Among the available non-pharmacological therapeutic approaches, crenotherapy is considered a valid complementary therapy in patients with CLBP, as highlighted by recently updated reviews and meta-analyses ,20,21 anOur previous data  also shoHowever, the efficacy of sulphurous crenotherapy in overweight/obese subjects affected by CLBP from spine osteoarthritis has not been investigated yet. Thus, there is an urgent need to test the feasibility of interventions that could be alternative or at least complementary to pharmacological therapy in overweight/obese subjects. The present study aims to investigate the efficacy of crenotherapy with sulphurous mineral water on pain and disability in overweight and obese patients suffering from CLBP with lumbar spine osteoarthritis, and to analyze whether the effects of sulphurous crenotherapy can vary between subjects with BMI within or above the normal range.An observational study was conducted on 43 patients suffering from CLBP with lumbar spine osteoarthritis, who were referred to crenotherapy by their general practitioners. Inclusion criteria was the diagnosis of lumbar spine osteoarthritis  in the presence of CLBP with an NRS  score > 3, lasting for at least 12 weeks.The enrolled subjects were divided into four groups: Group A1  and Group A2 (overweight/obese) received crenotherapy, Group B1  and Group B2 (overweight/obese) received medical supervision with no crenotherapy. See The exclusion criteria were acute low back pain and/or radicular pain, intra-articular injections of steroids in the previous 3 months, recent surgical interventions, serious venous insufficiency, cancers, uncontrolled hypertension, diabetes, pregnancy, coronary heart disease, metal implants, cardiac pacemakers, and cognitive impairment.n = 18, BMI = 23.7 ± 0.97; and A2: n = 25, BMI = 30.6 ± 4.2) underwent sulphurous crenotherapy, consisting of twelve applications of balneotherapy with medical sulphurous mineral water  and peloids at the Terme di Telese Spa .Groups A1 and A2  of sulphurous medical mineral water at room temperature once per day. The patients resided at home during the sulphurous crenotherapy. No patients used anti-inflammatory or muscle relaxant drugs, or performed physical therapy or exercises during the two weeks of sulphurous crenotherapy.Twenty healthy age-matched volunteers were recruited from the waiting list as controls (Group B). Group B1 consisted of 10 subjects with BMI in the normal range, and group B2 of 10 subjects with BMI above the normal range. All controls did not perform physical therapy or exercises but had occasionally used NSAIDs during the two weeks of intervention under medical supervision. Their demographic characteristics are illustrated in The study obtained the approval of the Ethics Committee (No. 7 r.p.s.o./2020) Campania Sud, Naples, Italy, according to the Declaration of Helsinki and its amendments. All participants provided their informed consent.n = 18, BMI = 23.7 ± 0.97; Group A2: n = 25, BMI = 30.6 ± 4.2). BMI, which combines a person’s weight with their height, is a screening tool that can indicate whether a person is underweight, has a healthy weight, overweight, or obese.Low back pain and disability function were evaluated before and after sulphurous crenotherapy, stratifying for BMI  score, which ranges from 0 to 10  ,31.The analysis of disability and function at the lumbar spine was performed using the Italian version of the Oswestry Disability Index (ODI) ,33, a toThe results are expressed as mean ± standard deviation (SD). The inferential statistics was performed by applying non parametric tests. A Kruskal–Wallis analysis was performed to compare the data of the four groups of subjects, followed by post hoc analysis performed by means of the Mann–Whitney u-test. The within-group differences between the first and the second evaluation were assessed using the Wilcoxon test. The alpha-level of significance was set at 0.05 for primary analyses and at 0.025 for post hoc analysis according to Bonferroni correction, which was performed to avoid the possible inflation of first type errors. The statistical analysis was performed using IBM SPSS Statistics, Version 23.0. NY, USA. p < 0.05) reduction in both painful symptomatology and functional disability of the lumbar spine in both subgroups vs. baseline, as demonstrated by the values of the NRS score  (The study population consisted of 43 patients (A group) subdivided into two subgroups (A1 and A2) on the basis of their BMI. The main demographic characteristics of the sample are summarized in the 2 ± 2.4)  and ODI 2 ± 2.4) . No signp = 0.597), yet conversely highlighted a statistically significant difference at the second assessment (p = 0.003). Post hoc analysis showed that this was due to the difference between A1 and B1 (p = 0.005), more so than the difference between A2 and B2 . The Wilcoxon test showed significant improvements from first to second assessment for A1  and A2 (p = 0.001 and p = 0.001), but neither for B1 (p = 0.285 and p = 0.655) nor for B2   at the first assessment in terms of NRS scores (rection) .p = 0.032) and increased differences at the second (p = 0.004). Post hoc analysis showed that the difference pre-intervention was due to the difference between B1 and B2 (p = 0.023), whereas post-intervention was due to the difference between A2 and B2 (p = 0.006) and not to that of A1 and B1 (p = 0.226)  . All theThis study aimed to investigate the efficacy of sulphurous crenotherapy on pain and functional mobility of overweight/obese subjects affected by CLBP, and evaluate the subjects’ response to sulphurous crenotherapy in comparison to normal weight subjects affected by CLBP.Smuck et al.  have demOur study highlights the beneficial effects  of the crenotherapy cycle with medical sulphurous mineral water  on the persistent disabling painful symptomatology that characterizes patients with CLBP associated with lumbar spine osteoarthritis, which is in accordance with the literature ,23,24,252S) in patients affected by metabolic and/or gastrointestinal disorders have been demonstrated [Our results are supported by the analysis of the distribution of the ODI categories. Indeed, at the end of the sulphurous crenotherapy in both groups, there was a disappearance of disability or a change from categories of greater to lower disability . Notablynstrated .Our study sheds light on the fact that patients suffering from CLBP with lumbar spine osteoarthritis who are overweight/obese have a NRS pain score higher than those who are normal weight, which is in line with important aggregate individual patient data . A signiInterestingly, our research highlighted that sulphurous crenotherapy is able to ameliorate lumbar pain and functional mobility in such overweight/obese subjects. However, the reduction was more consistent in patients with normal BMI, with a 60% reduction of pain symptomatology, when compared with overweight/obese patients who demonstrated a 46% reduction, despite all subjects undergoing the same sulphurous crenotherapic cycle of equal intensity and duration. This is an important result because it validates the claim that crenotherapy can be considered a valid therapeutic option for back pain and disabilities resulting from osteoarthritis, probably thanks to its antioxidant effect that can modulate patients’ anti-inflammatory status, which is particularly high in overweight and obese subjects.In line with our results, Karagulle et al. in their review have highlighted that balneotherapy was superior to long-term tap water therapy in relieving pain and improving function, and that spa therapy combining balneotherapy with mud pack therapy and/or exercise therapy, physiotherapy, and/or education, was effective in the management of lower back pain, and is also superior or equally effective to both short- and long-term control treatments .Nguyen et al.  in theirThis study has some limitations which deserve consideration. The first limitation of this study is the sue pf patients on a waiting list as the control group, as this might underestimate the effectiveness of the control intervention. A second limitation is the possible beneficial placebo effect related to the spa environment. However, these patients stayed in the spa only for the time period of the crenotherapy cycle. A third limitation is the small sample size of the study population. Further larger studies with a randomized controlled design are needed to confirm our results.In conclusion, our research suggests that crenotherapy with the use of sulphur medicinal waters in the form of peloid, bath, and drink, may represent a useful treatment for pain reduction and function improvement in overweight/obese patients suffering from CLBP associated to lumbar spine osteoarthritis. In addition, our study confirms the positive effect of crenotherapy in normal weight subjects affected by chronic low back pain caused by lumbar spine osteoarthritis.


