Recent evidence supports the use of immersive virtual reality (VR) as a means of delivering bodily illusions that may have therapeutic potential for the treatment of musculoskeletal conditions. We wanted to investigate whether a single session of an embodiment-based immersive VR training program influences pain-free range of motion in patients with shoulder pain.We designed a rehabilitation program based on developing ownership over a virtual body and then “exercising” the upper limb in immersive VR, while the real arm remains static. We then carried out a single-arm pre-post experiment in which 21 patients with movement-related musculoskeletal shoulder pain were exposed to the 15-min VR program and measured their active pain-free range of motion immediately before and afterwards.We found that shoulder abduction and hand-behind-back movements, but not shoulder flexion, were significantly and clinically improved post-intervention and that the level of improvement correlated with the level of embodiment. Following this one session, at 1-week follow-up the improvements were not maintained.Virtual embodiment may be a useful therapeutic tool to help improve range of motion in patients with movement-related shoulder pain in the short term, which in turn could expedite rehabilitation and recovery in these conditions. Musculoskeletal-related shoulder pain is a common and often highly disabling complaint with a lifetime prevalence of up to 70% . The majRecovery from these conditions is often slow. Twenty-five per cent of those affected by rotator-cuff-related shoulder pain (RCRSP) report previous episodes, and up to 50% of these patients still report persistent pain 6–12 months after initially seeking treatment . In the There are various interventions for these conditions, including physiotherapy , corticosteroid injections, medication and surgery. However, conservative therapy is the mainstay of treatment, as clinical trials suggest that long-term results of patients treated surgically are comparable to those receiving rehabilitation . UnfortuA movement or activity that is repeatedly experienced as painful over prolonged periods may eventually be enough to trigger a painful experience even with comparatively reduced nociceptive input ; for example, via the sensitization of second-order nociceptive neurons , which iThe degree of central sensitization may be associated with cognitive factors such as kinesiophobia or pain catastrophizing , as wellUsing immersive virtual reality (VR), it is possible to give the user a virtual body that can be experienced as one’s own –26, whicTherapeutic manipulation of virtual bodies may be relevant to particular types of chronic pain, especially in patients with deafferentation conditions, which often result in altered body image, for example in phantom limb pain . StudiesVR allows the performance of movements and tasks that are not possible in real life—whether because of immobilization, fear, pain or stiffness. Observing an embodied virtual body perform, such movements might therefore reduce movement-related fear and facilitate better real-life movements. Using embodiment of a virtual body, a false visual feedback of the body position can be provided, which can result in an unconscious enhancement of movement . SubjectThis was a single-centre case series with a pre-post quasi-experimental design. Subjects were recruited from the outpatient rehabilitation department of Quironsalud Barcelona, a large private hospital. They were assessed for suitability according to the inclusion criteria by the head of the rehabilitation service who reviewed their medical history. Suitable patients were then recruited by telephone. Patients were considered for inclusion if they were aged 18 to 80 years old with a diagnosis of rotator-cuff-related shoulder pain , with a duration of 6 weeks or longer, and were currently undergoing physiotherapy treatment at the hospital. For diagnosis, a combination of clinical findings with imaging confirmation (for RCRSP) or using imaging to exclude other pathologies (in the case of adhesive capsulitis) was used. Patients were excluded if they had severe cognitive impairment , severe visual deficit (if they were unable to read the introductory text when donning the HMD), epilepsy, an acute pain flare defined as greater than 7/10 pain over the previous 48 h, shoulder osteoarthritis or were pregnant.dz = 0.66, power = 0.80,  α = 0.05, correlation between measures 0.8) of the intervention on pain-free abduction range of motion with the rather conservative matched-pairs Wilcoxon signed-rank test, resulting in a required sample of 21 participants.Sample size was calculated using G*Power . Using At the start of the session, after reading and signing the consent form, the patient completed the QuickDASH and TSK-11 questionnaires (see Outcomes below). Then, their pain-free active range of shoulder abduction, flexion, and hand-behind-back was measured, as outlined above and shown in Fig. The patient was then seated with their hands resting quietly on their upper legs throughout the experiment. The patient then donned the head-mounted display (HMD) and was immersed in a virtual reality environment in which they viewed a generic gender-matched virtual body or avatar from a first-person perspective, with the upper body (head and trunk) movements of the avatar moving in synchrony with their real-life movements Fig. A. VirtuaAfter the exercises were completed, the HMD was removed, and shoulder ranges of motion were measured as previously. Finally, the patient completed the virtual experience questionnaire to assess their level of immersion, agency and embodiment. To assess whether there was any carryover of the intervention, or any impact on levels of fear or disability, range of motion, kinesiophobia and disability were measured again one week later.We used a head-mounted display  with a resolution of 1440 × 1600 pixels per eye and a nominal field of view of 110°, displayed at 72 Hz to show the virtual environment, which was programmed in Unity 2019.4.10f1 . The virtual therapist male and female body were taken from the Rocketbox library . The HMD was connected to a laptop via a Link cable. The coin vibrators were configured with an Arduino box and connected to the PC.https://www.kinovea.org), which enables half-automated movement annotation and has been demonstrated to thus facilitate very high inter- and intra-rater reliability in the measurement of shoulder range of motion [We measured pain-free range of motion in three movements of the shoulder: abduction, flexion, and a hand-behind-back movement . These movements were selected as they are functional and frequently reported as painful in shoulder conditions , 3. The f motion . AngularWe measured kinesiophobia (fear of movement) with the abbreviated version of Tampa scale of kinesiophobia (TSK-11), a patient-reported questionnaire consisting of 11 questions (scored 11–44) on movement-related fear, with higher scores indicating greater levels of kinesiophobia. The TSK-11 has been shown to be valid and reliable for shoulder pain , and a SWe measured self-reported levels of upper-limb disability using the QuickDASH questionnaire, a patient-reported questionnaire consisting of 11 questions  on symptoms and ability to do daily activities, with higher levels indicating greater disability. The QuickDash has been validated for shoulder conditions . MeasurFollowing the VR intervention, the patient completed a 7-item questionnaire regarding their virtual experience and indicated subjective levels of presence, virtual body ownership and agency over the virtual body movements . The pat-test). If the normality assumption was not met (p < 0.05), nonparametric testing was used (Wilcoxon signed-rank test). Additionally, nonparametric analysis was used for hand-behind-back range of motion, which used ordinal  rather than interval data. Statistically significant findings for parametric data  were further checked by repeating the analysis using the more conservative nonparametric Wilcoxon signed-rank test. The significance level was set at p < 0.05. To determine whether the VR program induced a change in pain-free range of motion, we compared pre-exposure and post-exposure range of motion by performing a paired t-test for flexion and abduction and a Wilcoxon signed-rank test for hand-behind-back movements , which is also a paired test. To determine whether aspects of the virtual reality experience, patient age, baseline levels of fear and disability and changes in range of motion were correlated, we used a Spearman’s correlation coefficient. Finally, to determine whether there was an effect of pathology/condition (adhesive capsulitis or RCRSP) or gender on degree of improvement in range of motion, we performed 3 (time) × 2 (pathology/condition or gender) repeated-measures ANOVA.All statistics were performed using Origin . Data were assessed for normality using visual inspection and Shapiro–Wilk testing. If the normality assumption was met, parametric testing was used /SD(c1 − c2) where c1 and c2 refer to pre- and post-measurements, respectively, and SD is the standard deviation of the difference scores.Finally, we calculated the effect size Cohen’s n = 10 males), with a mean age of 59 and mean duration of symptoms of 24 weeks, were recruited for the study and completed the VR intervention. Two patients did not return one week later to complete the follow-up measurements, one due to COVID-19 infection and the other for unknown reasons. We performed a baseline assessment consisting of a range-of-motion assessment and the QuickDASH and TSK-11 questionnaires. Full baseline participant demographics are provided in Table Twenty-one patients n = 0 males, mean = 8.58) compared with before the intervention . The mean improvement was 12.3°    compared with before the intervention   and post-intervention ; however, this was not significant   and flexion movements    Fig. . Howeverρ =  − 0.615, p = 0.005) and presence   Fig. ; that isρ=  − 0.488, p = 0.034); that is, patients who were less disabled at baseline were more likely to have improved flexion movements . For hand-behind-back movements, the median range of motion was maintained at 1 week, but this was not statistically significant . Patients then completed the TSK-11 and QuickDASH questionnaires. There were no differences in levels of kinesiophobia (TSK-11) between baseline  and 1-week post-intervention . Additionally, there were no differences in levels of disability (QuickDASH score) between baseline  and 1-week post-intervention .One week after completing the VR embodiment program and assessment, the patients returned, and range of motion was reassessed. We found that the increases in range of abduction or flexion range of motion seen immediately post-treatment were not maintained at 1 week  and supg., CRPS , which ag., CRPS .Structural and functional alterations in the primary somatosensory and motor cortices are associated with certain types of persistent pain, including shoulder pain , 9, and It is unlikely that the overall improvement in pain-free range of motion is