This study aimed to compare the effects of melatonin, dexmedetomidine, and gabapentin on postoperative pain and anxiety following laminectomy.In this randomized clinical trial, 99 patients aged 40–60 years old with American Society of Anesthesiologists physical status I-II undergoing laminectomy were divided into three groups receiving 600mg gabapentin (group G), 10mg melatonin (group M), or starch tablets (group D). The Hospital Anxiety and Depression Scale (HADS) was used to measure postoperative anxiety while a Visual Analogue Scale (VAS) was employed to measure pain severity. Patients’ satisfaction with pain treatment was also measured together with the frequency of nausea and vomiting.The postoperative HADS decreased in all groups over time. Time and group had no significant interaction effect on the HADS score. Patients in the melatonin group had lower HADS at 2 and 6h after surgery. According to the VAS, the groups significantly differed in pain scores 6 and 24h after surgery. Lower VAS scores were observed 6h after surgery in the dexmedetomidine group compared with the gabapentin group and 24h after surgery in the dexmedetomidine group compared with the gabapentin and melatonin groups. Narcotic requirements, patients’ satisfaction, and vital sign changes did not significantly vary among the groups. Notably, patients in the melatonin group had less nausea and vomiting.This study was registered in the Iranian Registry of Clinical Trials  where the trial protocol could be accessed.Melatonin is effective as a postoperative anti-anxiety drug. Dexmedetomidine is useful in reducing postoperative pain. Spinal procedures are associated with intense pain in the postoperative period, mostly in the first few days after surgery. Effective pain management leads to improved functional outcomes, early discharge, early ambulation, and prevention of chronic pain . The actVarious medications such as morphine , fentanyl , N-methyl-D-aspartate (NMDA) receptor antagonists, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), clonidine, capsaicin, and tapentadol are used to relieve post-laminectomy pain. The mechanism of each of the above drugs is different and they have several side effects such as nausea, vomiting, platelet dysfunction, hemorrhage, gastric ulceration, renal toxicity, and respiratory depression , 7–9.Dexmedetomidine is a selective α2 adrenergic receptor agonist that is metabolized in the liver and is primarily excreted via the kidneys. Dexmedetomidine facilitates arousable sedation with no effect on the respiratory drive; it also reduces the need for inhaled anesthetics. However, due to hemodynamic changes, the drug should be used carefully for conscious sedation (CS), monitored anesthetic care (MAC), or general anesthesia. –14. DespMelatonin is mainly secreted from the pineal gland by the suprachiasmatic nucleus. This neurohormone possesses a circadian secretion pattern and regulates the biological clock; it also offers antiemetic, analgesic, and anxiolytic effects. Due to its effect on both acute and chronic pain, melatonin fulfills a beneficial role in reducing postoperative opioid consumption while minimizing nausea and vomiting. In addition, melatonin can be used to moderate the effect of light on the autonomic system , 17–20.Several studies have reported that melatonin, as an analgesic, anti-inflammatory, anxiolytic, and anti-agitation premedication, is associated with sedation and anxiolysis without adverse effects on recall and driving performance. Furthermore, some studies have found confirmed the effects of melatonin on pain and anxiety, though a consensus is yet to be reached in this regard , 22.Gabapentin is an anticonvulsant drug classified under the category of gabapentinoids, which are prescribed for diabetic and post-herpetic neuralgia (PHN) patients. Preemptive use of gabapentin reduces the severity of postoperative pain, thereby minimizing the use of analgesics such as narcotics. On the other hand, gabapentin reduces postoperative stress, anxiety, nausea, and vomiting. The amount of anesthetic required for general anesthesia is also reduced when gabapentin is administered , 23–25.Based on the mentioned data, the present study aimed to compare the effects of melatonin, dexmedetomidine, and gabapentin on post-laminectomy pain, and anxiety.After procurement of the institutional ethics committee’s approval and registration with the Iranian Registry of Clinical Trials , written informed consent was obtained from all patients who met the inclusion criteria at Abu Ali Sina Hospital . We performed the study from August 2019 to November 2019. Ninety-nine patients aged 40–60 years old with American Society of Anesthesiologists (ASA) physical status I-II scheduled for laminectomy at one or two levels were recruited.2); liver disease ; psychological and cognitive disorders; dementia; major depression; circadian rhythm disorders such as chronic fatigue syndrome and drowsiness; or patients who had difficulty in communication were excluded from the study.Patients with a history of allergic reactions to melatonin, dexmedetomidine, and gabapentin ; history of cardiovascular disease ; history of kidney disease , fentanyl (2 mic/kg), and morphine (0.1mg/kg) were injected as premedication after entering to operation room as a routine of our experiences. Anesthesia was induced using propofol (1.5-2mg/kg) and cis-atracurium (0.15mg/kg). Intubation was performed with size 7 (women) or 8 (men) endotracheal tubes. Isoflurane and nitrous oxide-oxygen (50% /50%) were used for maintenance of anesthesia (1.2–2.5%) and repeated cis-atracurium for muscle relaxation during operation based on clinical judgment and monitoring.www.sealedenvelope.com, with both the investigators and patients being kept blind to the size of the blocks. Before the study, 99 closed envelopes were prepared to contain oral tablets in non-specified boxes. Each envelope had a specific number provided by a pharmacist who was blinded to the study groups. Two hours before the operation, a nurse randomly selected one of the envelopes and gave the pills to the patient.The sample size was calculated based on a study conducted by Cheghazardi et al. , which sIn the melatonin group (M), 10mg (two 5mg tablets) of melatonin  were given to the patients, while in the dexmedetomidine group (D), starch tablets, and in the gabapentin group (G), 600mg (two 300mg tablets) of gabapentin  were administered.To deliver the dexmedetomidine  while keeping the patients blinded, a nurse received a 20 ml syringe from a second nurse according to the patients’ code and weight. In the melatonin and gabapentin groups, the syringe contained normal saline, while in the dexmedetomidine group, it contained a diluted solution of dexmedetomidine (1µg/kg). All three syringes contained 20 ml of clear solution and were injected in the prone position within ten minutes after induction of anesthesia. Information was recorded by another nurse during the operation using forms included in the envelopes. The patients and nurses were unaware of the type of prescription drugs and the nature of the study group.All patients were visited by an anesthesiologist the night before surgery; a medical history was taken and a clinical examination was performed. Also, a green mark was placed on the patient’s file if he/she met the inclusion criteria and entered the study.In this study, we compared the effects of melatonin, dexmedetomidine, and gabapentin on the primary outcomes of postoperative pain and anxiety and the secondary outcomes of the occurrence of nausea and vomiting, required amount of analgesics after surgery, patients’ satisfaction, and hemodynamic changes. Psychological tests were validated for the Iranian study