In this study, we aim to evaluate the efficacy of adjunctive lidocaine and ketamine infusions for opioid reduction in the treatment of sickle cell disease in patients with vaso-occlusive crisis (VOC).We retrospectively reviewed a cohort of 330 adult sickle-cell crisis hospital encounters with 68 patients admitted to our institution from July 2017 to August 2018.Upon institutional IRB approval, we obtained initial data from billing records and performed chart reviews to obtain pain scores and confirm total opioid consumption. If provided by the acute pain consultation service, the patients received either a lidocaine or a ketamine infusion of 0.5–2 mg/min or 2–3 mcg/kg, respectively, for a maximum of 24–48 h. We compared the change in opioid consumption before and after infusion therapy to patients that did not receive ketamine or lidocaine.p = 0.02). Patients that received either infusion were 3 to 4 times more likely to decrease their opioid consumption independent of treatment length or baseline opioid doses (p < 0.01). Ketamine and lidocaine therapies were not associated with change in pain scores. When a patient had multiple admissions, opioid reduction was strongly correlated with initiation of infusions in the later visits.Compared to patients that did not receive infusion therapy, ketamine and lidocaine accounted for respective relative decreases of 28 and 23% in average daily morphine consumption (Both ketamine and lidocaine infusion therapies are effective in reducing opioid consumption for patients with vaso-occlusive crisis. Lidocaine infusion is emerging as an agent for stabilizing opioid doses in VOC for patients with high daily MME. Sickle cell disease (SCD) is currently estimated to affect 100,000 Americans and occurs in 1 out of every 365 African American births. Due to advances in comprehensive medical care, mortality has decreased in all age groups. From 1980 to 2009, the survival of patients 20 years of age and with sickle cell disease to rose from 50 to 85%. Subsequently, SCD prevalence among older patients is expected to rise along with comorbid conditions, including opioid tolerance and treatment-resistant pain syndromes. Moreover, Quinn et al. demonstrated that the current care of pediatric sickle cell disease allows for survival beyond 90%; as such, more than 93.5% of pediatric patients with sickle cell anemia and more than 98% of patients suffering from milder forms reach adulthood . The severe pain is accompanied by a significant inflammatory response that often requires hospitalization and treatment of organ failure and acute complications and such as acute chest syndrome, leg ulcers, and avascular necrosis of long bones .Opioids are the mainstay of treatment for both chronic pain and acute escalations of vaso-occlusive crisis (VOC) . Among pIn many cases, the chronic pain and undertreated acute pain in VOC may induce maladaptive changes in the central and peripheral nervous systems . CentralBoth ketamine and lidocaine are used routinely as part of multimodal perioperative analgesic protocols and have emerged as reasonable choices for attempting to relieve such poorly controlled pain. Ketamine is a potent NMDA-receptor antagonist that attenuates the central nervous system's processing of nociceptive afference. Subanesthetic doses of ketamine are analgesic for opioid-resistant or refractory cancer pain syndromes and are increasingly used in the treatment of chronic neuropathic and non-cancer pain –13. The Systemic effects of IV lidocaine, while less understood than its local anesthetic properties, have been demonstrated in patients with chronic neuropathic pain. Its systemic effects are believed to target dysfunctional nerves and prevent depolarization of neurons in the sodium channel. Also, IV lidocaine may prevent hypersensitization of sodium channels and block their spontaneous firing in a damaged tissue . In acutOur retrospective analysis uniquely compares hospitalized patients with SCD patients who were administered systemic lidocaine or ketamine infusions to those who did not. The primary goal of our study was to identify a clinically meaningful outcome in the use of either of the infusions to justify their continued study and use on patients with advanced pain syndromes. Therefore, our main outcome was decrease in average daily morphine dose when using either of the infusion therapies.Upon obtaining institutional IRB approval, we conducted a retrospective cohort analysis of adults with sickle cell disease admitted for vaso-occlusive crisis at the University of Chicago from January 2017 to August 2018. All opioid therapy and dose escalations were guided by the primary admitting team. When the internal medicine team treatment plan was not effective in reducing patient pain, an acute pain service consultation was initiated roughly within the first week of hospitalization, generally around day 4; however, late pain consultations (days 5–10) were also recorded and the reason for delayed consultation was unclear. If deemed appropriate by the consulting acute pain service, lidocaine or ketamine infusions were respectively administered at 0.5–2 mg/min and 2–3 mcg/kg/min until pain relief for a maximum of 48 h and a minimum of 24 h as per University of Chicago inpatient lidocaine and ketamine infusion protocols , 3. InfuPatients were excluded from analysis if there was evidence of ICU admission, invasive procedure, or cardiac disease that was determined by mention of arrhythmias, cardiomyopathy, ischemia, or heart failure in patient progress notes or problem lists. This was done because they were either contraindications to the interventions of interest or would separately require the use of opioids for sedation or post-procedural pain. We additionally omitted patients who received lidocaine and ketamine infusions on the first day of their admission, as there would be no way to establish their inpatient opioid requirements prior to the infusion.Overall, we reviewed three separate groups: those who received ketamine infusion (KET), those who received lidocaine infusion (LID), and those who received neither infusion (SOC-standard of care). All the patients received multi-modal analgesics including opioid therapy. The SOC (standard of care) group included patients who never received either infusion during hospital stay. The KET (ketamine-infused) and LID (lidocaine-infused) groups were not combined at any point during the analysis. We decided to conduct the analysis not only on independent patients but also on hospital encounters, as the patients studied had multiple admissions to the hospital due to VOC and were treated with different multimodal analgesic regimens by multiple admission teams. Given the fact that the analgesic regimen could differ between admissions, even for the same patient, we were able to analyze each encounter as a different event, thus likely limiting both bias and possible placebo effect.As primary outcome, we analyzed the reduction of opioid use before and after the treatment with either infusion or as standard of care. For each hospital