simply be due to a stretching effect due to movements undertaken in the initial assessment, since the 20-min VR program, in which the patient’s shoulder is completely static, is almost certainly long enough to eliminate any such potential gains. In addition, placebo analgesia, in which pain thresholds are increased simply through expecting less pain, may well play a role . PatientThe mechanisms outlined here are not necessarily mutually exclusive, and further experimental studies with appropriate controls are required to disentangle the neurophysiological mechanisms involved with embodiment illusions .There was no significant carryover of the intervention on any of the outcomes. At 1 week, none of these improvements were maintained and neither were there any changes in kinesiophobia or disability from baseline. There are several explanations for this. We would not reasonably expect a single short session of VR to have a lasting effect on range of motion, fear or disability. Whether repeated or longer sessions are more likely to have a carryover effect is unknown. Generally, the prescribed dosage for traditional mirror therapy is much higher in terms of both the number of sessions, and the number of times a movement is observed, so we would reasonably expect some sort of cumulative effect with repeated VR sessions. Future studies should explore optimal dosage in terms of length and number of sessions in further depth.The virtual embodiment and exercising approach described in this study have different potential future applications for pain and physical rehabilitation. Exercising the virtual body can have an impact at different levels, from facilitating movements to reducing kinesiophobia. The program could be combined with traditional physiotherapy, for example as part of a warm-up session that precedes the main treatment. It can also be used in patients with high levels of pain, anxiety or kinesiophobia as part of a cognitive-behavioural exposure therapy to address kinesiophobia and the resulting movement avoidance. Other approaches, such as gamification, have also been pursued for this purpose  and coulThere were several limitations to the current study. No control group was included, so we cannot fully rule out nonspecific effects such as the novelty of the intervention. In addition, while we recorded outcomes at 1-week post-intervention, the patients were all undergoing regular physiotherapy treatment at the time, so we cannot attribute any changes seen at 1 week to the intervention just to the VR intervention.Dosage may not have been sufficient (with just three repetitions for each movement), and we may have seen greater improvements with more repetition . However, this would have meant either spending longer in VR or reducing the number of exercises, which could reduce patient engagement. It was felt that on balance a wider variety of exercises with less repetitions were optimal. Generally, it should also be considered that longer interventions may increase the chances of inducing motion sickness, although with these contents, where the patient was static, the chances were lower.We did not monitor levels of fear or disability immediately post-treatment since it requires time to see and experience changes with the patient experimenting and testing movements and activities; however, with just a single session, a significant effect on these factors is less plausible.A single immersive VR session in which patients with movement-related shoulder pain observed their embodied virtual body performing previously painful movements was sufficient to induce clinically and significantly improvements in abduction and hand-behind-back range of motion. No such improvement was seen for flexion. The effect on range of motion appeared to be correlated with levels of virtual body ownership and therefore embodiment. Virtual embodiment may be a useful tool to improve active range of motion in patients with movement-related pain and may help expedite rehabilitation and recovery from a variety of such conditions, especially in the early stages of rehabilitation where patients are often highly anxious or fearful and avoidant of movement.


Though the literature suggests a strong association between depressive symptoms and suicidal ideation, in clinical practice, it is often observed that many patients who show those symptoms, even the most severe, do not experience suicidal ideation. Thus, the association between depressive symptoms and suicidal ideation is insufficient to explain the complexity behind suicide. From Shneidman’s point of view, the common feature in patients with suicidal ideation and suicidal behavior seems to be mental pain, defined by the author as “psychache” and characterized by a distressed state of mind, in which the subject experiences extreme angst, hopelessness and in which pain is seen as unsolvable. Individuals with depressive symptoms are suicidal only when psychache is so unbearable that suicide is perceived as the only option.Our study aimed to investigate the association among depressive symptoms, mental pain, and recent suicidal ideation, specifically whether mental pain could mediate the relationship between depressive symptoms and current suicidal ideation in a sample of psychiatric patients.Participants were 206 adult patients . Patients were assessed for psychiatric diagnoses according to DSM-5. For the study, the following instruments were administered: the Columbia-Suicide Severity Rating Scale (C-SSRS), the Beck Depression Inventory-2 (BDI-2), and the Orbach & Mikulincer Mental Pain Questionnaire (OMMP).32.5% of the patients had bipolar disorder, 21.4% had MDD, 24.8% had schizophrenia or other psychotic disorders, and 15% had a personality disorder. About 34% of the patients reported recent suicidal ideation with at least some intent to act. Recent suicidal ideation was associated with both mental pain and depressive symptoms, but mental pain completely mediated the association between depression and suicidal ideation .Our study indicated that patients with more severe depressive symptoms are more likely to report suicidal ideation and that the presence of mental pain could explain this association thoroughly. Thus, in clinical practice, the identification of mental pain confirms its crucial role in the assessment of suicide risk and in the understanding of the individual’s unique pain.None Declared


Duloxetine’s analgesic efficacy in individuals with total knee arthroplasty (TKA), particularly caused by chronic knee osteoarthritis, has been extensively established2. We read with great interest the article entitled ‘Duloxetine for rehabilitation after total knee arthroplasty: a systematic review and meta-analysis’. In this study, Yang et al.3 discussed the efficacy and safety of duloxetine for postoperative recovery after TKA. They concluded that duloxetine reduced pain over a time span of 3 days to 8 weeks, lower cumulative opioid consumption within 1 day, and improved the physical function of the knee with a time span of 1–6 weeks. This paper is undoubtedly impressive in terms of innovative findings but disappointing in its high unexplained heterogeneity, not performing subgroup analysis regarding main outcomes, as well as not discussing the relevance between statistical and clinical differences.Duloxetine is a norepinephrine reuptake inhibitor (SNRI) that inhibits serotonin and norepinephrine reuptake and modulates the descending inhibitory pain pathways in the central nervous system5. Hereby, we presented the following subgroup analysis based on 6 factors: follow-up period, surgery type (knee or hip), the usage of duloxetine (30 or 60 mg), duration of medication administration (<2 weeks or >2 weeks), patients’ mental status at baseline (with and without depression), and patients’ status of central sensitization . We made a comprehensive synthesis of randomized controlled trials investigating the efficacy of duloxetine in both TKA and total hip arthroplasty (THA) and, for the first time, got the raw data from two enrolled trials, which only provided figures in their published articles. We also regrouped the follow-up period according to the guidelines of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). Pain should be evaluated short-term (≤24 h), medium-term (2–4 weeks), and long-term (3–6 months or longer)4.A better understanding of the confounding factors which affect the efficacy and safety of duloxetine is in urgent need3. Our analysis found that both 30 and 60 mg doses of duloxetine were effective in reducing pain. It is astonishing that 30 mg was superior to 60 mg in reducing ambulation pain (30 mg: −0.73 vs. 60 mg: −0.39) and rest pain (30 mg: −0.81 vs. 60 mg: −0.22). Therefore, we would like to suggest a dose of 30 mg daily in patients with total joint arthroplasty.Despite several meta-analyses published regarding the efficacy of duloxetine. The optimal dose and duration for duloxetine remain obscure. The dosage of duloxetine should be more than 60 mg when treating neuropathic pain, whereas a third of the studies used 30 mgMoreover, our data also showed that a lengthier administration period of duloxetine was associated with lower pain scores similarly at ambulation (>2 weeks: −0.46 vs. <2 weeks: −0.39) and rest (>2 weeks: −0.50 vs. <2 weeks: −0.13). However, side effects should be closely and cautiously monitored when using duloxetine for more than 2 weeks since most total joint arthroplasties are carried out in day surgery centers.In our review, we could not differentiate the effect of duloxetine between TKA and THA patients regarding ambulation (TKA: −0.46 vs. THA: −0.49) and rest (TKA: −0.64 vs. THA: −0.34) pain scores Figs , 2.The success of duloxetine administration requires precisely selecting the target population, and identifying the optimization patients is of vital importance. Factors under consideration are patients’ preoperative pain catastrophizing and psychiatric status. In CS patients, the serotonin–norepinephrine descending inhibitory pathway decreases, resulting in a decrease in serotonin and norepinephrine.Our study found that patients with central sensitization (CS) could benefit more from duloxetine despite the status of measuring pain scores .Moreover, it is well-recognized that depression can have a profound influence on pain perception, and the antidepressant effect of duloxetine may upregulate the patient’s pain threshold and emotional experience. Our study reveals that baseline depression status did not influence the effects of duloxetine on pain .In conclusion, the current evidence supports the 30 mg and beyond 2 weeks of use of duloxetine for the purpose of reducing postoperative pain. We used appropriate subgroup analysis, which revealed the beneficial patient population and dosing schedule, and dissolving high heterogeneity.Not applicable.Not applicable.Not applicable.X.T., Y.Y., and F.Z.: study design and writing; X.T., L.M., and P.L.: language polishing and final approval.The authors declare that they have no conflicts of interest.Not applicable.Xiumei Tang and Li Ma.Not applicable.Commentary, internally reviewed.