populations used in this study.To measure the severity of pain, a VAS was used; the patients’ pain levels were measured at 2, 6, and 24h after surgery. The total consumption of analgesics  was also recorded. In the recovery room, the patients were trained to inform the nurses whenever their pain score was four or higher on the VAS. At such times, the patients received an IV bolus of 0.02mg/kg morphine and were re-evaluated after 20min. If the patient’s pain score was four or above again, the same dose of morphine was injected with/under respiratory monitoring (rate and depth of breathing). In the ward, patients with pain (VAS score ≥ 4) were given an IV infusion of 1g acetaminophen (Apotel®). The patient was re-evaluated after an hour and given a 25mg meperidine injection if the pain score remained greater than or equal to four.The Hospital Anxiety and Depression Scale (HADS) was used to measure postoperative anxiety 2, 6, and 24h after surgery . Scores In this study, continuous variables were reported as mean and standard deviation or median and interquartile range (IQR). Categorical variables were reported as numbers and percentage. Differences between groups were examined by analysis of variance (ANOVA); the Tukey post hoc test was utilized to analyze parametric variables and the Kruskal-Wallis test was used for non-parametric variables. Also, the chi-squared test or Fisher’s exact test was applied to assess differences in categorical variables. We accessed the repeated measure ANOVA test for comparing the HADS within groups over time. Data were analyzed using SPSS 21  and P-values < 0.05 were considered statistically significant.In our study, 115 patients were screened for eligibility. Among them, eight were excluded due to a lack of inclusion criteria and three declined to participate. Therefore, 104 patients were enrolled and divided into three groups melatonin (N = 35), dexmedetomidine (N = 35), and gabapentin (N = 34). In the follow-up, five patients were excluded . A total of ninety-nine patients completed the study ; however, significant differences were observed between the groups at 6 and 24h after surgery . The patients had a lower VAS score in the dexmedetomidine group compared with the gabapentin group at 6h (P = 0.046) and the gabapentin(p = 0.018) and melatonin groups in 24h (p < 0.001) . Time and group did not have a significant interaction effect on the HADS score (P = 0.065). In general, the melatonin group had a lower mean HADS score compared with the other two groups (P < 0.001) Fig.. AccordiThe median change in HADS score between the second and twenty-fourth hours varied significantly between the groups (P = 0.007); there was significantly less change in the melatonin group compared with the dexmedetomidine P = 0.04) and gabapentin (P = 0.01) groups. A significant difference also existed in the median change in HADS score between 2 and 6h (P = 0.017), with the melatonin group having less change relative to the gabapentin group (P = 0.025). There was no significant difference between the groups in terms of median change in HADS score between 6 and 24h (P = 0.228) (Table and gabaDifferences in requirement of narcotics P = 0.457), patient satisfaction (P = 0.193), and vital sign changes (P = 0.451) among the groups were not statistically significant. However, the occurrence of nausea and vomiting was significantly different among the groups . In other words, patients who received melatonin had less nausea and vomiting compared with those receiving dexmedetomidine or gabapentin , as we approached the end of the first day after surgery, the effectiveness of the drug decreased. It is likely that by re-administering the drug after surgery, its effect can be sustained.The anxiolytic effect of melatonin and gabapentin was also reported in a study by Marzieh-Beigom Khezri et al. However, in our study, 2 and 6h after surgery, the anti-anxiety effect of melatonin was significantly greater than dexmedetomidine and gabapentin, while in the mentioned study, no significant difference in postoperative anxiety was observed between patients receiving melatonin and gabapentin . Anti-anAs far as we know, no other study has compared the efficacy of melatonin, dexmedetomidine, and gabapentin in terms of postoperative pain and anxiety. Here, we conclude that melatonin is more effective in reducing postoperative anxiety than the other two drugs.In our study, the closer we got to 24h after surgery, the less pain there was in all three groups. However, what is important was the greater analgesic efficacy of dexmedetomidine at 6h relative to gabapentin (P = 0.046), and at 24h compared with both melatonin and gabapentin .The analgesic effects of each of the above drugs have been studied in several studies and the effectiveness of each in reducing postoperative pain has been proven . GabapenIn a study by Borazan et al., the analgesic effects of melatonin after surgery were shown . In CaumDexmedetomidine exerts its analgesic effects by reducing the expression of the glucocorticoid receptor. The elevation of glucocorticoids during surgery causes an increase in the incidence of pain resistance due to anxiety. In fact, dexmedetomidine probably mitigates this destructive effect of glucocorticoids, thereby minimizing postoperative pain. In the study of Lu Li et al. on mice, the possible mechanism behind the reduction of anxiety-induced persistent pain by dexmedetomidine was a decrement in the expression of the glucocorticoid receptor . On the In our study, the comparison between the three drugs showed that dexmedetomidine was more effective than the other two in postoperative pain management. However, no significant difference was found in the amount of postoperative narcotic consumption between the three groups. This can probably be explained by the duration of the drugs’ action, their different mechanisms in pain control, as well as their anti-anxiety effects.In our study, the rate of post-operative nausea and vomiting (PONV) was lower in the melatonin group than in the other two groups. In the study of Hyunjeong Kwak et al., the effects of administering a single dose of dexmedetomidine at the end of the operation on PONV were reported. However, in our study, dexmedetomidine was administered at the beginning of the operation as a single dose, meaning that a pronounced effect on postoperative PONV probably could not be observed considering the onset time and duration of the drug’s 15-minute peak effect . In the Our study has some limitations. If this study had been performed on larger sample size, there would probably have been more significant results in terms of the analgesic and anti-anxiety effects of the drugs. On the other hand, the use of dexmedetomidine as an infusion during the operation and oral reingestion of melatonin after surgery could have led to more pronounced results. To measure narcotic consumption after surgery, the use of a patient-controlled infusion pump may be better as it prevents bolus administration and its possible side effects while facilitating more accurate recordings.In conclusion, melatonin is effective as a postoperative anxiolytic, while dexmedetomidine can be used to reduce postoperative pain. Furthermore, nausea and vomiting occurred less in the melatonin group compared with the dexmedetomidine and gabapentin groups. The mechanism of action behind these effects of melatonin should be investigated further.In conclusion, melatonin is more effective than dexmedetomidine and gabapentin groups as a postoperative anxiolytic and nausea - vomiting medication. However, the mechanism of the antiemetic of melatonin should be investigated further. Dexmedetomidine in reducing postoperative pain is more effective than two others.