encounter, we determined opioid use before and after a “therapeutic window”. For encounters with infusion therapy, the therapeutic window coincided with the treatment, the infusion. At baseline, the average daily morphine miliequivalent (MME) dose was obtained for up to 3 days prior to the start of infusion therapy and for up to 3 days following the therapy . For encAs secondary outcomes, we aimed to identify and compare length of stay and changes in subjective pain scores before and after the treatment window in the KET (ketamine-infused), LID (lidocaine-infused), and SOC (non-infused) groups.t-tests were conducted to compare the mean daily MME change before and after the treatment between each infused group and the same standard-care group. Initial analysis was performed using patient encounters. To compare the likelihood of dose reduction in MME after therapy, generalized estimating equations (GEEs), with opioid dose decrease (yes vs. no) as the dependent variable, were used for the analysis of direct comparisons of the effectiveness of ketamine over no infusion or lidocaine over no infusion. The GEE technique with an exchangeable correlation structure took into account the within-subject correlation structure and provided robust standard errors. GEE analyses with the same dependent variable were also conducted to identify predictors of outcome. The following variables were analyzed: age, sex, treatment window length, baseline opioid dose, day of stay, and weather any NSAIDs, membrane stabilizers, methadone, or acetaminophen had been administered in the days leading to the treatment window. Because of the difficulty of converting methadone to morphine equivalents due to its unpredictable half-life, we decided to account for its use and dosing separately from the opioid use.Two separate We lastly performed a separate analysis to estimate the adjusted risk ratio by stratified analysis and using a log-binomial model with a 2:1 matched group  based on age, sex, and baseline MME. Adjusted relative risk was also calculated because of the tendency of odds ratios to overestimate the impact of predictors on common events . All theOverall, 330 hospitalizations of 68 patients met the study criteria. Of these encounters, ketamine and lidocaine infusions were administered in 28 and 29 of the admissions for 16 and 21 unique patients, respectively. Twenty-seven patient encounters were omitted as a result of the exclusion criteria. During four separate encounters, patients received both lidocaine and ketamine (not concomitantly). They were not included in the analysis, as the reason for switching between infusions was not clear (adverse event vs. futility). Both infusion groups, KET (ketamine infusions) and LID (lidocaine infusions), were different from the SOC (standard of care) group, as they had a greater proportion of females who were younger and consumed more morphine equivalents per day at baseline. Additionally, when compared to patients receiving lidocaine, patients receiving ketamine infusions typically had longer hospital stays and received ketamine 1.5 days later than patients who received lidocaine .A total of 299 patient encounters from 68 unique patients remained for analysis. Twenty-four encounters received ketamine , 24 encounters received lidocaine . A total of 251 inpatient encounters had no administration of either infusion drug (42 unique patients).p < 0.05) , KET (ketamine infusion group), and LID (lidocaine infusion group) increased by +13% (± 4) in the SOC group and decreased by −15% (± 13), and −10% (± 10) in KET and LID, respectively. It was statistically significant ( < 0.05) .p < 0.01) when compared with SOC (standard of care group) patients who never received either of the infusions. Similarly, the LID (lidocaine infusingroup) patients who received lidocaine infusions were 73% less likely to increase their opioid consumption  when compared with the SOC (standard of care group) patients who never received either of the infusions (The KET (ketamine infusion group) patients who received ketamine infusions during their admissions were 65% less likely to increase their daily MME after the treatment window  after the treatment window had 5.83 (± 0.73) days until hospital discharge, whereas those who had a decrease in MME (n = 158) had, on average, 4.54 (±0.73) days until discharge. The difference among the groups was significant (p < 0.01). However, the KET and LID groups were not independently associated a shortened stay or change in pain score during the therapeutic window.On average, patients that had an increase in MME  and LID (lidocaine infusion) groups compared to SOC (standard of care) group respectively , perhapsWith the advent of routine pneumococcal vaccination and penicillin prophylaxis in the pediatric population, most patients with SCD have begun to live and thrive well past age 20 . MoreoveBoth earlier and higher opioid doses in the emergency department were shown to be associated with shorter hospital stays . Still, In the search for multimodal abortive agents, infusion therapies, traditionally used in perioperative periods, may also prove beneficial for patients with SCD admitted for VOC.Our study is unique in that we specifically compare, albeit retrospective, the use of ketamine and lidocaine infusions with encounters that received neither. While we suggest ketamine infusions to be an emerging modality for the treatment of sickle cell pain, thus far, there is little evidence to support the use of systemic lidocaine in this setting on general adult population . ReportsFrom our results, there is evidence that both ketamine and lidocaine are equally efficacious in stabilizing, and even reducing, the daily demand for opioid management independent of baseline opioid doses, length of therapy, and co-administration of other analgesics, especially in later visits of multiple admissions. While reduction in daily MME was associated with shorter duration until discharge, this effect was not mediated by ketamine or lidocaine infusion. Similarly, neither infusion had any effect on change in daily numerical pain scores. However, reducing opioid use may have been essential in further mitigating dose escalation and development of tolerance and opioid-induced hyperalgesia, thus allowing patients to progress, with proper support and medical treatment, toward overcoming the vaso-occlusive crisis and to subsequent hospital discharge.Of note, our analysis showed that both the LID and KET groups appear to have had longer hospital stays than the SOC group; as the infusion groups do seem to represent a small percentage of all analyzed hospitalizations for patients with VOC, the KET and LID groups may indeed indicate a group of patients with more refractory pain that may benefit from initiation of infusion therapies earlier in their hospitalization course.Our study has limitations. Its greatest limitations are those inherent to its single-center retrospective nature and lack of prospective controls. Importantly, while patients are hospitalized and treatment was at the primary care