This review was designed to compile the currently available evidence on the prophylactic use of gabapentin in the head and neck cancer patient population.A systematic search was conducted of PubMed, Web of Science, and Google Scholar to identify articles related to the use of prophylactic gabapentin in patients undergoing head and neck cancer therapy. Candidate studies were screened for inclusion and a subsequent bias assessment was conducted by multiple reviewers. Meta-analysis was conducted in cases in which the studies used compatible outcome measures.p = 0.962) but substantially less weight loss among those in the treatment arm (p = 0.047).Ten studies were identified that met the inclusion criteria and were assessed for bias. Among the four small studies that examined pain prevention, 2 were positive and 2 were inconclusive. Three of the four studies examiniRDng opioid use noted less need for opioids in the treatment arm. Meta-analysis of the pertinent studies showed no difference in feeding tube placement , Prophylactic gabapentin appears to be a promising treatment option for preventing pain, reducing opioids, and reducing weight loss in patients undergoing head and neck cancer therapy. However, the studies on the treatment to date are small and several have a substantial risk of bias. An estimated 65,000 patients will be diagnosed with head and neck cancer (HNC) in the USA each year resulting in over 15,000 deaths annually . In addiPatients undergoing concurrent chemotherapy and radiation therapy for HNC experience a wide variety of acute toxicities secondary to treatment. One of the most challenging toxicities to manage is mucositis and associated pain. Mucositis-associated pain can lead to numerous complications including dysphagia, odynophagia, dehydration, and weight loss. This pain may lead to feeding tube placement to maintain adequate nutrition and hydration. Standard pain management regimens in HNC patients are generally reactive and include opioids in combination with various adjunct medications . MucositGabapentin is a potent anti-inflammatory and neuromodulator agent that is frequently used in the treatment of neuropathic pain . It has Searches were conducted on Pubmed, Web of Science, and Google Scholar to identify candidate manuscripts. Search terms included [gabapentin OR Neurontin] And [head and neck OR oral OR oropharyngeal] AND cancer. Once a study was accepted for inclusion in the review, its references were also searched for additional studies that may have been omitted. Two reviewers screened each article for eligibility, and data abstraction was conducted in duplicate. Discrepancies were resolved by group consensus. In order to be considered for inclusion, a study had to be an investigation of prophylactic gabapentin during concurrent chemoradiation for head and neck cancer. To be included, the study also needed to report one of the following outcomes: pain score, opioid use, feeding tube placement, or weight loss. Articles were excluded if they were (1) not published in the previous 10 years, (2) were case studies or case series, (3) were studies in which gabapentin was not administered prophylactically during chemoradiation for head and neck cancer, or (4) were studies in which the reviewers were unable to ascertain study characteristics or outcomes. A risk of bias assessment was conducted using Cochrane’s ROBINS-I tool. Assessments were conducted in duplicate and discrepancies were resolved by consensus.p-values from each of the three studies with assessable risk of bias were combined using Fisher’s Method. In the analysis of feeding tube placement, for which traditional meta-analysis was possible, a sensitivity analysis was conducted by excluding one study which induced extreme heterogeneity into the result demonstrated by funnel plot assessment and I2. Unfortunately, the pain was not consistently reported among the identified studies. Each identified study that examined pain as an outcome utilized a different patient-reported outcome (PRO)-based pain measure tool, making synthesis impossible.A synthesis of results was conducted for outcomes for which comparable data could be identified. Critical outcome parameters consistently reported by multiple studies included reactive feeding tube placement and percent change from baseline weight. The number of feeding tubes placed was analyzed via a random effects model for the risk difference between controls and those receiving prophylactic gabapentin. The manuscripts that investigated weight loss presented point estimates, but no uniform measure of dispersion was present amongst the studies, so the The results of the search are detailed in Fig. Gabapentin’s efficacy in the treatment of neuropathic pain makes it a plausible candidate for managing pain secondary to radiation treatment, which can be the result of radiation-induced inflammation, mucositis, or direct nerve injury. The first study meeting the inclusion criteria to investigate the use of prophylactic gabapentin for pain during head and neck cancer therapy was Starmer et al. in 2014 . In thisp = 0.026). Though the post hoc nature of this analysis does not conclusively prove the assertion, it is suggestive that if Kataoka et al. had undertaken a longitudinal quantile regression of the 75th percentile, they may have identified a difference in pain scores between their treatment groups.In addition to Starmer, three randomized studies exist which investigated the impact of prophylactic gabapentin on pain during HNC treatment –12. Unfop = 0.004). In the Smith et al. manuscript, a similar boxplot was presented to that in Kataoka et al. [The second randomized trial of prophylactic gabapentin during HNC chemoradiation treatment was performed by Smith et al. The planned recruitment for this randomized trial was 150 patients with an interim analysis at 75 patients. Interim analysis at 79 patients demonstrated efficacy for both primary and secondary endpoints and the trial was halted . HNC pata et al.  showing Similar to Kataoka et al., Smith et al. suggested that gabapentin affects those at high levels of pain more profoundly than patients at lower pain levels. The differential effect of gabapentin depending on pain score level implies the effect of gabapentin will differ over the course of therapy, since pain scores tend to be low at the beginning of HNC treatment and increase over time. This suggests that statistical analyses relying on differences in mean pain scores will lack power, even beyond what is estimated based on a study’s design. This is due to the fact that comparisons of mean pain scores are pooling a heterogeneous treatment effect between patients with either no or mild pain, who receive little benefit, and patients with moderate to severe pain who receive greater benefit from gabapentin treatment.p = 0.11). This baseline imbalance would have been even more severe if not for one patient in the control group with an extremely high baseline pain score. Though this study benefits from its double-blind design, like Kataoka et al., it lacks statistical power to detect moderately sized effects of gabapentin both due to its small size and its choice of mean-based analysis. This study does provide some degree of evidence against very large effects which it had modest power to detect. It is noteworthy that this study had a large number of patients at baseline with elevated pain scores prior to therapy and a greater proportion of these patients being assigned to the gabapentin arm. It is possible that pre-HNC treatment pain is less likely to be neuropathic in nature and therefore less responsive to the gabapentin therapy.The third trial of prophylactic gabapentin for pain control during chemoradiation for HNC, published by Cook et al., randomized 58 patients to receive standard management with or without 2700 mg/day of gabapentin . As the Due to the variety of instruments selected by the investigators in these studies to quantify pain, it would be difficult to perform a meaningful meta-analysis of this data. The current state of evidence rests on the fact that there are two clinical trials demonstrating improved pain with gabapentin during HNC treatment and two trials which are inconclusive due to their profound lack of statistical power to detect moderate improvements in pain scores. Estimates using empirical data suggest that the Cook et al. study had an estimated statistical power of just 25.5% . At lessp = 0.32) [p < 0.001) [Several studies have examined whether prophylactic gabapentin during HNC chemoradiation therapy can either eliminate, reduce the dosage, or reduce the timeframe in which opioid therapy is necessary. The first study to examine this outcome was by Stramer et al. in 2014. They observed reduced doses of opioids among patients given gabapentin during HNC therapy compared to historic controls, but no statistical comparisons were performed to support these observations . In cont = 0.32) . In a co< 0.001) .Overall, the majority of studies examining the effect of gabapentin treatment on opioid use during HNC therapy have demonstrated an association between gabapentin use and a reduced need for opioids, supporting the hypothesis that gabapentin reduces opioid use in HNC patients undergoing chemoradiation.p = 0.013) and was associated with earlier feeding tube removal (p = 0.029) compared to historic controls who received standard management [p = 0.094) [p < 0.01), and demonstrated that gabapentin use was independently associated with a lower risk of PEG tube utilization (p < 0.01). The randomized trial of prophylactic gabapentin vs. standard management by Smith et al. found no difference in feeding tube placement rate between the two treatment groups  [p = 0.001) [A number of studies have examined the effect of prophylactic gabapentin on swallow function and the need to provide enteral nutrition through feeding tubes. Starmer et al. demonstrated that gabapentin use was associated with patients beginning the use of their prophylactically placed feeding tubes later into HNC therapy ( p = 0.02 comparednagement . In a re= 0.094) . In cont= 0.858) . In Herm= 0.858) . In Jun = 0.858) . In cont= 0.001) .I2 = 72.1%, Q = 16.93, p = 0.005, Fig. p = 0.962). Sensitivity analysis, which eliminated the Cook et al. study, removed the heterogeneity  and demonstrated a pooled risk difference that nearly missed statistical significance in favor of gabapentin , p = 0.054). This meta-analysis suggests that despite the findings in Cook et al., there is no evidence for an increased need for feeding tube placement among those taking prophylactic gabapentin, and the degree of heterogeneity between the Cook et al. study and others suggests some other undefined process may have influenced the data from that study.Given the risk of an invasive procedure and the emotional distress feeding tube placement can induce, the finding by Cook et al. must be seriously considered. Unlike most of the outcomes discussed in this review which are measured using varying scales, feeding tube placement is consistently reported and is therefore a candidate for meta-analysis. Data from five studies were pooled using a random-effects model see Fig. . There wp = 0.037) [p = 0.057) [p = 0.81) [p-value from the three studies  can be obtained and gives an overall p = 0.047 in favor of gabapentin reducing weight loss during chemoradiation therapy for HNC.Difficulty maintaining weight during cancer therapy can be secondary to a number of complications including depression, loss of appetite, pain, mucositis, and dysphagia. Starmer et al. found that patients on gabapentin lost less weight than controls  . Quon et= 0.057) . Cook et = 0.81) . UnfortuCurrently, few studies of prophylactic gabapentin use in HNC patients during concurrent chemotherapy and radiation have been completed. Among completed studies, few are randomized trials, most are very small, and all but two have a moderate to high risk of bias. Available evidence from these studies supports the use of prophylactic gabapentin in HNC patients to prevent treatment-induced pain, with the most likely benefit in patients who develop moderate to severe HNC treatment-related pain. Data also support the use of prophylactic gabapentin as a means of reducing opioid use during HNC treatment.One somewhat concerning finding in the Cook et al. study was that their treatment group required the placement of substantially more feeding tubes than the control group. However, the meta-analysis of current studies demonstrates that there is no evidence for increased feeding tube placement in HNC patients who receive gabapentin during treatment. Indeed, if the results of Cook et al. are excluded due to high heterogeneity between this trial and other published studies, there is a trend toward a reduced risk of feeding tube placement with gabapentin use during HNC treatment. Although the Cook finding is somewhat concerning in isolation, when viewed in the totality of the evidence, it appears to be anomalous.Furthermore, by employing Fisher’s method, we were able to identify that prophylactic gabapentin use is associated with less weight loss during HNC treatment. Therefore, overall, current data support the use of prophylactic gabapentin in HNC patients to reduce pain, opioid use, and weight loss during treatment. However, caution should be used when applying these findings to patient care due to the small sizes of most currently available studies for meta-analysis. A large, multicenter randomized trial of prophylactic gabapentin use in HNC patients during concurrent chemoradiation therapy, which is adequately powered to detect clinically meaningful changes in pain scores, duration of pain, opioid use, and weight loss, is needed.