Pain is one of the most common, yet challenging problems leading to emergency department (ED) presentation, despite the availability of a wide range of pharmacological therapies. Virtual reality (VR) simulations are well studied in a wide variety of clinical settings, including acute and chronic pain management, as well as anxiety disorders. However, studies in the busy environment of an adult ED are scarce.The aim of this study is to explore the feasibility and effectiveness of a VR simulation for pain and anxiety control in a convenience sample of adult ED patients presenting with traumatic and non-traumatic pain triaged 2–5  with a pain rating of ≥ 3 on a numeric rating scale (NRS 0–10).Prospective within-subject, repeated measures interventional feasibility pilot study at a Swiss University ED. The intervention consisted of a virtual reality simulation in addition to usual care. Pain and anxiety levels were measured using a verbally administered numeric rating scale (NRS) before and after the intervention. Information on patient experience was collected using established rating scales.n = 15, 28.8%) and abdomen . About one third of patients presented with trauma-associated pain . Duration of pain was mainly acute (< 24 h)  or subacute (> 24 h) . The majority of patients were triage category 3, i.e. semi-urgent . Significant reduction in pain (NRS median pre-VR simulation 4.5 (IQR 3–7) vs. median post-VR simulation 3 (IQR 2–5), p < 0.001), and anxiety levels (NRS median pre-VR simulation 4 (IQR 2–5) vs. median post-VR simulation 2 (IQR 0–3), p < 0.001) was achieved, yielding moderate to large effect sizes (Cohen’s d estimate for pain reduction = 0.59 (95% CI 0.19—0.98), for anxiety level on NRS = 0.75 (95% CI 0.34—1.15). With medium immersion and good tolerability of the VR simulation, user satisfaction was high.Fifty-two patients were enrolled. The most common pain localisations were extremities (Virtual reality analgesia for pain and anxiety reduction in the busy setting of an ED is feasible, effective, with high user satisfaction. Further randomized controlled studies are needed to better characterize its impact on pain perception and resource utilization.The online version contains supplementary material available at 10.1186/s12873-022-00671-z. Pain is one of the most common problems leading to emergency department (ED) presentation. However, pain management in the ED remains challenging –3. Many Virtual Reality (VR) affects the visual and the auditory senses allowing immersion in a virtual world thanks to a VR headset, giving participants the illusion of “being there” in the 3 dimensional computer generated world as if it is a place they are visiting. The mechanism of how VR works to alleviate pain is only partially known. The gate control theory postulates pain perception to be modulated by interaction among different neurons. VR or other stimuli might lead to a closure of the neural gateways, thus reducing pain perception . In addiStudies in the busy environment of an adult ED are scarce , and maii)The feasibility of deployment of a VR simulation in the busy setting of the ED for an adult population presenting with traumatic or non-traumatic pain ≥ 3 on a numerical rating scale (NRS) (0–10).ii)The effectiveness of the VR simulation in pain and anxiety control. Impact of gender and pain location on response.iii)The acceptance of the VR simulation in the study population and patient experience .Thus, we conducted a within-subject, repeated measure interventional feasibility pilot study to investigate:This is a prospective self-controlled interventional feasibility pilot study at the ED of the University Hospital of Bern, Switzerland. Our ED is a tertiary care centre, caring for a patient population of around 2 million and treating over 45,000 adult patients each year with an interdisciplinary team , 36.nd, 2021 until July 9th, 2021, during daytime hours depending on availability of the study investigator.The study took place from March 22All patients admitted to the ED were triaged by registered nurses using the Swiss triage scale, a five-level triage scale with high inter-rater and intra-rater reliability . Chief cThis study was classified as a quality evaluation study by the local institutional review board , BASEC-Number Req-2020–01,266).n = 52) of adult (≥ 18 years of age) ED patients triaged 2–5 on the Swiss triage scale, i.e. excluding critically ill/injured patients in shock, with a pain rating of NRS ≥ 3 on a numeric rating scale (0–10) who presented to the ED with the following complaints: traumatic and non-traumatic musculosceletal pain , abdominal or chest pain, or headache.We recruited a convenience sample Patients without decision-making capacity or with communication deficits Altered mental status .History of drug abusePatient unable to use VR due to vision problems .Patient suffering from epilepsy or other sensitivity to flashing light or motionPregnancy or other medical condition prone to severe nausea and vomitingPatient suffering from claustrophobiaPatients on non-invasive ventilation and patients requiring oxygen delivered by face maskPatients requiring droplet, aerosol and contact precautionsPatient with injuries/skin affections  to face/neck including traumatic brain injury that prevents the use of the VR headsetImprisoned patientsPatient who participated in this study at a previous consultationRefusal to participate in the studySociodemographic data , clinical data regarding pain presentation  and triage level according to the Swiss triage scale)  were colThe study investigator (FB) informed the patient about the study aims, handed out the information form and ensured the absence of contraindications, responded to the patient's questions and collected the patient’s free, informed and expressed consent.The intervention consisted of the application of the Healthymind VR simulation , using a Pico G2 4 K VR headset  with resolution of 1920 × 2160 and a diagonal field of view of 101 degrees and Bose Quiet Comfort 35 II noise-cancelling headphones  as an adjunct to usual care in the ED. Pain medication was administered throughout the patient’s stay in the ED as it would be during a usual ED visit. In our ED, analgesia is administered according to a clearly defined standard and protocol, which was also adhered to unchanged during the study. If necessary the VR simulation was interrupted, so that medication  could be provided. The content of the simulation has been developed by a private company  and is a registered Class I medical device that is commercially available. The company was not involved in any aspects of the study. The immersive, but not interactive experience, consists of a contemplative relaxing landscape accompanied by a sound universe specifically composed to relax the patient. The patient could choose between either a forest or beach setting . The study investigator (FB) was always present during the simulation and worked with ED staff as necessary to ensure the patient was receiving appropriate clinical care throughout the duration of the intervention.Effectiveness of the VR simulation on the patients' self-assessment of their current pain intensity by a verbally administered numeric rating scale (NRS from 0 to 10 integers) immediately pre- and post-intervention. This scale has been demonstrated to be a valid and reliable tool for the assessment of acute pain in the ED .Effectiveness of VR simulation on the patients' self-assessment of their current anxiety measured on a verbally administered numeric rating scale (NRS from 0 to 10 integers) immediately pre- and post-intervention. Furthermore, the validated Patient-Reported Outcomes Measurement Information System (PROMIS®) Anxiety short form 8a (8 Items) was filled out by the patient immediately before and after the intervention , 40.To evaluate the raw score of the anxiety intensity on the PROMIS Anxiety short form 8a, the value of the response options ranging from one to five for each of the eight items is summarized .Vital signs  were collected within a 10-min time-frame before and after the simulation.Motion sickness was assessed on a verbally administered numeric rating scale (NRS 0 to 10), immediately before and after the procedure.