providers' discretion, we can neither determine exactly why certain individuals who qualified for ketamine or lidocaine infusions did not receive them, nor can we determine exactly why doses of opioids were manipulated. In addition, from reviewing of medical records, it did not seem that the choosing of the lidocaine or ketamine as a treatment was correlated with the state of “responder” to either of these medications but it was left at the discretion of the acute pain service attending and based on drug availability. The validity of our analysis of daily morphine requirements hinges on the assumption that subjective pain is treated with nearly on-demand dosing of opioids. In other words, as pain subsides, so should doses. Our study does not take into account social and psychological aspects related to long-term opioid use.Another limitation of our retrospective review is the small number of subjects. While there were many encounters, only 68 individual patients were actually identified and 59 were included in the final GEE analysis. The correlation between infusion treatment and number of visits seems to show that patients with multiple admissions seem to rely more on the infusions to decrease opioid consumption during later hospitalization and not the initial ones. In these instances, our findings suggest that either infusion, ketamine or lidocaine, would be equally effective in maintaining and/or decreasing high opioid doses employed in hard to treat crises.Multiple providers with various treatment plans made our study challenging to interpret as well. With involvement of the consulting pain service and initiation of infusions, data recorded in electronic medical record during those treatments may have been more easily retrievable than in the “no infusion”, SOC or standard of care groups, as acute pain service note has standardized elements to identify pain management treatment outcomes. This was another challenge of our study.As there is a strong correlation between decrease in opioid consumption and initiation of either infusion the more frequent a patient is admitted to the hospital, we hypothesize that our treatments do have a stabilizing effect on opioid dose, especially in patients with significant exposure during earlier visits. It would be therefore worth investigating the initiation of lidocaine or ketamine infusions early in the admission process to perhaps limit the further use of opioids in this challenging patient population. Therefore, our institution initiated a multidisciplinary task force to develop a comprehensive clinical pathway for the treatment of VOC . As suchDespite its limitations, because prospective studies on ketamine are difficult to conduct as patients can easily identify the treatment received due to side effects encountered, our retrospective review provided evidence by simple and robust analysis for the continued use and study on lidocaine and ketamine infusions in VOCs. Our analysis seems to suggest that both ketamine and lidocaine have similar effects in decreasing opioids when initiated in refractory and painful VOC. More research is needed to identify proper doses and outcomes in patients with SCD admitted for painful occlusive crises.Patients with SCD often reach adulthood as opioid-tolerant adults due to their long-term use of opioids to treat chronic pain and acute exacerbations. When opioid dose escalation alone does not provide relief during painful crises, multimodal analgesia is required; therefore, every hospital that treats SCD should have such protocols for these events. While ketamine has been used before in VOC, lidocaine has been studied more on pediatric and adolescent patients with VOC –34. ThisThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Chicago. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.NZ conducted the research and wrote the manuscript. RK contributed to manuscript preparation and conducted the research. MA conducted the research, led the team, and wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Diclofenac sodium is a nonsteroidal anti-inflammatory drug that effectively manages pain following therapeutic extractions. Post-extraction pain is commonly treated with non-steroidal anti-inflammatory drugs (NSAIDs). In addition to their high bioavailability and long duration of action, transdermal NSAIDS have several other advantages. The review tries to understand and elucidate the use of transdermal patches, here Diclofenac, as a postoperative pain management modality. Drug delivery is one of the essential aspects of drug administration where transdermal patches are to be found equally effective when compared to oral administration of drugs. Various analgesics can be administered as patches, for example, ketoprofen, diclofenac, etc. There are also comparative studies between diclofenac and ketoprofen to see and understand the efficacy of transdermal patches compared with oral administration. Compared to oral administration, transdermal patches offer numerous benefits. These include avoidance of first-pass metabolism, sustained and non-rapid absorption, steady plasma levels that remain for prolonged periods, lack of patient dependence on drugs, prevention of gastric distress, and flexibility of stopping delivery of medications by simply removing the patch. This review aims to examine the diclofenac transdermal patch's effectiveness in reducing postoperative pain after orthodontic extraction. Drug delivery is an essential aspect of drug administration, where transdermal patches are found to be equally effective compared to oral drug administration. Various analgesics can be administered as patches, e.g., ketoprofen, diclofenac, etc. There are also comparative studies between diclofenac and ketoprofen that compare their efficacy in transdermal and oral administration . SeveralIn any dental treatment, the dentist's primary goal is to relieve pain as effectively as possible for patients. The experience of pain is a complication involving specific sensations and reactions that occur in response, making it both a physiological and psychological challenge. Monitoring pain relief after surgery using the Visual Analog Scale (VAS) has become an essential postoperative quality assessment procedure because it offers considerable physiological benefits. The dentist must select an analgesic regimen to help eliminate pain effectively while minimizing side effects. Can manage pain through opioids as well as non-opioid medications. Several routes of administration are available . As an alternative method of achieving analgesia, transdermal patches are gaining popularity .Transdermal patches, commonly referred to as transdermal delivery systems, are non-invasive systems for delivering medications into the dermis. This method of drug delivery is a potential alternative to oral ingestion of medications and can improve patient compliance. The first transdermal patch was developed in the 1970s, and the Food and Drug Administration (FDA) approved it as a motion sickness treatment in 1979 . It is aDiclofenac is a NSAIDs that inhibits both