The EORTC-PAN26 revealed significant improvements in symptom scales for pancreatic pain, bloating, digestive symptoms, taste, indigestion, weight loss, body image, and future worries. The comprehensive surveys in such a large cohort expands the QoL criterion in CP patients and indicates significant improvement in QoL post-TPIAT, further validating TPIAT as a treatment option for refractory CP.Total pancreatectomy with islet autotransplantation (TPIAT) is the treatment of choice to preserve pancreatic endocrine function, alleviate pain, and improve quality of life (QoL) when other strategies are ineffective for chronic pancreatitis (CP) patients. This study utilized pancreatic disease-specific surveys developed by the European Organisation for Research and Treatment of Cancer (EORTC) to conduct a comprehensive, single-center examination of a large cohort of patients to gain understanding of QoL post-TPIAT. Two validated QoL surveys of the EORTC—QLQ-C30 and QLQ-PAN26—were administered in a prospective cohort of CP patients during pre-and post-operative scheduled visits. A total of 116 patients responded to the preoperative survey and were included in this study. The global health scale of QLQ-C30 was significantly improved after TPIAT when compared to baseline with delta scores of 24.26, 20.54, and 26.7 at 1, 2, and 3 years post-TPIAT (  Chronic pancreatitis (CP) is an irreversible inflammatory and fibrotic disease of the pancreas leading to varying degrees of exocrine and endocrine dysfunction. In severe cases, CP can lead to permanent loss of exocrine and endocrine function . FurtherTotal pancreatectomy followed by islet autotransplantation (TPIAT) is a preferred technique to preserve endocrine function and alleviate pain when other strategies are ineffective . The firDuring the last 30 years, numerous collaborations between various North American centers, including ours, have developed the TPIAT program and documented metabolic outcomes. Many studies have reported achieving the main objective, improvement of QoL, through the SF-36 questionnaire, which evaluates health-related QoL –15. In tThis prospective observational study assessed the patient-oriented outcomes of QoL in CP patients who underwent TPIAT at Baylor University Medical Center. All patients were evaluated by a multidisciplinary team and had multiple indications for TPIAT. Patient eligibility for TPIAT includes intractable pain despite previous medical treatment, detectable endogenous insulin secretion capacity evident by serum C-peptide, and the capacity to consent to the treatment. Pregnant women were not eligible for the surgical procedure. We obtained consent for the intervention and study enrollment from all participants after they had been adequately informed of the risks. This study was conducted after approval of the institutional review board of Baylor Scott and White Research Institute (IRB#009-271).Patients were asked to answer two QoL surveys of the EORTC—QLQ-C30 and QLQ-PAN26—before TPIAT and completed the survey during follow-up or by mail at 1, 2, and 3 years after transplantation. The EORTC QLQ-C30 and QLQ-PAN26 instruments were selected because they have been validated and used in trials to evaluate other pancreatic procedures –19. The The patients completed these surveys during their regularly scheduled follow-up appointments in electronic or hard copy format. We confirmed the validity of the electronic format. Surveys were completed via telephone or mail for 2 and 3 years post-TPIAT if the patients were unable to attend their clinic visits. Subjects with reduced ability to understand the questionnaires were excluded from the study. Details on the patient participation in these surveys is shown in no pain) to 10 (most severe pain). The daily dose of opioids was converted into morphine milligram equivalents (MME).All clinical data were recorded for each patient in a prospectively maintained database. Preoperative and postoperative clinical data in this study included levels of hemoglobin A1c, serum C-peptide, exogenous insulin requirement, pain score based on visual analog scale (VAS), and morphine equivalent dose. The VAS for pain ranged from 0  or Collagenase NB with neutral proteases  was infused into the pancreatic duct for digestion. Islets were isolated by the modified Ricordi method, which has been previously described , 25. WheData were presented as numbers and percentages for binary and categorical variables or as median and interquartile range (IQR) or as mean with standard deviations (SD) for continuous variables. The primary outcomes in this study were independent trends over time of the various scales and items of the EORTC QLQ-C30 and QLQ-PAN26. The surveys were administered at four time points: baseline, 1, 2, and 3 years. Raw scores measured at baseline and at years 1 and 2 were analyzed in longitudinal repeated measures analyses.Generalized least square models without random effects, fitted by restricted maximum likelihood (REML) were used to examine if there was a differential effect across time (baseline to follow-up) in score measurements. The analysis focused on longitudinal single group analyses, where a single homogeneous population was followed over time. To account for the correlation in repeated measurements on the same subject, using various correlation structures with constant variance were considered. The correlation structure was selected based on AIC .Due to the small sample size of respondents, scores measured at year 3 were not considered in longitudinal analyses. Additionally, a generalized least square model without random effects with restricted maximum likelihood (REML) was used instead of ordinary maximum likelihood estimation (MLE) , 27.The constant variance assumption was checked using typical residual plots. The univariate normality assumption was checked using typical Q-Q plots on residuals. For checking the correlation pattern, variograms based on estimating correlations of all possible pairs of residuals at different time points were used –30.Delta, defined as a difference over time from baseline, was assessed to estimate clinical significance in the EORTC questionnaires, according to recommendations by Osoba, where a difference in health-related QoL score of 10 points or more is regarded as clinically significant , 32. The30.4–49.0) years, 35% were male, and the median body mass index was 26.3 (21.5–29.8) kg/m2. To better understand our patient cohort disease progression, we looked at prior pancreatic interventions. Prior endoscopic stent management failed for 82 patients (71%). 18 patients (16%) had previous pancreatic surgery before TPIAT. Within this cohort, the median duration of diagnosed pancreatitis was 5.0  years. Post-TPIAT data revealed a median transplanted islet equivalent dose was 5.1 (2.9–7.2) × 103 IEQ/kg patient body weight. The median follow-up was 78.8 months (range 9.4–125.5 months) and at 1, 2, and 3 year follow-up, 2, 6, and 9 patients had died, respectively.Between 31 March 2011, and 1 April 2021, 178 consecutive patients underwent TPIAT at our center. Among that group, 116 patients agreed to answer the two QoL surveys before transplant (65% participation rate) and were included in this study. The demographic and clinical characteristics of the study participants are presented in p < 0.001) (137) mg before TPIAT and 44 (±93), 42 (±68), and 35 (±65) mg at years 1, 2, and 3, respectively. Pain scores evaluated with VAS also decreased after TPIAT: 5.7 (±2.1) at baseline, 2.2 (±2.9) at year 1, 2.1 (±2.8) at year 2, and 1.9 (±2.6) at year 3.12.1% of patients had diabetes before TPIAT, and 78%, 73%, and 71% were insulin-dependent at 1, 2, and 3 years after TPIAT, respectively. Glycemic outcomes pre- and post-TPIAT are outlined in < 0.001) . There wInitially, 116 patients responded to the preoperative survey and respondents decreased at yearly follow-up. 54 patients completed the survey at year 1, 31 patients at year 2, and 13 patients at year 3. Radar charts visually display each domain of the EORTC QLQ-C30 functional scales and symptom scales of EORTC QLQ-C30 and EORTC QLQ-PAN26 . We dispp < 0.001, <0.001, <0.001, <0.001, = 0.007, and <0.001, respectively). Delta mean scores outlined in EORTC QLQ-30 survey functional scores increase with improved QoL after 1, 2, and 3 years . In our p < 0.001, <0.001, <0.001, <0.001, = 0.001, and <0.001, respectively). Moreover, the corresponding delta scores showed changes of ≥20 points, indicating that the reduction in these symptoms was also clinically meaningful . The corresponding delta scores indicated clinically meaningful reductions in symptoms in all domains except flatulence, hepatic symptoms, and trouble with side effects .EORTC QLQ-PAN26 surveyed symptom scales pre- and post- TPIAT in which lower scores indicate better QoL . Again,  effects . Functiop = 0.036) with a median of 27.7, (IQR 23.6–32.0), compared to participants with follow-up measures, who had a median of 25.2 (IQR: 20.7–28.9).To safeguard against potential bias in study findings, an analysis was conducted to examine whether study patients who completed at least a baseline questionnaire and excluded patients that never participated in the study, displayed distinct characteristics worth exploring . MoreoveIn North America, multiple centers perform TPIAT and have demonstrated an improvement in health-related QoL in patients with CP and recurrent acute pancreatitis. The objective means used to ascertain an improvement in QoL were the SF-36 and SF-12 questionnaires –15, 33. Body Pain scale in the SF-36. We utilized surveys with more specific measures to more accurately present statistical and clinical evidence of persistent pain reduction for up to 3 years. Pancreatic pain evaluated with the QLQ-PAN26 revealed clinical and statistical improvement with a delta score of 27.90. It is noteworthy that 71% of patients had a previous pancreatic duct stent inserted and 16% had a previous pancreas operation with neither resolving pain maintenance. The survey showed an average percent reduction in morphine dose of approximately 37%, 35%, and 30% at 1, 2, and 3 years, respectively, with mean daily MME decreasing from 118 (±137) mg at baseline to 35 (±65) mg at 3 years. Our results are consistent with the international consensus guideline, where opioid doses were reduced by 71%, 69%, and 67% at 1, 2, and 5 years [Management of pain is a major objective of TPIAT and thus another critical metric for success. Nonetheless, pancreatic pain can be misinterpreted or reported generically through the use of the VAS score and the In addition to the pain reduction of TPIAT, we observed a significant reduction of other symptoms of CP including nausea, vomiting, weight loss, and digestive disturbances. Our study found no statistical variation in diarrhea symptoms, but there was an overall decreasing trend. This is similar to Crosby et al. report in which more than 60% of patients still reported diarrhea after TPIAT, adding that enzyme non-adherence was not a major contributor . Our surA limitation of this study was reduced sample size in follow-up years as patient participation waned. We have observed reports of similar instances in other centers , 40, 41.In conclusion, we found that pancreatic disease-specific surveys allow us to gain a deeper understanding of patient QoL post-TPIAT for CP. We observed significant improvements in QoL after TPIAT, and expanded our knowledge in the functional and symptom scales for CP patients up to 3 years post-transplant. Our study strongly supports the benefits of TPIAT as a treatment option for refractory CP.