“Visually-induced motion sickness” was assessed with four-items  according to the Simulator Sickness Questionnaire (SSQ) adapted from Kennedy et al.  .Presence and immersion in the virtual world was determined according to the 6-item questionnaire developed by Slater-Usoh-Steed  .User satisfaction was assessed using a 7-item questionnaire  directly after the procedure.Information on the analgesic and anxiolytic medication administered in the ED was collected from the electronic patient healthcare dossier (e-care).Data was analysed in Stata® 16.1 .Baseline characteristics are presented as numbers and percentage or median and interquartile range (IQR) using descriptive statistics as appropriate. Comparisons between two independent groups  were carried out by Chi-square or Wilcoxon rank sum test depending on variable .p-value < 0.05 was considered significant. There was no p-value adjustment in this exploratory data analysis. Effect sizes with 95% confidence intervals (CI) for pain and anxiety levels before and after the simulation were determined by Cohen’s d. Effect size was determined as follows: Cohen’s d < 0.5 small, 0.5 – 0.8 moderate, and > 0.8 large.Pre- and post-simulation comparisons (e.g. pain) were performed with McNemars test or Wilcoxon signed rank test. Incomplete variables are indicated. No data were imputed. Only complete data pairs could be evaluated. A A total of 310 ED patients were screened, with in 194 patients meeting eligibility criteria , abdomen , head , back, and chest . About one third of patients presented with trauma-associated pain . No patient presented with tumor-associated pain. Duration of pain was mainly acute (< 24 h)  or subacute (> 24 h) . Over ninety percent of patients were triaged level 3 . Median pain level before VR on a NRS from 0 to 10 was 4.5 (IQR 3–7), median anxiety level was 4 (IQR 2–5). Median anxiety level on the 8-item PROMIS questionnaire was 14 out of a maximum of 40 points (IQR 11–21), with significant differences between females  and males , p = 0.002.Baseline characteristics of the patient population are detailed in Table Technical details of the VR simulation are described in Supplement Table p < 0.001), and anxiety levels (NRS median pre-simulation 4 (IQR 2–5) vs. median post-simulation 2 (IQR 0–3), p < 0.001; PROMIS median pre-simulation 14 (IQR 11–21) vs. median post-simulation 8 (IQR 8–11), p < 0.001) was achieved (Table Significant reduction in pain (NRS median pre-simulation 4.5 (IQR 3–7) vs. median post-simulation 3 IQR 2–5), –5, p < 0No significant differences in vital parameters were observed pre- and post-simulation .Effects of the VR simulation on pain and anxiety levels (NRS 0–10) according to pain location are detailed in Fig. n = 22) received analgesics before the simulation, and only 11% (n = 6) received opioids. Compared to males, the proportion of females receiving pain medications and opioids was significantly higher  . The overall responses in the user satisfaction survey were positive. Over half of the patients agreed to the statement that the simulation helped with their pain , and over 90% would recommend the simulation  . The 4-item Simulator Sickness Questionnaire in the intervention group revealed a good tolerability of the VR simulation. Motion sickness measured on a NRS (0–10) was significantly lower after than before the simulation  with good tolerability. However, as a main limitation, they did not provide information regarding concurrent analgesic medication administered. In our study, we noticed a significant reduction of pain and anxiety levels, regardless of administration of analgesics before the simulation.The current study found a significant reduction in pain and anxiety levels through the VR simulation. Our results confirm the little existing evidence regarding effectiveness of VR on pain reduction in the ED. Sikka et al. were the first to study of the effect of VR in ED patients with acute pain . In theiSpiegel et al. conducted a prospective randomized controlled study  in hospitalized patients with pain scores of at least 3 out of 10 on a NRS and achieved a similar level of pain reduction , with a significantly greater pain reduction in the VR group than in the control group  . AlthougWe did not find a significant change in physiological parameters, in line with the current lack of firm evidence that VR therapy can affect autonomic arousal or demonstrate its analgesic properties through modulation of these parameters .Increased levels of anxiety can lead to worsening pain perception, decreased pain threshold and less cooperative patients , 48. We Our simulation was well tolerated, with a low incidence of side effects such as nausea, headache, blurred vision or dizziness or motion sickness, in accordance with previous other reports , 21. TheStrong evidence has also shown that the quality of VR and the amount of immersion as well as interactivity delivered by the VR technology directly correlates with the measured quantity of analgesic effect , 9, 48. These results need to be interpreted with some reservations. First, this was a single tertiary care academic center study with a limited number of participants, that may be affected by selection bias, and thus have impact on generalizability. Furthermore, as this was a feasibility study, we included an uncontrolled convenience sample (no randomization or blinding), and results may been influenced by performance bias. We cannot exclude the novelty effect of using a previously unknown technique , but othAlthough premature to recommend VR as standard of care in the ED, the current results warrant consideration of a multicenter study in a larger patient group. Further comprehensive and structured research is needed to measure additional confounders and outcomes to identify optimal use of the VR simulation application in the ED setting. In addition, studies on the exact mechanism of action of the VR simulation beyond simple distraction would be valuable.VR simulation for pain and anxiety reduction in the busy setting of an ED is feasible, effective, and safe. Further and larger randomized controlled studies are needed to better characterize its impact on pain perception and resource utilization.Additional file 1:Supplement table 1. Technical details of the VR simulation. Supplement table 2. Vital parameters before and after the VR simulation. Supplement table 3 Analgesics administered before, during or after the simulation, according to gender. Supplement figure 1. Beach simulation. Supplement figure 2. Forest simulation.