cyclooxygenase (COX) -1 and cyclooxygenase (COX) -2 enzymes. NSAIDs inhibit the synthesis of prostanoids  by binding to COX isozymes -9. PGE2 The benefits of using transdermal delivery systemsIn comparison to oral administration, transdermal patches offer numerous advantages. Among them is the avoidance of first-pass metabolism, sustained and non-rapid absorption, stable plasma levels for prolonged periods, the absence of drug dependence, the prevention of gastric distress, and the ability to stop drug delivery by simply taking off the patch Table  1]..1].Use of diclofenac as a transdermal patchOne of the many nonsteroidal anti-inflammatory medications used in clinical practice, diclofenac is frequently used to manage postoperative pain. According to Selvi et al., intramuscular Diclofenac and transdermal Diclofenac patches (TDP) effectively provided analgesia following third molar extractions. The study showed that a Diclofenac patch provided adequate analgesia to manage mild to moderate pain following therapeutic extractions . FurtherMedicated skin patches are adhesive patches applied cutaneously to carry a specific drug dose via the skin directly into circulation. The use of transdermal delivery is regarded as a reliable way to relieve postoperative pain due to the absence of gastrointestinal problems associated with oral administration and the risk associated with invasive intramuscular or intravenous injections. As the transdermal patch is applied to the skin, the drug is absorbed into the dermis and distributed into the capillaries for systemic absorption. Consistent and uniform serum drug levels result from constant absorption across the dermis. Pharmacokinetic data show that transdermal NSAIDs patches exert therapeutically. Effect with higher tissue concentrations and low plasma concentrations that do not adversely affect the system. Advanced therapeutic delivery systems have emerged as an essential topic in pharmaceutical technology and are one of the most recently developed pharmaceutical products in the global market . Thus, dDrawbacks of using transdermal patchHowever, despite their benefits, transdermal patches have certain drawbacks, which are shown in Table DiscussionThis review discusses the diclofenac transdermal patch's effectiveness in reducing postoperative pain after orthodontic extraction. In our report, we analyzed previously available literature discovered through a thorough search of several sources. In PubMed, Web of Science, and Google Scholar, we searched for current related data and literature to better understand the effectiveness of transdermal diclofenac patches Figure .A study conducted by Bhaskar, Kapoor, and Ragini et al. in 2013 evaluated postoperative pain within three consecutive days in 20 subjects with a pain measurement scale and a pain relief measure. Patients with transdermal patches were given paracetamol tablets as an emergency treatment. According to the results, transdermal diclofenac patch 100 mg and diclofenac tablets showed a marked reduction in pain intensity from day 1 to day 3. After three days, the transdermal patch and the oral diclofenac showed an easing of pain. According to their findings, transdermal diclofenac 100 mg was just as effective as oral diclofenac tablets, plus it was more patient-friendly . KrishnaBachalli et al. studied the effects of transdermal diclofenac patches and oral diclofenac following surgical extraction of an impacted third molar. They evaluated the postoperative pain within two hours, four hours, eight hours, 12 hours, and 24 hours on three consecutive days. On a postoperative day, oral diclofenac 100 mg was statistically and clinically more effective than a transdermal diclofenac patch. However, oral diclofenac and a diclofenac patch were similarly effective at relieving postoperative pain on days 2 and 3. A transdermal diclofenac patch can be used as an alternative to oral diclofenac during the extraction of an impacted mandibular molar. However, the analgesic effect is less in the immediate postoperative period . DiclofeIn 2015, Bhargava et al. compared postoperative pain after abdominal surgeries with diclofenac intramuscular injection and transdermal diclofenac patches. Applied transdermal diclofenac patches an hour before surgery, and 75 mg of diclofenac injections were injected 30 minutes before surgery ended. A Visual Analog Scale was used to evaluate the postoperative pain in the immediate postoperative period: four hours after surgery, eight hours after surgery, 12 hours after surgery, and 24 hours after surgery. Transdermal diclofenac groups had a mean time of 7.21 hours first supplement of analgesia, while oral diclofenac groups had a mean time of 7.43 hours first supplement of analgesia. The authors found that a diclofenac patch is as helpful in providing postoperative analgesia as a diclofenac intramuscular injection .In a study by Krishna and Natraj in 2012, a 100 mg diclofenac patch and a 75 mg diclofenac injection were compared as an analgesic postoperatively for subarachnoid block-induced lower limb surgeries. Diclofenac 100 mg transdermally and 75 mg intramuscularly were administered to the study group at the beginning and the control group at the end of the surgery, respectively. The Visual Analog Scale measured postoperative pain after two hours and six hours. Those with a score greater than or equal to 5 requested rescue anesthesia. For injection of tramadol 2 mg/kg, the meantime to achieve rescue analgesia was approximately seven hours in the control group and eight hours and six minutes in the study group. A transdermal diclofenac patch provides the same relief for acute postoperative pain as an intramuscular diclofenac patch without side effects .The tolerability of diclofenac transdermal patches in the treatment of sports injuries was evaluated by a randomized, placebo-controlled, double-blind study conducted by Predel et al. in 2003. The study involved 120 patients. Patients were assessed twice a day for seven days for their tenderness to pressure. It has been shown that patients treated with the diclofenac patch displayed a clinically significant and statistically significant reduction in pain scores and were able to stop experiencing pain sooner than the placebo group, as well as a more excellent tenderness ratio concerning the contralateral limb than an injured limb. It was practical to use the patch of diclofenac; acute traumatic blunt and soft tissue injuries treated with this medication reported no significant adverse events . In a meA double-blind study was conducted with 136 patients; Bailey et al. investigated the effectiveness of using diclofenac 50 mg and aspirin 600 mg for pain after removing the third molar. Diclofenac dispersible tablets reduced the intensity of pain in patients. Aspirin and diclofenac dispersible tablets reduced post-extraction pain equally, but diclofenac was more effective at opening the mouth during extraction of impacted third molars than soluble aspirin .In 2004, Joshi et al., diclofenac sodium, ibuprofen, and paracetamol with codeine were tested