The COVID-19 pandemic has brought about significant changes in the medical field, yet the use of botulinum toxin type A has remained uninterrupted. Plastic surgeons must carefully consider the timing of administering botulinum toxin type A to patients who have recovered from COVID-19.A questionnaire survey was conducted among patients who had contracted and recovered from SARS-CoV-2 within a month. The survey aimed to investigate various indicators in patients who had received botulinum toxin A injections at the same site before and after their infection, including pain scores and allergic reactions and the occurrence of complications.The pain scores of patients who contracted SARS-CoV-2 infection between 14-21 days post-infection exhibited significant variation from previous injections. However, patients who contracted the infection between 22-28 days post-infection did not exhibit significant variation from previous injections. Furthermore, the incidence of allergic reactions and complications following botulinum toxin injection within one month after contracting the infection did not significantly differ from that observed prior to infection.Administering botulinum toxin type A three weeks after COVID-19 recovery is a justifiable and comparatively secure approach. The Coronavirus Disease 2019 (COVID-19) pandemic has triggered an unprecedented transformation across all domains of medicine, significantly impacting patient management, and necessitating the modification of our clinical and surgical practices. Therefore, it is imperative for plastic surgeons to carefully contemplate the scheduling of elective cosmetic procedures for patients convalescing from COVID-19.Since its inaugural authorization in 1989, Botulinum toxin type A has emerged as one of the most extensively employed injectables for both cosmetic and therapeutic applications, witnessing an escalating demand globally. Despite the COVID-19 pandemic, the utilization of Botulinum toxin type A remained undeterred. Astonishingly, in the statistics of patients receiving minimally invasive cosmetic procedures in the United States from 2021 to 2022, botulinum toxin type A treatment ranks first .Current literature indicates that COVID-19 frequently manifests with symptoms such as myalgia, pain, and pervasive hyperalgesia . Severe In December 2022, a sudden and large-scale SARS-CoV-2 infection occurred among the populace in China. As the virus exhibited a diminished potency, the majority experienced mild symptoms and recuperated within a fortnight, subsequently seeking botulinum toxin type A injections per their routine. Consequently, the impact of COVID-19 on the pain and hypersensitivity reaction following botulinum toxin injection warrants comprehensive exploration. The objective of our research is to determine whether significant disparities exist in the manifestation of pain and other hypersensitive reactions in patients subjected to periocular injections following a SARS-CoV-2 infection.A questionnaire-based survey was conducted among patients from December 2022 to February 2023 at the Plastic Surgery Hospital of the Chinese Academy of Medical Sciences and ADD+ Medical Esthetic Clinic in China. Inclusion criteria encompassed: (1) prior receipt of Botulinum toxin A  injections at least once by the same practitioner at the same institution; (2) documented SARS-CoV-2 infection and recovery within a month, with recovery criteria entailing the absence of fever, dyspnea, fatigue, cough, headache, sore throat, body aches, chills, anosmia, ageusia ; and (3)The survey was administered by four resident physicians and two graduate students, all of whom had undergone standard training prior to the survey to ensure comprehension of survey methods, questionnaire distribution techniques, data acquisition protocols, and guidelines for data cleansing and organization. Each physician was assisted by 2-3 investigators during the visit. Potential participants were informed about the survey’s purpose, and the paper-based questionnaire was provided after securing informed consent One investigator clarified the survey items to the participants. Upon completion of the questionnaire, two investigators simultaneously collected the data. During the three-month study period, a total of 150 questionnaires were disseminated, and 146 questionnaires were retrieved, with four patients failing to complete the questionnaire. The survey response rate was 97.3%. The questionnaire comprised two parts:(1) patient demographics such as name, age, gender, timeline of COVID-19 infection, previous and current botulinum toxin injection sites. The treatment sites investigated included lateral canthal lines, glabellar frown lines, nasal dorsal lines, and forehead wrinkles. Each treated site was considered as a standalone treatment unit for statistical evaluation. Treatment units that had been addressed in both previous and current sessions were included in the analysis.(2) Patients were asked to score the pain level  for each treatment unit during both past and present injections. Any allergic reaction or complication occurring during the present or previous injection for each treatment unit was also documented. The allergic reaction survey included inquiries about localized swelling, itching, red bumps, and systemic breathing difficulties. The complication survey queried the presence of ptosis, strabismus, diplopia, eyelid paralysis, and brow ptosis.Continuous variables were compared by Student’s t-test for variables with normal distribution, or the Mann–Whitney U test for variables without normal distribution; categorical variables were compared by Pearson’s Chi-square test or Fisher’s exact test. Two-sided p-values <0.05 were considered statistically significant. Analyses were performed using the software packages SPSS v.19.0 , Stata v.12.0  and R v.3.2.2 .The study encompassed a total of 146 subjects, with an average age of 41.0 ± 9.7 years, which include 12 males (12/146) and 134 females (134/146) Table 1.The analysis divided the time since SARS-CoV-2 infection into two periods: 14-21 days and 22-28 days.(1) In the 14–21-day window: For the lateral canthal lines unit, the pain score was 3.4 ± 1.5 on average for previous injections, and 3.4 ± 1.7 for the current treatment, indicating no significant difference. For the glabellar frown lines unit, the average previous pain score was 3.6 ± 1.2, and 4.4 ± 1.5 for the current treatment, showing a significant difference. For the forehead wrinkles unit, the average previous pain score was 3.6 ± 1.5, and 5.2 ± 1.8 for the current treatment, displaying a significant difference. For the nasal wrinkle unit, the average previous pain score was 3.2 ± 1.4, and 5.2 ± 1.4 for the current treatment, also revealing a significant difference Figure 1(2) In the 22–28-day window: For the lateral canthal lines unit, the average previous pain score was 4.3 ± 1.6, and 4.1 ± 1.6 for the current treatment, showing no significant difference. For the glabellar frown lines unit, the average previous pain score was 3.7 ± 1.6, and 4.0 ± 1.7 for the current treatment, again demonstrating no significant difference. For the forehead wrinkles unit, the average previous pain score was 3.8 ± 1.6, and 3.7 ± 1.4 for the current treatment, indicating no significant difference. For the nasal wrinkle unit, the average previous pain score was 3.9 ± 1.3, and 3.8 ± 1.2 for the current treatment, also indicating no significant difference Figure 2These findings suggest that, while there were significant differences in pain scores for the glabellar frown lines, forehead wrinkles and nasal dorsal lines units between 14-21 days after infection, no significant differences were observed 22-28 days after infection across all treatment units Table 3.Botulinum toxin, a protein and neurotoxin produced by the bacterium Clostridium botulinum , inhibitAlthough allergic reactions to Botulinum toxin are documented in literature, they are exceedingly rare . AllergiIn our study, one patient developed urticaria-like plaques around the injection site five minutes post-injection on the lateral canthal lines. The symptoms, however, subsided on their own within three hours without any intervention. Another patient developed right upper eyelid edema and periocular itch eight hours post-injection on the lateral canthal lines, which was relieved within three days using Loratadine tablets. The treatments for both patients were successful in achieving wrinkle reduction, with patients expressing satisfaction with the outcome. Our analysis revealed no significant difference in the incidence of complications between botulinum toxin injections administered before and after a SARS-CoV-2 infection.Upon exposure to a virus or viral antigen, both innate and adaptive immune cells collaborate to mount an antiviral response . Upon exIn our research, we observed significant differences in the analysis of pre- and post-infection pain scores across all treatment units for patients 14-21 days post-SARS-CoV-2 infection. However, no such differences were seen in patients 22-28 days post-infection. For the 14-21 day group, notable differences between the two pain scores were identified in the treatment units for glabellar frown lines, forehead wrinkles, and nasal wrinkles. A case report highlights a 55-year-old female patient who experienced severe hyperalgesia and pain during botulinum toxin injection one-week post-recovery from a COVID-19 infection. Her pain severity, rated on a 10-point scale, was 10 during this session compared to a score of 3 during her last session, performed four months prior . The aveWith the rising number of SARS-CoV-2 infections, we are witnessing an increasing number of reported adverse events associated with botulinum toxin A (BTA) treatments. This correlation underscores the importance of understanding the potential complications and long-term safety of these treatments . AlthougLimitations of this study include: a sudden surge of SARS-CoV-2 infections in December, which limited the number of individuals who met the study criteria. Most patients in the study resided in Beijing, and the majority of the coronavirus subtypes were BF7. The botulinum toxin brand used in this study was BTA , leaving no opportunity to study other brands. While the injections were performed by the same physician who had administered BTA several times before, individual injection methods varied due to differences in wrinkles presented by each patient, introducing a variable that could not be completely controlled . AdditioThis study found a significant difference in pain scores between patients 14-21 days post-SARS-CoV-2 infection and their prior injection experiences. However, for patients 22-28 days post-infection, the pain scores were not significantly different from prior instances. The incidence of allergic reactions and complications within one-month post-infection did not significantly differ from pre-infection rates following botulinum toxin injections. We suggest that administering botulinum toxin type A injections three weeks post-recovery from COVID-19 is relatively safe and reasonable. This study provides an essential reference for plastic surgeons when determining the optimal timing for botulinum toxin type A injections in their patients.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by the Ethics Committee of the Plastic Surgery Hospital of the Chinese Academy of Medical Sciences. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.XL, YT: subjects enrollment, statistical analysis, and draft manuscript. CJ, HS: conceptualization, methodology, statistical analysis, writing, and editing. MD, ML: statistical analysis. All authors contributed to the article and approved the submitted version.