Central-sensitization-associated symptoms were present in up to 64.3% of patients post-COVID-19 infection, based on a PROM, i.e., the CSI. A more objective evaluation of nociceptive processing through experimental pain measurements was less suggestive of indicators of central sensitization. Only a small negative correlation between pressure sensitivity and the CSI was observed, thereby pointing towards the discrepancy between the CSI and experimental pain measurements and presumably the complementary need for both to evaluate potential indicators of central sensitization in this population.Fatigue, pain, headache, brain fog, anosmia, ageusia, mood symptoms, and sleep disorders are symptoms commonly experienced by people with post-COVID-19 condition. These symptoms could be considered as manifestations of central sensitization. The aim of this study is to evaluate whether there are indicators of central sensitization by using experimental pain measurements and to determine their association with patient-reported outcome measures (PROMs). A cross-sectional study including 42 patients after COVID-19 infection was conducted. The central sensitization inventory (CSI) was administered as a PROM to evaluate central-sensitization-associated symptoms. Pressure pain thresholds (PPT), temporal summation, and descending nociceptive pain inhibition (CPM) were assessed as experimental pain measurements. The median score on the CSI was 46.5 (Q1–Q3: 33–54). The presence of central-sensitization-associated symptoms was seen in 64.3% of patients based on the CSI (≥40/100 points). A deficient CPM was seen in 12% and 14% of patients when measured at the trapezius and rectus femoris, respectively. A negative correlation between pressure sensitivity on the rectus femoris and the CSI score (r = −0.36, 95%CI −0.13 to −0.65,  The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has resulted in worldwide strict lockdowns, physical distancing, and home isolation to slow down the spread of the pandemic and to avoid fatalities . A netwoFatigue is one of the core symptoms in central-sensitization-associated disorders ,13, leadThe exclusive use of a screening questionnaire such as the CSI for inferring sensitization in people with post-COVID-19 condition is not recommended because a self-reported tool cannot capture the complexity of a nervous system impairment such as central sensitization . Accordiclinicaltrials.gov (NCT04703452) and was conducted according to the revised Declaration of Helsinki (1998).This is a cross-sectional study investigating the symptoms of central sensitization and impaired nociceptive processing in individuals post-COVID-19 infection. Both male and female patients who had been previously infected with SARS-CoV-2 were eligible to participate. The patients were only eligible if they had had a positive COVID-19 test at least 3 months before inclusion. The patients were recruited through various ways. Firstly, the patients were invited to participate by physicians in cases where they were consulted after a SARS-CoV-2 infection at the Department of Physical Medicine and Rehabilitation of UZ Brussel. Secondly, advertisements and announcements from patient support groups were used as an additional recruitment strategy. Finally, social media was used to recruit patients. The study protocol was approved by the central ethics committee of Universitair Ziekenhuis Brussels (B.U.N. 1432020000348) on 16 December 2020. The study was registered on The patients included had one study visit to UZ Brussel, which was scheduled according to patient preferences. During the study visit, the patients first filled out the following three PROMs in a randomized order: the central sensitization inventory, the post-COVID-19 functional status scale, and the London chest activity of daily living. After filling out the questionnaires, the following experimental pain measurements were performed: pressure pain thresholds (PPT), temporal summation, and descending nociceptive inhibition. The complete testing protocol lasted for maximally 1 h. All of the participants were asked to refrain from consuming caffeine, alcohol, or nicotine 24 h before the study.https://www.pridedallas.com/questionnaires, accessed on 19 November 2021) [The primary outcome was the presence of central-sensitization-associated symptoms, as assessed by the central sensitization inventory (CSI). The CSI consists of 25 symptom-related items that the patient has to score on a five-point Likert scale [er 2021) . The CSIer 2021) ,28.Post-COVID-19 functional status was evaluated by the post-COVID-19 functional status scale (PCFS). This scale is ordinal, has six steps ranging from 0 (no symptoms) to 5 (death) and covers the entire range of functional outcomes by focusing on limitations in usual activities either at home or at work/study, as well as lifestyle changes. More specifically, the following scale grades are included: 0 , 1 , 2 , 3 , 4 , and death. The PCFS was assessed twice, once by the interviewers during a short-structured interview, as well as with self-reporting by the patient ,30.The London chest activity of daily living (LCADL) scale was assessed to evaluate the level of dyspnea during activities of daily living (0–75 points). This questionnaire consists of 15 items and contains the following answer options: 0 (I do not perform this activity because I’ve never had to do it or it is irrelevant), 1 (I do not feel any breathless when performing this activity), 2 (I feel moderate breathless when performing this activity), 3 (I feel a lot of breathless in performing this activity), 4 (I cannot perform this activity due to breathless and I have no one who can perform the activity for me) or 5 (I cannot perform this activity anymore and I need someone to perform it for me or help me because of breathless). Greater dyspnea-related limitation in activities of daily living translates into higher scores on the LCADL. It has four domains: self-care (0–20 points), domestic activities (0–30 points), physical activities (0–8 points), and leisure time (0–12 points) ,32.2. Pressure algometry has been found to be an efficient and reliable technique for PPT determination and examination of sensitivity to pressure pain [Pressure pain sensitivity was measured at the middle of the trapezius muscle   and at ture pain .Temporal summation (TS) was evaluated with 10 consecutive pressure pulses at the intensity of the PPT (previously determined) on the same areas. For each pulse of the TS procedure, the pressure was increased at a rate of 2 kg/s until the previously determined PPT, where it was maintained for one second before being released. An inter-stimulus interval of one second was used. The participants were instructed to rate the pain intensity of the first, fifth, and tenth pressure pulse according to a verbal numeric pain rating scale (vNPRS). The TS score was obtained by subtracting the first vNPRS score from the last vNPRS . The higTo assess the efficacy of endogenous pain inhibition, the conditioned pain modulation (CPM) paradigm was used ,39,40. Ap-values of 0.05 or less were considered statistically significant. Statistics for quantitative variables included median and 1st and 3rd quartiles, the number of observations, and number of missing values. For categorical variables, the absolute counts (n) and percentages (%) of patients were presented.All of the analyses were performed in R Studio version 1.4.1106 . The primary outcome of this study is to identify whether patients post-COVID-19 infection suffer from central-sensitization-associated symptoms, based on the total CSI score. Therefore, the percentages of patients with central sensitization were reported based on the cut-off value of 40/100 on the CSI and the central-sensitization-related symptom severity categories. Furthermore, correlation analyses were performed between total CSI scores and experimental pain measurements  and the total LCADL score using Spearman rank correlations. A Bonferroni correction was applied to correct for multiple testing (seven comparisons for each variable). Agreement between the PCFS scores rated by the patient and the physician was evaluated using a weighted kappa with linear weights. Kruskal–Wallis tests were used to explore the effect of the presence of symptoms of central sensitization on experimental pain measurements, total LCADL scores, and PCFS scores.Finally, K-means clustering was performed to classify patients according to shared features of self-reported data and experimental measurements. For the clustering, the centroids of hierarchical clustering (squared Euclidean distances with the method of Ward) were used as starting points. All of the variables were standardized before clustering and only patients with complete data were incorporated into the cluster analysis. All of the analyses were performed on the data as observed. This means that no data imputation strategies, nor observation carried forward techniques, were