before surgery. One hundred nineteen patients scheduled for surgery on a daycare basis to remove their third molar under general anesthesia were randomly assigned to a double-blinded, randomized study. Use a VAS  and a VAS  to evaluate postoperative pain within 15 minutes, 30 minutes, one hour, three hours, six hours, and 24 hours. Analgesics were required for an additional 17 minutes for the placebo group and 32 minutes for the diclofenac group after surgery. In conclusion, paracetamol, Ibuprofen, diclofenac 600 mg, and codeine 60 mg were equally effective in managing postoperative discomfort when teeth were removed .Devireddy et al. reported that orally administered diclofenac could cause complications in the gastrointestinal system (GI). The diclofenac patch was applied transdermally. Diclofenac sodium was administered orally at the control sites. TDP effectively reduced postoperative pain after root coverage with subepithelial connective tissue grafts. In contrast to oral administration, TDP did not cause GI complications, resulting in a higher level of pain tolerance .According to Sanjay Talnia et al., it was shown that for consecutive postoperative days, transdermal diclofenac patches were slightly more effective at controlling postoperative pain in orthodontic extractions than oral diclofenac tablets. Still, no significant difference was observed using the Chi-square test (P > 0.05) among their study population. Premolar orthodontic extraction pain was successfully managed with a transdermal diclofenac patch, with fewer systemic side effects. Despite this, transdermal patches may be limited by their cost and availability .It is noteworthy that, according to the study conducted by Chaitanya et al., diclofenac transdermal patches have shown significant improvements in moderate pain. Compared to the transdermal route, diclofenac administered orally and intravenously significantly reduced pain scores and showed transdermal patches to be effective in mild pain cases with better patient compliance and well-tolerated by patients .Raja Rajeswari et al. reviewed postoperative pain and used a numerical rating scale, a verbal rating scale, and a pain relief scale to measure postoperative pain. All patients had comparable demographics and intraoperative and postoperative characteristics. A Mann-Whitney test was used to analyze the data obtained from the three subjective scales. Oral and transdermal delivery of diclofenac had no statistically significant differences in scores. Three patients reported gastric irritation and a mild burning sensation when taking oral diclofenac, while none developed any adverse effects while using the transdermal patch. Transdermal diclofenac patches have a superior safety profile and better gastric tolerability compared with oral diclofenac patches, despite having the same efficacy ,33.In a study conducted by Samal et al., transdermal diclofenac was found to be a promising analgesic modality to manage mild to moderate postoperative pain following impacted third molar extractions. Diclofenac transdermal is an advantageous alternative to oral and parenteral routes of drug administration because of its proven analgesic efficacy, patient compliance, and side-effect profile. Therefore, it can be used for post-surgical and post-traumatic pain. More extensive clinical trials are needed to establish the scope of transdermal diclofenac in other oral surgical procedures .Khan et al. found that ketoprofen and diclofenac transdermal patches provided adequate postoperative analgesia, but the ketoprofen group needed fewer rescue analgesics . AccordiThe analgesic efficacy of diclofenac transdermal patches is promising. Pain in dentistry is inevitable and can often plague both the patient and the dentist. Future developments may make it easier to administer analgesics transdermally. Due to improved delivery and a more comprehensive selection of painkillers, this method is expected to become more popular and widely used. Compared with oral treatment, the transdermal route is the most successful innovative research area in the new drug delivery system. A transdermal drug delivery system (TDDS) is the most efficient, safest, and easiest way for systemic drug delivery. Longer clinical trials with a larger sample are required to determine the true scope of the transdermal diclofenac patch.


ObjectiveGamma Knife® radiosurgery (GKRS) has been demonstrated to be a well-known approach for treating patients with medical refractory trigeminal neuralgia (TN). Herein, the authors review the outcomes of pain among a large cohort of patients who had undergone a second GKRS delivered at a significantly reduced dose.MethodsThe authors conducted a prospective analysis of patients who have undergone two GKRS procedures between the years 2012 to 2021 at one institution. Baseline characteristics, radiosurgical dosimetry and technique, pain outcomes, and adverse effects were reviewed. Pain outcomes were measured with the Barrow Neurological Institute (BNI) pain intensity scale, which included the best BNI attained after the last treatment and recurrence.ResultsA total of 202 patients were identified, including 55 males and 147 females. Pain recurrence was reported in all patients prior to the second GKRS treatment (median = 4 months). Pain recurrence in the preceding Japan Neuroscience Society (JNS) 2021 study was also reported in all patients after each GKRS with a median value of 20 months between the second and third procedures. Complete to partial pain relief (BNI ≤ III) was achieved in 80% of patients after the second treatment. Over a median of 12 months of follow-up, 60% of patients maintained complete to partial pain relief compared to 77% of patients over the course of three treatments. In the present study, one patient developed facial spasms while 10 patients experienced persistent facial tingling. Subjective mild numbness was also found to be present in 16% of patients, with only 2% being bothersome, as compared to the JNS study, where subjective mild numbness was found to be present in 14%, with only 14.3% being bothersome. Among the 202 patients, 74 (37%) patients had undergone subsequent additional procedures such as a third GKRS, microvascular decompression (MVD), or other percutaneous procedures.ConclusionThe authors describe the largest study to date of patients undergoing a second GKRS treatment for type 1 medical refractory trigeminal neuralgia. A reduced dose of radiation for a second treatment may produce outcomes similar to those of three consecutive treatments in regard to limiting recurrence and adverse effects. Trigeminal neuralgia (TN) is a rare facial pain disorder characterized by severe unilateral “electric shock-like” pain in one or more divisions of the trigeminal nerve. Type I TN is characterized by episodic attacks while type II TN is characterized by persistent facial pain . While aGamma Knife® radiosurgery (GKRS) is a well-studied, noninvasive treatment modality for medically refractory and high-risk surgical TN patients -4. Like In the present study, we determine the