Necrotizing enterocolitis (NEC) is a highly painful intestinal complication in preterm infants that requires adequate pain management to prevent short- and long-term effects of neonatal pain. There is a lack of international guidelines for pain management in NEC patients. Therefore, this study aims to describe current pain management for NEC patients in European neonatal intensive care units (NICUs).An online survey was designed and conducted to assess current practices in pain management for NEC patients in European NICUs. The survey was distributed via neonatal societies, digital platforms, and professional contacts.Out of the 259 responding unique European NICUs from 36 countries, 61% had a standard protocol for analgesic therapy, 73% assessed pain during NEC, and 92% treated NEC patients with intravenous analgosedatives. There was strong heterogeneity in the used pain scales and initial analgesic therapy, which mainly included acetaminophen (70%), fentanyl (56%), and/or morphine (49%). A third of NICU representatives considered their pain assessment adequate, and half considered their analgesic therapy adequate for NEC patients.Various pain scales and analgesics are used to treat NEC patients in European NICUs. Our results provide the first step towards an international guideline to improve pain management for NEC patients.This study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units.Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries.A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU.The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC. In the Netherlands, acetaminophen and opioids such as morphine and fentanyl are most commonly used for treating pain in patients with NEC.27 A retrospective study has shown that despite analgesic therapy during NEC, most patients still experienced episodes of pain and a quarter of patients experienced persisting periods of pain, with a median duration of 7 h.27 This observation suggests that current pain management in patients with NEC may be inadequate. Since pain management is based on pain assessment, (non-)pharmacological therapy and subsequent re-assessment, inadequate pain management reflects deficiencies in either one or a combination of these steps.Optimal pain treatment in patients with NEC is not only needed to protect against the burden of pain, but also to promote recovery and outcome. Exposure to pain during the neonatal period has been associated with negative short-term effects, such as increased circulatory and metabolic complications.To our knowledge, international guidelines for pain management for patients with NEC have not been developed yet. Therefore, pain management practices for patients with NEC among European neonatal intensive care units (NICUs) may vary considerably. Insight into pain management practices across Europe and possible consensus therein may contribute to identifying the optimal pain management strategy for patients with NEC and may thereby improve their outcomes. Therefore, this study aims to describe current pain management practices for patients with NEC in European NICUs, including pain assessment and (non-)pharmacological therapy, with the ultimate goal to develop European consensus guidelines for pain management in patients with NEC.A cross-sectional study was conducted to assess pain management practices  across European NICUs via a web-based survey. The head of the NICU or another senior neonatologist was requested to complete the survey. This study aimed to include one representative per European NICU, although there were no restrictions, because the survey was open-access. This study was deemed exempt from ethical approval, due to the voluntary and anonymous nature of the physicians’ responses. Participants were informed that submitting the survey meant agreeing to participate.The survey was developed in LimeSurvey version 2.06 . The included items were generated based on a literature review and the expert opinion of the authors. The validity of the content of the survey was ensured in a two-step process. Firstly, the survey was pre-tested by NICU clinicians working at the Erasmus MC—Sophia Children’s Hospital and subsequently revised based on their feedback. Secondly, an international group of eight neonatologists and a nurse specialist, all having expertise in pain management and/or survey research, evaluated the content validity of the survey by assessing its relevance, comprehensiveness, and comprehensibility. Based on their feedback, six questions were added, one answer option was added, and one question was rephrased.The final version of the survey included 39 questions about NICU demographics, protocols for analgesic therapy, pain assessment, non-pharmacological interventions, use of intravenous analgesics, dosing regimen, and the respondent’s expert opinion on current pain management in his/her NICU , 99NICU, LinkedIn, and professional contacts. The survey was open from November 25, 2021, until February 3, 2022. In order to maximize the response rate, reminders were sent to contacts in countries with a low response rate.All submitted responses were checked for duplicates from the same center. Only responses from unique European centers were included in the primary analysis. In case of more than one response per NICU, only the first response was included in the primary analysis. Non-European responses and duplicate responses were included in secondary analyses.Descriptive statistics have been presented as median (interquartile range) or number (percentage), depending on the type of data. Analyses were conducted with RStudio version 2021.09.2 and R version 4.1.2 . In order to prevent distortion of the results by typographical errors, respondents whose dose response deviated at least fourfold from the median dose of that analgesic were contacted to verify their response. Response percentages per country were calculated by dividing the number of responses from a country by the total number of NICUs in that country, as indicated by professional contacts or online sources.29 Within-NICU agreement was summarized by calculating the median (IQR) of the ICC’s and Fleiss’ Kappa statistics per NICU.To evaluate whether the response of one neonatologist is a reliable measure of pain management practices in the NICU, we assessed the consistency between the numerical and multiple choice responses of duplicate responses from NICUs. Within-NICU agreement was evaluated by calculating the Intraclass Correlation Coefficient (ICC) for numerical questions, based on an average measures, absolute-agreement, two-way random-effects model, and Fleiss’ Kappa statistic for multiple choice questions.30 Responses were coded with NVivo version 1.6.2 .Responses to the final open question, regarding the respondent’s suggestions for improvement of pain management for patients with NEC, were analyzed with thematic content analysis, using the approach described by Braun and Clarke.A total number of 306 responses were submitted, of which 288 originated from European NICUs and 18 from non-European NICUs. Figure NICU representatives from 36 out of 44 European countries 82%) responded to the survey. Figure % respondOut of the 259 unique European NICUs, 158 NICUs (61%) had a written protocol for analgesic therapy in neonates. In 64% of these NICUs, this protocol included clear definitions for starting, stopping, and adjusting analgesics. Only 7% of NICUs with a protocol for analgesic therapy  had a specific NEC pain management protocol. The level of adherence to the protocol, as rated by the respondent, was very high in 25% of NICUs, high in 43%, intermediate in 27%, and low in 5%.Seventy-three percent of NICUs assessed pain levels in patients with NEC. Figure Non-pharmacological interventions, sucrose, intravenous analgesics, and epidural analgesics were used in 58%, 39%, 92%, and 2% of NICUs treating patients with NEC, respectively.In addition to sucrose, the following non-pharmacological interventions were most commonly reported: containment  in 35% of NICUs, touch  in 18%, non-nutritive sucking in 18%, positioning in 9%, and parental involvement in 5%. Supplementary Material Out of the 225 NICUs using intravenous analgesics for patients with NEC, 53 NICUs (24%) initiated analgesic therapy pre-emptively. The most common moments to initiate pre-emptive analgesic therapy were after diagnosis of NEC stage ≥II (70%) or surgery (45%). In 44% of NICUs, analgesic therapy was different for ventilated versus spontaneously breathing patients with NEC. NICU representatives mostly commented that in those who breath spontaneously, lower opioid doses are used or that opioids are (preferably) avoided. In 11% of NICUs using intravenous analgesics for patients with NEC, certain analgosedatives were classified as contra-indicated, such as midazolam (3.1%), morphine (2.2%), ibuprofen (1.8%), propofol (1.3%), and fentanyl (1.3%).The most commonly used analgosedatives for initial analgesic therapy were acetaminophen , fentanyl 56%), morphine 49%), midazolam 25%), sufentanil (11%), and ketamine (6.7%). Acetaminophen, fentanyl, and/or morphine were often  used in combinations of two or three of these analgesics. The use of analgosedatives varied across countries, with some countries mainly using fentanyl and others mainly using acetaminophen or morphine  intensified analgesic therapy by increasing the dose of the current analgosedatives, 120 NICUs (53%) by adding another analgosedative, and 51 NICUs (23%) by switching to other analgosedatives. NICUs that chose to increase the dose most commonly increased the dose of fentanyl (49%) or morphine (42%). The most commonly added analgosedatives were midazolam (13%), ketamine (11%), dexmedetomidine 7.6%), fentanyl (7.1%), and acetaminophen (7.1%). Figure %, fentanAnother total of 18 neonatologists working in NICUs in 14 non-European countries completed the survey. Supplementary Material 29 The median Fleiss’ Kappa statistic was 0.690 (IQR 0.604-0.742), indicating fair to good agreement in the multiple choice answers.31There were 23 cases in which two neonatologists from the same NICU submitted the survey and three cases in which three neonatologists from the same NICU submitted the survey, resulting in a total of 29 duplicate  responses. In general, agreement