performed.In total, 42 patients were included in this study  with a mean age of 48 (SD: 12) years. All of the visits took place between 19 January 2021 and 20 December 2021, whereby only one patient was hospitalized for COVID-19 infection at the time of the study visit. The median time between confirmation of SARS-CoV-2 infection and the study visit was 190.5 (Q1–Q3: 117–360) days. Four patients were on non-steroidal anti-inflammatory drugs, four patients were on paracetamol, five patients were on antidepressants, one patient was on opioids, two patients were on benzodiazepines, and one patient received a combination product. For female patients, oral anticonceptives were taken by two patients and two patients took hormone replacement therapy.p = 0.02).The median score on the CSI was 46.5 points (Q1–Q3: 33–54), whereby 15 patients (35.7%) had a score < 40/100 on the CSI and 27 patients (64.3%) had a score ≥ 40/100. In terms of severity, 5 patients (11.9%) could be classified as low level of central-sensitization-related symptom severity , 12 (28.6%) as medium-level , and 25 (59.5%) as high-level of central-sensitization-related symptom severity . The median CSI score in males  was significantly lower compared to females  (sample difference −13 (95% CI −2 to −24), p < 0.001). The strength of agreement was classified as moderate [p = 0.21) and interviews . Concerning the PCFS, 4 persons (9.5%) had no functional limitations (grade 0), 7 (16.7%) had negligible functional limitations (grade 1), 15 (35.7%) reported slight functional limitations (grade 2), 14 (33.3%) indicated moderate functional limitations (grade 3), and 2 (4.8%) scored severe functional limitations (grade 4) according to the patient ratings. For the interviews conducted by the physician, 2 persons (4.8%) had no functional limitations (grade 0), 6 (14.3%) had negligible functional limitations (grade 1), 14 (33.3%) reported slight functional limitations (grade 2), 18 42.8%) indicated moderate functional limitations (grade 3), and 1 (2.4%) scored severe functional limitations (grade 4). There was missing data for one patient (2.4%). The median time to conduct this interview entailed 1245 (Q1–Q3: 738–2218) seconds, corresponding to 20.75 min. There was a statistically significant agreement between both ratings, kw = 0.546 .Concerning the LCADL, median scores of 22/75 (Q1–Q3: 17.25–27.50) were revealed, whereby higher scores indicate higher dyspnea-related limitation in activities of daily living. For self-care, a median value of 4.5/20 (Q1–Q3: 4–6) was revealed. For domestic activities, physical activities and leisure time median values of 8.5/30 (Q1–Q3: 6–11.75), 4/8 (Q1–Q3: 3–4) and 4/12 (Q1–Q3: 3–5) were reported, respectively. The median LCADL score in males  was significantly lower compared to females  (sample difference −6 (95% CI −1 to −10), 2 and 4.4 (Q1–Q3: 3.4–6.5) kg/cm2 on the quadriceps muscle. For temporal summation, the first score was subtracted from the final score, leading to a median value of 3 (Q1–Q3: 1.25–4) for the trapezius and 4 (Q1–Q3: 2–5) for the quadriceps point.The median PPT on the trapezius muscle was 4.4 (Q1–Q3: 3.1–5.6) kg/cmFor functioning of the descending inhibitory pathways, 35 patients demonstrated an efficient CPM  and 5 patients did not  when measured on the trapezius muscle. On the quadriceps muscle, 6 patients did not demonstrate an efficient CPM , while 34 patients demonstrated an efficient CPM . In two patients, no CPM effect was measured.p < 0.001) and between TS on the trapezius and quadriceps  was observed. The total scores on the LCADL and CSI were also positively correlated . A negative correlation between PPTs on the quadriceps and the CSI score  was also identified   = 4.46,  = 0.03) . The effp < 0.001). There was a significant effect of central sensitization-associated symptoms on the PCFS with higher median values in patients with sensitization symptomatology, both for the PCFS scores derived from the self-reporting of patients (χ² (df = 1) = 12.67, p < 0.001) as well as from the interviews (χ² (df = 1) = 9.91, p = 0.002, For the LCADL, the median score in patients with the presence of symptoms of central sensitization was higher compared to patients with the absence of these symptoms (χ² (df = 1) = 27.18, n = 39). A visual presentation of the clusters is graphically presented in The K-means clustering resulted in five clusters, whereby 5, 8, 10, 13, and 3 patients were classified  is characterized by high PPTs on the trapezius and rectus femoris, while cluster 5 (7.7%) is characterized by high values of descending nociceptive inhibitory control. Cluster 3 (25.6%) predominantly reveals a high contribution of limitations in usual activities based on the PCFS. Finally, 20.5% of patients are attributed to cluster 2 in which rather low PPTs, lower contribution of PROMs, high values of descending inhibitory control and a limited contribution of nociceptive facilitation are present.The current study observed the presence of central-sensitization-associated symptomatology in up to 64.3% of patients post-COVID-19 infection, based on self-reporting through the CSI. Most patients (69%) reported slight to moderate functional limitations. Physical activities were responsible for most of the dyspnea-related limitations in activities of daily life. For patients with central-sensitization-associated symptoms, greater dyspnea-related limitations and higher limitations in functional status were observed. A small negative correlation between pressure pain sensitivity on the rectus femoris and the CSI score was observed. No other correlations between experimental pain measurements and CSI were observed. Clustering analysis identified that 33% of patients in this sample demonstrated a profile featuring a high CSI score, nociceptive pain facilitation, and malfunctioning of the nociceptive inhibitory pathways.Based on the WHO definition, individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months, could be classified as suffering from post-COVID-19 condition . The patSince the use of PROMs such as the CSI is not able to further ascertain the presence of altered nociceptive pain processing, we included, for the first time, experimental pain measurements in people post-COVID-19 infection. The presence of pressure pain hyperalgesia increased temporal summation and impaired descending inhibition are manifestations of central nervous system sensitization . We wereNevertheless, our main objective was to further identify the association of experimental pain measurements with the self-reported CSI. We identified a small correlation between sensitivity to pressure pain and the CSI score suggesting that both outcomes represent different aspects of the sensitization spectrum. This weak correlation is in line with previous data in chronic spinal pain patients where a weak correlation was found between the CSI and PPT , as was p < 0.001), meaning that patients with higher symptomatology of central sensitization present more dyspnea during activities of daily living. Furthermore, patients with high central sensitization symptomatology also revealed more limitations in functional outcomes. Previous studies have already demonstrated correlations between CSI and functionality, work ability, depression, and social support scales in patients with spinal pain [Concerning the PROMs, a positive correlation was revealed between the LCADL and the CSI  was used, whereas the available guidelines recommend the use of different modalities . This chIn patients post-COVID-19 infection, symptoms of central sensitization were present in 64.3% of the sample based on a self-reported questionnaire. A more objective evaluation of nociceptive pain processing was less suggestive for indicators of central sensitization, thereby pointing towards a discrepancy between the CSI and experimental pain measurements in patients post-COVID-19 infection.