clinical outcome of patients with type 1 TN that underwent two GKRS treatments, which accounts for the largest study to date. Additionally, we explore the significance of decreasing the dosage of the second GKRS treatment on pain relief durability and toxicity.Patient populationWe performed a prospective review of patients who had undergone two GKRS procedures for type 1 medically refractory TN between the years 2012 and 2021 at the Miami Neuroscience Center at Larkin Community Hospital. An initial cohort of 226 patients was identified using electronic health records. We excluded patients with incomplete records (n = 1) and type 2 trigeminal neuralgia (n = 23). The final cohort comprised 202 patients. All patient interactions were reviewed from documentation within the electronic health records. Data pertaining to demographics, past medical history, radiosurgical technique, age at second treatment, pertinent procedures before the initial GKRS, pertinent past medical history, pain outcomes, and postoperative adverse effects were all collected from the electronic health records. This study was approved by the Larkin Community Hospital International Review Board (LCH IRB) (F-0822CSW).Radiosurgical ProceduresGKRS treatments were performed on a Leksell model G by a team consisting of a neurosurgeon and a medical physicist. The head frame was placed by the neurosurgeon under local anesthesia. Dose selection and anterior target shift were performed on Leksell computerized software. A max initial dose of typically 38-40 Gy at least 1 mm anterior to the 50% isodose line within the dorsal root entry zone was delivered for the first treatment. A max dose of 25 Gy was delivered for the second treatment. The volumes for each procedure were calculated from the computerized software. The 50% isodose line was typically tangential to the brainstem for all patients. Imaging with MRI or CT cisternogram was performed using axial sequences.Statistical AnalysisData collection was performed using Microsoft Excel . Descriptive statistics pertaining to patient baseline characteristics, radiosurgical parameters, and treatment outcomes were categorized into tables. Pain intensity after the second GKRS procedure and at the last follow-up after the second GKRS was categorized using the Barrow Neurological Institute (BNI) scale . CompletPostoperative adverse effects were categorized into tables. The adverse outcomes were grouped according to symptoms, including facial tingling, spasms, and numbness. Facial numbness was grouped into two categories: mild and bothersome. All adverse effects were counted as subjective in nature because the symptoms were mostly patient-declared.No statistical tests determining statistical significance were performed. Descriptive statistics pertaining to baseline characteristics and treatment outcomes were tabulated as frequency. Categorical (age) and continuous (duration) data were tabulated as a median with a corresponding interquartile range. Dosimetric data were performed in the same manner.Patient demographicsDemographic and baseline characteristics are shown in Table Pain Relief OutcomesUsing the BNI scoring method, complete to partial pain relief was achieved in 80% of the patients, and 60% maintained long-term relief. Repeat treatments  were done when the pain returned, worsened, or remained unchanged from the second GKRS with BNI scores of IV or V. The time intervals (in months) were reported as both a range and a median value for the following: pain recurrence, between the first and second procedure, and the last follow-up. The results are summarized in Table ToxicityThe most common adverse effects were mild subjective facial numbness, spasms, and tingling. Subjective mild numbness was found to be present in 16% of patients, with only 2% reporting the symptoms as bothersome. Three patients with bothersome numbness achieved and maintained partial alleviation of pain (BNI of III) while two patients in this category failed to achieve or maintain pain alleviation . One patient experienced spasms and 12 patients experienced tingling. No patients experienced anesthesia dolorosa.DosimetryDosimetric data are depicted in Table Additional ProceduresA subset of patients underwent additional procedures such as third GKRS (5%), MVD (21%), balloon compression (9%), or other percutaneous procedures (0.5%). All these patients did not achieve resolution of pain following the second GKRS. As a result, they were offered, or sought out, other methods of pain relief. The patients (42) who underwent an MVD have, to date, not had any future relapses in pain.Despite a wide, diverse selection of medical and surgical management having been well-established, long-term relief remains a challenge because of the recurrent nature of the disease. Evidence from Burchiel et al. suggests a simple framework for understanding and categorizing TN. Type 1 TN is defined as pain that is episodic while type 2 is defined as pain that is consistently greater than 50% . First-lEvidence from two recently published works from 2020 and 2021 on the results of having three Gamma Knife procedures suggest that a third procedure reduces relapses and produces comparable effects for long-term pain relief in at least 77% of patients when compared to the initial or second treatments, respectively ,15. HighCombined findings in the two studies on outcomes of pain relief involving three or more GKRS in a heterogeneous group of patients are subject to the fundamental limitations of small sample size and study design. Our results are thus comparable to studies showing improved and controlled pain relief in patients having at least three procedures . We once again highlight the safety and efficacy of having a second GKRS without the need for subsequent treatments in patients with type 1 TN. Herein, lies future opportunities for emerging studies on GKRS effectiveness for recurrence for the type 1 TN population.This study is subject to the intrinsic limitations of a small sample size and study design. Although this is considered the largest study to date, the reduced sample size precludes the power to detect differences in postoperative outcomes. The single institution and exclusion criteria inherently introduce a selection bias, subsequently limiting the study’s external validity.We introduce the largest prospective analysis of patients treated with a second GKRS with a reduced dose of radiation for recurrent type 1 TN. Our results suggest that limiting the treatment to two sessions and lessening the radiation is highly effective, with at least 80% of patients gaining complete to partial pain relief. Our results also suggest that in the long term, at least 60% of patients retain complete to partial relief for a median of 12 months. Subjective postoperative numbness was the most common adverse effect. Although all patients with reported mild numbness had concomitant complete or partial pain relief, additional studies are needed to verify the validity of this treatment strategy to other patient populations, specifically patients with type 2 TN.