between responses from different respondents working in the same NICU was good to excellent, with a median Intraclass Correlation Coefficient of 0.899 (IQR 0.865–0.974) for the numerical answers.Approximately a third of NICU representatives considered their locally used pain measurement instrument adequate in patients with NEC. Half of the NICU representatives considered their analgesic therapy regimen adequate for patients with NEC.n = 159), 62 NICU representatives (39%) identified pain assessment as a target to improve pain management, with 40 of them mentioning that better tools for pain assessment are needed  and 12 mentioning that pain should be assessed more frequently. (2) Pain protocols: Forty-nine NICU representatives (31%) expressed a need for more standardization in pain management for patients with NEC by establishing protocols/guidelines. Eleven of them remarked that these protocols should be specific for NEC, and four remarked that they should be evidence-based. (3) Analgesic therapy: According to 43 NICU representatives (27%), better analgesic therapy was needed to improve pain management for patients with NEC. This most commonly entailed using another analgesic (n = 25), administering pre-emptive analgesic therapy (n = 6), or “more aggressive” analgesic therapy (n = 5). Out of those preferring to use another analgesic, a few mentioned a specific agent, but the majority mentioned that new drugs are needed which are more effective and/or have fewer adverse effects. Additional common themes included: need for more research, education of staff, awareness, non-pharmacological interventions, parental involvement, and teamwork.Three major themes were identified in NICU representatives’ responses to the open question on suggestions to improve pain management for patients with NEC. (1) Pain assessment: Of those with suggestions  or adding another analgosedative . The maximum used doses of analgosedatives varied considerably between NICUs, suggesting that currently at least some NEC patients may receive excessive or insufficient dosages of analgosedatives.33 Regarding pain assessment, this EUROPAIN study found that half of the included NICUs ever performed assessments of prolonged pain.33 Furthermore, the EUROPAIN study found that the EDIN scale (57%) was most commonly used, followed by the COMFORTneo scale (20%) and the N-PASS (13%). Our study found a larger proportion of NICUs assessing pain in NEC patients (73%), although unlike the EUROPAIN study, we did not specify that a pain measurement instrument designed for prolonged pain assessment had to be used. Two of the most used instruments reported in our study, the NIPS and the PIPP, have been validated for assessing procedural pain, not prolonged pain.36 The COMFORTneo, EDIN and N-PASS have been validated for assessing prolonged pain in infants, although not specifically for use in patients with NEC.39 Behavioral pain scales may be less valid in patients with NEC, since these patients are known to exhibit few movements and diminished facial expression due to their clinical condition.37 Instruments incorporating physiological parameters, such as NIPE, might provide a solution. However, studies evaluating the validity of NIPE are scarce and report contradictory results.40To our knowledge, pain management for patients with NEC in different NICUs has not been studied before in Europe nor in other parts of the world. A previous study which assessed overall pain management practices  in Europe focused on the general NICU population, not on NEC patients specifically.32 Our study shows that these medications are also commonly used in patients with NEC. In addition to these medications, we found that sufentanil, ketamine, and dexmedetomidine are frequently used, especially for intensified therapy. This confirms the observation by Stark et al that dexmedetomidine is increasingly being used in neonatal care.41 Our study extends the EUROPAIN study by not only assessing choice of analgosedatives, but also strategies for intensified analgesic therapy and dose ranges used. We found that the maximum used doses of morphine, fentanyl, and midazolam varied considerably. In over a quarter of NICUs using these analgesics, the used maximum maintenance doses of morphine and fentanyl exceeded the dosing ranges recommended in a consensus statement for neonatal pain management.42 The reported midazolam maintenance doses varied over a thousand fold range, likely reflecting a mix-up between microgram and milligram in the outlier responses.Regarding analgesic therapy, the EUROPAIN study found that acetaminophen, morphine, fentanyl, and midazolam were the most used analgosedatives.A major strength of our study is the coverage of over 250 NICUs from 36 countries, resulting in an extensive overview of pain management for patients with NEC across Europe. However, the response percentage varied significantly between countries, which may partly be explained by the high number of smaller NICUs in some countries. It cannot be ruled out that NICUs with an interest in pain management were more likely to respond to the survey, thereby causing selection bias. For feasibility reasons, only one neonatologist per NICU was requested to complete the survey. Targeting the head of the NICU or another senior neonatologist may have resulted in exaggerated satisfaction with current practices in comparison with junior neonatologists and nurses. Moreover, the response of one neonatologist may not have been representative for practices in the NICU, since practices and interpretation of guidelines may differ among neonatologists working in the same NICU. However, evaluation of the consistency between responses of different neonatologists working in the same NICU showed good agreement within NICUs.27 Inadequate analgesia may hamper the recovery from NEC, and exposure to pain during the neonatal period is associated with negative short-term and long-term effects, including altered brain development.43 Currently, there seems to be consensus on the necessity of performing pain assessments and administering analgesic therapy, but limited consensus on choice of pain measurement instruments, analgesics, and dosages. The large variety in pain management practices suggests that currently some patients with NEC may receive excessive or insufficient treatment, leaving them vulnerable to negative consequences of exposure to pain or excessive use of opioids or other potentially toxic drugs. In order to establish good pain management guidelines for patients with NEC, future studies are needed on effectiveness and safety of different analgesic therapy regimens. Meanwhile, a debate among neonatal pain experts is necessary to reach a consensus on pain management recommendations, including pain assessment tools and analgesic algorithms, using for example the Delphi method.44The results of this study provide a first step towards improvement of pain management for patients with NEC, which is crucial since (severe) pain is common in preterm infants with NEC.There is large variability in the use of pain protocols, pain scales and analgesic therapies for preterm infants with NEC across European NICUs. Data from the current study may provide the basis to develop consensus pain management guidelines and highlight opportunities to improve pain management for preterm infants with NEC.Supplementary Material 1


This study indicates that MMRPs in primary care improved pain and physical and emotional health and reduced sick leave, which was maintained at the 1-year follow-up.Chronic pain is a major public health issue. Mounting evidence suggests that interdisciplinary multimodal pain rehabilitation programs (IMMRPs) performed in specialist pain care are an effective treatment for patients with chronic pain, but the effects of such treatment if performed in primary care settings have been less studied. The aims of this pragmatic study were to (1) describe characteristics of patients participating in IMMRPs in primary care; (2) examine whether IMMRPs in primary care improve pain, disability, quality of life, and sick leave 1-year post discharge in patients with chronic pain; and (3) investigate if outcomes differ between women and men. Data from 744  patients with non-malignant chronic pain included in the Swedish Quality Registry for Pain Rehabilitation Primary Care were used to describe patient characteristics and changes in health and sick leave. At 1-year follow-up, the patients had improved significantly ( Chronic pain >3 months)  is a maj months  Chronic pain has an impact on and interacts with various social, physical, emotional, and psychological factors  such as Although chronic pain has a significant impact on both individuals and society, Breivik et al. (2006) found that up to 50% of persons with chronic pain had not received adequate treatment for their pain [Since chronic pain is a complex condition, a biopsychosocial (BPS) framework is used in interdisciplinary multimodal pain rehabilitation programs (IMMRPs), which take into account biological, psychological, and social/contextual factors ,5. IMMRPResearch mostly based on studies in specialist care has shown that IMMR is an effective and evidence-based intervention for persons with chronic pain, reducing sick leave and improving return to work ,11,12,13IMMR is a well-established method in specialist care in Sweden for patients with severe complex chronic pain. Since most patients with chronic pain are seen in primary care and because up to 40% of primary care visits are made up of patients with chronic pain , the SweChronic pain is more frequently reported among women than men , but theThus, there is a gap in knowledge regarding the long-term results of IMMR in primary care on a national level. The aims of this study were to (a) describe characteristics of patients with chronic pain participating in IMMRPs in primary care; (b) to examine if patients participating in IMMRPs improve regarding pain aspects, emotional and physical functioning, coping, health-related quality of life, and sick leave at 1-year follow-up; and (c) investigate whether outcomes for IMMRPs differ between women and men. This was a registry study with a 1-year follow-up based on data obtained from the SQRP-pc . SQRP-pcThis study included