Our previous research reported a novel deeper intubation technique (DIT) of the ileus tube for acute bowel obstruction patients. The present study was designed to evaluate the effect of this novel technique on the clinical outcomes of patients with obstruction using a large cohort.The detailed clinical data were analyzed retrospectively from 496 obstruction patients who underwent intubation technique from 2014 to 2019 in five hospitals. The patients were divided into either the DIT group or the traditional intubation technique (TIT) group. The groups were matched in a 1:1 ratio using propensity scores, and the primary outcome was the short-term clinical outcomes for patients.The baseline characteristics were similar between the DIT group and the TIT group after matching. Compared with the TIT group, the DIT group had a significantly deeper intubation depth, with shorter hospital days, shorter time to first flatus and defecation, lower pain score, increased drainage volume, and lower emergency surgery rate. Importantly, the inflammatory factors such as white blood cell, C-reactive protein, and procalcitonin levels were significantly lower in the DIT group. In addition, the DIT treatment was significantly useful for adhesive obstruction patients.The DIT procedure led to better short-term clinical outcomes compared with the TIT procedure, indicating that DIT is a safe and feasible technique for the treatment of intestinal obstruction that is worthy of further popularization and clinical application. Then, the short-term clinical outcomes as well as the inflammatory parameters of these subjects were compared.etc., and (5) detailed medical records and follow-up information were available.This study was designed as a multicenter, retrospective case–control study comparing the short-term clinical outcomes and safety of the DIT procedure and the TIT procedure. The present study investigated 496 hospitalized patients with acute intestinal obstruction in five hospitals from January 2018 to December 2020. The inclusion criteria were as follows (1): the hospitalized patients had acute intestinal obstruction symptoms like nausea and vomiting, abdominal pain, abdominal distension, and exhaust defecation ceasing, (2) the patients were diagnosed with intestinal obstruction by abdominal X-ray plain films and abdominal CT examination, (3) the patients were suitable for conservative treatment, with no severe abdominal pain or persistent abdominal pain, bloody vomiting or bloody stool, asymmetric abdominal distension, respiratory instability, and even shock, peritoneal irritation, and other strangulated intestinal obstruction symptoms, (4) the patients had no contraindications of tube intubation, such as a history of ENT surgery, esophageal disease, etc. When patients presented with symptoms of severe abdominal pain, distension worsening, tachycardia, hematemesis, hematochezia, peritoneal irritation, isolated swelling, bowel loops, and even shock, timely surgical treatment would be needed. After multidisciplinary discussions, patients who failed to be intubated were treated surgically. The surgeon probes the abdominal cavity to find and remove the obstructed bowel. An anastomosis or ileostomy is performed depending upon the condition of the patient and the contamination involved.The DIT and TIT procedures were performed using the CLINY Ileus Tube suite  according to the protocol reported previously. All the enrolled patients were given conservative treatment methods as fasting, intravenous nutrition, anti-infection, maintenance of water, electrolyte, and acid–base balance, Details on the average intubation depth, the daily drainage of the gastrointestinal decompression tube, the abdominal pain relief rate, the recovery time for anal exhaust defecation, and the length of hospital stay were recorded. The treatment efficiency was defined as a clinical or radiological improvement, relief of abdominal symptoms, decreased drainage volume, and disappearance of air–fluid levels.The patients’ pain score and defecation situation were monitored and recorded before and every 24 h after intubation using the Numeric Rating Scale (NRS) , 12. TheWe used propensity score matching (PSM) to limit confounders and overcome possible patient selection bias due to the retrospective study design. A regression model was created based on potential variables  associated with the selection of treatment. A 1:1 nearest neighbor matching algorithm with an optimal caliper width of 0.2 without replacement was applied to match the propensity scores.t-test for continuous variables and chi-square test or Fisher’s exact test for categorical variables. All statistical tests were two-sided, and P-values less than 0.05 were considered statistically significant.The data in this study were processed by SPSS 26.0 software . Comparisons between the two groups were performed by Student’s n = 496) and propensity score-matched (n = 426) cohorts. After PSM, 426 patients were identified, and the clinical characteristics among the two groups were well balanced .Following the DIT procedure, abdominal radiographs showed an effective therapeutic effect in two example patients with intestinal obstruction Figure 1vs. 5.06 ± 1.21, P = 0.103), while after intubation, the NRS score in the DIT group was significantly lower than that in the TIT group .Before intubation, there was no difference in the NRS score between the DIT group and the TIT group . The defecation rate within 24 h  and 48 h  after intubation was significantly increased in the DIT group. Most of the patients in both the DIT group and the TIT group recovered defecation within 1 week after intubation .With respect to remission of the disease, the study showed that both the first flatus time and exhaust defecation time were markedly shortened in the DIT group compared with the TIT group . Although the emergency surgery rate was lower in the DIT group, the difference was of no significance , and patients in the DIT group had a shortened hospital stay . As for intubation-related complications, there was no significant difference between the two groups , and according to the Clavien–Dindo classification, the two groups also showed no significant difference regarding the complication grade . In accordance with our previous research, no significant difference was shown between the two groups when it comes to fecal obstruction (P = 0.538) and cancerous obstruction (P = 0.328).To further evaluate the effect of DIT procedure in the treatment of different types of intestinal obstruction, we analyzed the data according to the etiology of obstruction and divided the patients into three groups: adhesive obstruction, fecal obstruction, and cancerous obstruction. As shown in Inflammatory indexes such as the WBC, CRP, and PCT were used to evaluate the level of infection and remission of the disease. As shown in Intestinal obstruction is one of the most common reasons of all emergency department visits for acute abdominal pain . SeriousFor the TIT procedure, the diameter of the matching guide wire of the intestinal obstruction catheter is 0.045 cm with high hardness, and the friction between the catheter and the guide wire is large, so it is difficult to control the catheter and the guide wire . Moreovevia the catheter to change the stereo direction of the bowel, changing the patients’ posture and guiding the weighted tip to conform to the track of the bowel at the same time. In addition, water-soluble iodine contrast medium could also be injected into the bowl to observe the stereo track of the bowel and stimulate peristalsis. Therefore, we could effectively forward the tip of the tube closer to the obstruction site and decompress the intestinal contents more sufficiently.Our previous research presented a novel DIT procedure. Using the CLINY Ileus Tube suite, a zebra guide wire with a diameter of 0.035 with ideal flexibility was selected, which made it easier to control the catheter, and the catheter was as close to the obstructed site as possible without the aid of intestinal peristalsis. Moreover, digital gastrointestinal fluoroscopy technology can not only expose and collect images in real time, realize intermittent operation, and avoid X-ray radiation of the operator but also allow patients to change position at any time. Furthermore, when intubation encounters obstacles such as intestinal folds or swerve, an appropriate volume of air could be injected into the bowel To confirm the safety and effectiveness of this procedure, we conducted a multicenter, retrospective cohort study comprising 496 subjects. Although there were no significant differences in baseline characteristics between the two groups, we still tried to minimize potential imbalances, such as in the PSM analysis. The two groups were matched in a 1:1 ratio using propensity scores, and after matching, the two groups were comparable. The present study showed that the intubation depth in the DIT group was significantly deeper than that in the TIT group. As is known to all, intestinal peristalsis is the main power forwarding the tube in the TIT group, and patients usually present weakened or even vanished intestinal peristalsis due to the application of analgesics, abdominal  infection, and electrolyte disorders . The deeIt is worth noting that the emergency surgery rate was lower in the DIT group, although the difference was of no significance. The tendency may also benefit patients with acute intestinal obstruction a lot. The shortened hospital stay reduces the burdens of the patients’ family and leads to better social economic benefits. Moreover, intubation-related complications such as catheterization discomfort/pain, catheter obstruction, catheter shift/falling off, aspiration pneumonia, and intestinal hemorrhage/perforation were of no significant difference between the two groups. All the aforementioned results indicated that the DIT procedure was a safe and effective treatment strategy for patients with acute intestinal obstruction.The effect of DIT on different types of intestinal obstruction was also investigated. Consistent with our previous research, the overall efficacy of the DIT procedure was up to 91.7% for adhesive intestinal obstruction, the most common type of intestinal obstruction , 22. ThiImportantly, to evaluate the effect of the DIT procedure, the study also analyzed the inflammatory indexes such as WBC, CRP, and PCT, as these indicators could simply and practicably reflect the severity of the disease, the degree of inflammatory responses, and the infectious condition , 27. ThuThe highlight of this study mainly relies on the large sample size and the multicenter design. Moreover, related data were matched using propensity scores to eliminate the base discrepancies, which made the results more rigorous. Compared with our previous research, the present study proved that the DIT procedure is more convincingly a safe and effective treatment strategy for acute intestinal obstruction. Of course, long-term survival data is warranted in a further study. Based on the aforementioned results, a multicenter randomized controlled trial would be welcome and provide higher-level data of evidence-based medicine.In conclusion, the DIT procedure is a safe and effective treatment strategy for acute intestinal obstruction. Compared with the TIT procedure, the DIT procedure showed better short-term clinical outcomes and decreased the inflammatory responses more effectively, which is worthy of clinical application and popularization.The 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 The Clinical Ethical Committee of Central Hospital of Zibo. The patients/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.ZD and SW designed the research. YT, FY, and ZL were involved in data acquisition, analysis, and interpretation. YT wrote the paper. PH and CZ contributed to make the tables and figures. JS revised the paper. All authors contributed to the article and approved the submitted version.