Stroke-associated infection (SAI) is a common and serious complication in patients with IS. This study aimed to evaluate the impact of nutritional status at admission assessed on SAI, explore the predictive value of the Nutritional Risk Screening 2002  for SAI (P < 0.001). Logistic regression analysis showed that patients with NRS-2002 score ≥ 3 had significantly higher risks of SAI (NRS-2002: odds ratios (OR) = 1.450, 95% confidence interval (CI): 1.184–1.692, P < 0.001).A total of 594 patients with IS were included in this study; among them, 215 (36.20%) patients were at risk of malnutrition, and 216 (36.36%) patients developed SAI. The area under the curve of the NRS-2002 scores was smaller than A2DS2 (0.644 vs. 0.779), and NRS-2002 improved the predictive values of the ANRS-2002 is a useful and simple tool for identifying the risk of SAI. Malnutrition is related to the development of SAI. Malnourished patients with stroke may benefit from further nutritional supplements and management. Ischemic stroke (IS) is the main type of stroke in clinical practice, accounting for approximately 69.6% of all strokes , with thMalnutrition is a common condition in patients with stroke. The prevalence of malnutrition is up to 62% in patients with stroke . MalnutrThe Nutritional Risk Screening 2002 (NRS-2002) tool , 13 is aThis study aimed to evaluate the nutritional status of patients with IS using the NRS-2002 tool and explore its correlation with SAI occurrence to screen for high risk of SAI and early clinical intervention to improve the prognosis of patients with IS.www.chictr.org.cn (Identifier: ChiCTR2100052025) and conducted in accordance with the Helsinki Declaration. The research plan was approved by the Human Ethics Committee of West China Hospital of Sichuan University. Informed consent was obtained from each participant.This is a retrospective multicenter study based on recovery trajectory data to assess whether NRS-2002 can predict the incidence of SAI in patients with IS. Patients were recruited from the stroke centers of five hospitals. This study was registered at Patients with acute stroke admitted to the Emergency Stroke Center of five major hospitals in Chengdu, Sichuan, from January 2017 to February 2019 were retrospectively included in this study. The inclusion criteria were as follows: (1) in line with diagnostic criteria for IS . Blood biochemical tests were performed using an Architect C16000 analyzer .2DS2 score  was calculated  score ≥ 5 = 3)  , which ihe NIHSS  which caThe NRS-2002 tool  was usedThe main outcome was SAI during hospitalization. According to the revised standard definition of the Centers for Disease Control and Prevention based on electronic medical records , SAI wast-test was used for comparison between groups with parametric characteristics, and the Mann–Whitney U test was used for comparison between groups with non-parametric characteristics. A chi-square test or Fisher's exact test was used to compare categorical variables.Parametric continuous variables were represented by mean ± standard deviation, and nonparametric continuous variables were represented by the median of the quartile interval. Categorical variables were reported in the form of frequencies and percentages. The 2DS2 for SAI.Logistic regression analysis was performed to analyze the relationship between malnutrition and SAI. The logistic regression model was adjusted for demographic variables , physiological variables (body mass index and blood pressure), laboratory tests , and chronic diseases  to further determine whether these relationships were independent of risk factors. In the model, the patients were divided into groups according to age (<65 years vs. ≥65 years), sex , hypertension (yes vs. no), diabetes (yes vs. no), treatment (conservative vs. thrombolysis or thrombectomy), and NIHSS score (≤ 7 vs. >7). The area under the receiver operating characteristic (ROC) curve and continuous net reclassification improvement (NRI) were established to evaluate the predictive ability of NRS-2002 and AThe significance level was set at 0.05. All statistical analyses were performed using SPSS version 26.0  and R software 3.5.0 .2DS2 score. The baseline characteristics of the patients are presented in Finally, after an overview of the inclusion and exclusion criteria, 594 patients were included in this study. The average age was 58.79 ± 11.97 years. Of these participants, 378 (63.6%) were male. In addition, 215 (36.20%) patients were at risk of malnutrition (NRS-2000≥3). A total of 216 (36.36%) patients developed SAI during hospitalization. At admission, patients with NRS-2002 score ≥3 were found to be older, have a lower Barthel index and hemoglobin, have a higher D-dimer, and high-density lipoprotein, and have a higher NIHSS score and AP < 0.001) . Restricted cubic spline analyses demonstrated continuous relationships between NRS-2002 and odds for SAI (Patients with NRS-2002 score ≥3 were more likely to develop SAI (< 0.001) . In the < 0.001) , after a for SAI .2DS2 for SAI was 0.644  and 0.779 , respectively. A2DS2 combined with NRS-2002 achieved a higher AUC  than A2DS2 alone (P < 0.001). Additionally, NRS-2002 combined with A2DS2 achieved additional predictive values for SAI beyond A2DS2 according to the NRI analysis   of NRS-2002 and A< 0.001) .An NRS-2002 score ≥5 had optimal specificity (95.69%) to predict SAI .Subgroup analyses stratified by age, sex, hypertension, diabetes, treatment, and NIHSS score were performed .P < 0.001), female , hypertension , diabetes , and NIHSS score >7  have a higher risk of SAI. In contrast, the risk of SAI associated with NRS-2002 was significantly stronger for patients with diabetes than for those without diabetes (P for interaction: 0.032).The results showed that patients with NRS-2002 score ≥3 combined with other factors including age ≥ 65 . The logistic regression model showed that patients with malnutrition risk (assessed by NRS-2002) or neurological deficit (assessed by NIHSS) had significantly higher risks of SAI, which is consistent with previous studies . Because the A2DS2 does not include the evaluation of nutrition and malnutrition increases the SAI incidence, it is meaningful to include the evaluation of nutrition in the tool for predicting SAI. Subgroup analysis shows that NRS-2002 predicts a better value in SAI for patients with diabetes. In hyperglycemic patients, insulin is relatively insufficient due to insulin resistance, and glucose utilization is reduced. This increases the nutritional risk of the patient. The risk of malnutrition assessed using NRS-2002 is related to the development of SAI. NRS-2002 may be a useful and simple tool for identifying SAI.In this study, we validated the diagnostic value of NRS-2002 for SAI in patients with IS. Our data showed that NRS-2002 could predict the SAI. Moreover, considering sensitivity, specificity, and AUC, the results showed that NRS-2002 combined with AThis study also has some limitations. First, this is a retrospective study and needs to be confirmed by prospective studies. Second, the evaluation results of the scale were not compared with the infection biomarkers, and the evaluation results were not further verified. Third, the study failed to use NRS-2002 for continuity assessment during hospitalization.IS is a common disease in clinical neurology. Generally, early nutritional screening should be part of the standard clinical treatment management for patients with IS. It is necessary to check the nutritional status and risk factors for patients with IS. The risk of malnutrition assessed using the NRS-2002 score is related to the development of SAI. NRS-2002 may be a useful and simple tool for identifying SAI. Patients with malnutrition and malnutrition risk should be given appropriate nutritional management as soon as possible to help reduce infection complications, improve prognosis, and reduce medical costs. However, how to provide nutritional supplements and management for malnourished patients with stroke is still a key issue faced by clinicians. Thus, further research is needed to explore an effective approach to address malnutrition in patients with IS.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Human Ethics Committee of West China Hospital of Sichuan University. The patients/participants provided their written informed consent to participate in this study.XC, DL, and YG conceived the study design and interpreted the data and drafted the manuscript. XC, YJ, YL, and LZ collected the epidemiological and clinical data. XC, YJ, and YL summarized the data and performed the statistical analysis. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.This work was supported financially by grants from Sichuan Science and Technology Program , Sichuan University West China Nursing Discipline Development Special Fund Project (HXHL20017 and HXHL21016).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.