SQRP-pc data from patients ≥18 years old with chronic (≥3 months), nonmalignant pain who were referred to primary healthcare centers from 2016 to the spring of 2021 and answered the baseline questionnaire. Inclusion criteria for IMMRP were (i) age between 18–65 years; (ii) disabling, nonmalignant chronic pain (on sick leave or experiencing major interference in daily life due to chronic pain); (iii) no further medical investigations needed; and (iv) written consent to participate in and attend IMMRP. Exclusion criteria for IMMRP were severe psychiatric comorbidity, abuse of alcohol and/or drugs, diseases that did not allow physical exercise, and specific pain conditions associated with red flags. These criteria follow national guidelines for IMMRP in primary care, which also require that pharmacological treatment and non-pharmacological unimodal rehabilitation, e.g., physiotherapy, have been tested without satisfactory effect .The IMMRPs were based on a bio-psycho-social approach with interdisciplinary teamwork and included goalsetting together with the patient and interventions such as physical exercise, relaxation, training in coping strategies based on cognitive behavioral therapy (CBT), and education in pain management. The IMMRPs lasted for a limited time  with several meetings a week and were carried out in groups, individually, or as a mixture of both group and individual sessions. The composition of the team varied depending on the health center. A team could consist of a general practitioner, a sociologist, a psychologist, a physiotherapist, an occupational therapist, a nurse, and a dietitian in different combinations and to different degrees of involvement. Both the content of the IMMRP and the professional competencies were according to the national guidelines for IMMRP in primary care .The variables and instruments used in this study are mandatory for the primary care rehabilitation centers registering their data with the SQRP-pc. They cover important outcome domains for the evaluation of chronic pain, as recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)  and the The following background characteristics were extracted from the SQRP-pv: age (years); gender (man or woman); education level ; and country of birth . Data on household ; employment status ; and income support (yes/no) were also extracted. Expectations of IMMR were reported on a 4-point scale . Number of visits to a doctor during the last year was reported at 4 levels .Current pain intensity and pain intensity over the last 7 days were marked on an 11-point numeric pain rating scale (NPRS), with 0 representing “no pain” and 10 “worst pain imaginable”. NPRS 0–5 was defined as mild pain, 6–7 as moderate pain, and 8–10 as severe pain . Pain van = 18) and on the right side of the body (n = 18) for a total of 36 locations. These pain sites were (1) head/face, (2) neck, (3) shoulder, (4) upper arm, (5) elbow, (6) forearm, (7) hand, (8) anterior aspect of chest, (9) lateral aspect of chest, (10) belly, (11) sexual organs, (12) upper back, (13) lower back, (14) hip/gluteal area, (15) thigh, (16) knee, (17) shank, and (18) foot. The total score ranges between 1–36.The number of pain sites was registered using 36 pre-defined anatomical areas. The patient reported the number of sites with pain on the left side of the body (Duration of pain was reported as years with pain (number of days since pain started and the number of days with persistent/chronic pain).The hospital anxiety and depression scale (HADS) contains 14 items: 7 items to measure anxiety (HADS-A) and 7 items to measure depression (HADS-D) ,34,35. EThe functional rating index (FRI) measures activity and participation in relation to the International Classification of Functioning Disability and Health (ICF) . The FRIThe Godin–Shephard leisure-time physical activity questionnaire (GSLTPAQ) captures how many times a week a respondent performs different leisure activities and at what level: strenuous, moderately strenuous, or light exercise. The participant is also asked how many times on average they engage in physical activity that leads to an increase in pulse rate. The points are added together to make a total score. Strenuous activity is multiplied by 9, while light activity is multiplied by 3 ,41.The pain catastrophizing scale (PCS) consists of 13 items describing different thoughts and feelings when experiencing pain . The PCSThe EQ-5D European quality of life instrument measures HRQoL . The EurSick leave was reported as full time (100%) or part time (25–75%). t-test, Mann–Whitney U Test, chi-square test, and chi-square test of trend (linear-by-linear association). Change over time between baseline, after MMR, and at 1-year follow-up was analyzed using paired t-test, Wilcoxon signed-rank test, and McNemar’s test. Effect sizes with 95% confidence intervals (95% CI) on comparison between women and men and change over time were calculated using the website Psychometrica [p-value < 0.05 were statistically significant. The statistics were processed in IBM Statistical Package for the Social Sciences .Descriptive data were presented as mean with standard deviation (SD), median and interquartile range (IQR), or numbers and percentages. Comparisons between women and men were analyzed using unpaired ometrica , and theometrica . Resultsn = 3542, 81.3%; men: n = 815, 18.7%). The number of years of pain duration varied, and the mean was 7.4 ± 8.3 years. Of the 4357 patients registered in the SQRP-pc, 2809 (64.5%) answered the questionnaire after completion of the IMMRP. Of the patients who filled in the questionnaire after IMMRP, 26.5% also filled in the questionnaires after one year. In total, 744 (17.1%) patients filled in all three questionnaires at baseline, after MMR, and at 1-year follow-up , they were older (mean (SD) 44.7 (10.1) vs. 43.5 (12.2) years, respectively, p = <0.010), a higher proportion was born in Sweden , more had a high education , more were working , and fewer had income support . Regarding background factors, there were some differences between those who completed the 1-year follow-up SQPR-pc compared with those who did not. Among completers, there was a higher proportion of women (18.1%) than men , a lower proportion of completers rated their pain intensity as severe , and completers reported more pain sites (15.4 (7.8) vs. 13.9 (8.2), respectively, p = <0.001).Regarding pain variables, there were also some differences between those who completed the 1-year follow-up SQPR-pc compared with those who did not. Among completers, there was a higher proportion with persistent pain  compared with those who did not complete the follow-up. Completers also had a lower proportion of patients with clinical anxiety  and clinical depression .Regarding emotional and physical functioning, completers rated lower on PCS (25.2 (10.8) vs. 26.3 (11.6), respectively, p = 0.048) and had a higher EQ-5D-index (0.37 (0.32) vs. 0.33 (0.33), respectively, p = 0.017) compared with those who did not complete the follow-up.Health-related quality of life differed as well, where completers rated higher on EQ-5D-VAS (43.8 (20.4) vs. 42.2 (18.3), respectively, p = 0.002), and HADS depression deteriorated (−0.5 (3.5), p < 0.001).In patients who answered the questionnaires at baseline, after IMMRP, and at 1-year follow-up, most outcome measures improved between baseline and after IMMRP  and to a somewhat lesser extent between baseline and 1-year follow-up see . Godin 7p = 0.020, 0.026, and 0.013, respectively; see Appendix p = 0.018). Women reported lower HADS depression compared with men at 1-year follow-up . Women had a lower Godin activity level compared with men at baseline (p = 0.047). EQ-VAS was higher in women compared with men after IMMRP and at 1-year follow-up , and EQ-VAS also improved more in women compared with men between baseline and 1-year follow-up (p = 0.035).There were no statistically significant differences between women and men in most of the PROMS at the three reporting time points, such as pain variables, pain catastrophizing, physical activity during last seven days, and EQ-5D index. Women reported lower FRI compared with men at all three time points  and at 1-year follow-up (p = 0.154).Sick leave decreased significantly between baseline and 1-year follow-up both for all patients and for women and men separately  prevail regarding which patient characteristics are suitable for IMMRP programs. Are the programs designed to suit all patients? A qualitative study in primary care expressed opinions about which patients are suitable for participation in a group program but also stated that it is impossible to know in advance who will benefit from MMRP .There may be reason to reflect on which patients we address with IMMRP and which patients can be attracted and benefit from the scheme. Lehti et al.  found thAlthough the competencies of the professionals were according to the national guidelines, the composition of the team varied depending on the health center. We can therefore not rule out that this may have affected the treatment and could be considered a confounding variable.Since all questionnaires are self-assessments, including the question regarding sick leave, misunderstandings can easily arise, as some patients do not know if they have been entitled to sick leave by the Social Insurance Office. In addition, it must be considered that the requirements for receiving sick leave have changed over the years. For these reasons, the positive results of reducing the degree of sick leave should be interpreted with some caution. A major strength of the study was that this is the first study to investigate IMMRP in primary care on a national level based on the SQRP-pc. Previous studies ,20,49 haThis study indicates that patients with chronic pain may benefit from IMMRP in primary care settings in terms of pain intensity, physical and emotional function, physical activity, health-related quality of life, and reduction in sick leave both in the short and long term.The large number of dropouts, i.e., the decrease in numbers of those who participated at the beginning versus those who participated at the end, highlights the importance of strengthening the routines for the follow-up of patients participating in IMMRP in primary care.