Methods. ICU nurses were randomly divided into a control group  and an experimental group (managed pain based on the Precede-Proceed model). The nurses from the experimental group were trained in the Precede-Proceed-based management. The nurses then treated a total of 410 critically ill patients, and the patients were randomly divided into a control and an intervention group (205 cases/nursing group), and the data were prospectively recorded. Before and after the intervention, the pain assessment ability, discomfort level, satisfaction degree, usage of the analgesic drug, and the incidence of delirium of the patients from the two groups were evaluated. Nurses from both groups also assessed their knowledge of pain, attitude, and pain nursing behaviors using indicated self-designed questionnaires.  This study's objective is to establish a nurse-led pain management model for neurointensive care based on the Precede-Proceed model to provide a theoretical basis for clinical pain management in neurointensive care. Conclusion. Pain management based on the Precede-Proceed model was beneficial in improving the care of neurointensive patients. Before the intervention, there was no statistical difference between the two groups of nurses in their baseline characteristics, pain knowledge, attitude, pain nursing behavior, and pain assessment ability for the patients. After the intervention, the nurses in the experimental group had better pain knowledge, attitude, pain nursing behavior, and pain assessment ability to patients than the nurses in the control group. Patients in the intervention group felt less discomfort, a higher satisfaction degree, reduced use of analgesics, and a lower incidence of delirium than patients in the control group Neurointensive refers to serious nervous system diseases, mainly including severe head trauma, severe cerebrovascular disease, complex intracranial tumors, and increased intracranial pressure, which may significantly influence patients' neurological function and even lead to coma . A previMost critically ill patients may still feel pain when transferred to the ICU , but theIn recent years, the Precede-Proceed model has been used widely in the field of pain-reducing. Chen et al.  suggesten = 100; giving conventional routine pain care) and an experimental group . The nurses then treated a total of 410 critically ill patients who were admitted to our hospital ICU department. According to the different nursing methods, the patients were randomly divided into a control (n = 205) and an intervention group (n = 205), and the data were prospectively recorded. In this study, purposive sampling was used to select all nurses in the intensive care unit of the investigator's hospital as the research objects. All nurses and patients provided a signed informed consent form. This study was approved by the Ethics Committee of Taizhou Hospital of Zhejiang Province (K20200785).Self-designed questionnaire surveys, including general information, Pain Knowledge and Attitudes Questionnaire (KASRP), and ICU pain nursing questionnaire were used to conduct a survey among 200 registered nurses in our hospital. ICU nurses were randomly divided into a control group (The study inclusion criteria for the nurses were (1) the nurses investigated had a registered nurse qualification certificate; (2) worked in the NICU of our hospital for ≥1 year; and (3) provided a signed informed consent and voluntarily participated in this study.The study exclusion criteria for the nurses were (1) registered nurses were not on duty due to training, vacation, sickness, and pregnancy; (2) nurses who had been on vacation and returned to work for less than 3 months; and (3) also worked outside the hospital for further training or reemployment.We collected the baseline characteristics of all nurses, including age, gender, education level, and working years.The random function was used to randomly divide the research subjects into two groups. ICU nurses in the control group performed conventional pain care, while the experimental group managed pain based on the Precede-Proceed model to train the ICU nurses about their pain knowledge, nursing skills, and pain management on ICU patients. The ICU patients nursed by the nurses in the control group did not have any additional treatment and followed the conventional nursing methods for pain management, including admission checking and cooperating with doctors for various indicators checking and complication assessment. The ICU patients nursed by nurses in the experimental group were managed by the Precede-Proceed model, and the pain management personnel for the ICU patients were interviewed through the semistructured in-depth method, including physicians, nurses, respiratory therapists, rehabilitation therapists, and anesthesiologists, to analyze the various factors of influencing the pain management behaviors of the nurses which were then classified as the predisposing factor, reinforcing factor, and contributory factor, and corresponding measures were taken to promote the clearance of these factors, and finally, a nurse-led ICU pain management model was constructed. The research process is shown in Observation indicators included (1) comparison of the baseline characteristics between the two groups of nurses; (2) according to a self-designed KASRP, we scored the two groups of ICU nurses before and after the intervention, with a total score of 50 points; (3) according to a self-designed ICU pain nursing questionnaire, we scored the pain nursing skills of the two groups of ICU nurses before and after the intervention, with a total score of 100; and (4) according to a self-designed questionnaire, we scored the pain assessment ability of the nurses to the ICU patients of the two groups before and after the intervention, with a total score of 10 points.Effect evaluation was performed based on the following: (1) comparison of the discomfort level between the two groups of patients according to the ICU Patient Discomfort Assessment Scale after the intervention, with a total score of 100; (2) the incidence of complications after the intervention of the two groups of patients; (3) patient's satisfaction degree between the two groups of patients after the intervention according to the self-designed questionnaire using the following scale: 1, dissatisfaction; 2, moderately satisfied, and 3, very satisfied; (4) the usage of analgesic drugs of patients after the intervention; and (5) the incidence of delirium after the intervention.t-test was used to compare quantitative data conformed to normal distribution. P < 0.05 represented that the difference was distinct.The SPSS 22.0 software was used to analyze the data, described as the frequency, percentage, mean, and standard deviation of the research object. The chi-squared test was used to compare the general data between the two groups. The nonparametric test was used to compare rank data, and The general information of the two groups of nurses involved is shown in P = 0.256), pain nursing behavior (P = 0.672), and pain assessment ability (P = 0.823) to the patients between the two groups of nurses before the intervention   .P < 0.001)  .n (%). aThe data were analyzed by t-test; bthe data were analyzed by χ2.Values are in mean ± SD or Pain can cause excessive psychological pressure on patients, create negative emotions, reduce their quality of life, and affect postoperative recovery. Therefore, it is necessary to conduct routine and reproducible pain assessments for all critically ill patients to identify and reduce the pain as soon as possible, rather than waiting until the pain intensifies . The patInsufficient pain control often occurs before and after transferring patients out of the ICU, which can cause sleep disorders, delirium, and other post-ICU syndromes and increase the average hospitalization duration . In addiIn this study, the analgesic usage and the incidence of delirium in different groups were compared. Our results showed that pain management based on the Precede-Proceed model was better, suggesting that this model has promising potential in helping nurses to better communicate with patients and encourage them to improvise individualized ways to help patients improve their mood and decrease the level of stress and anxiety.n = 410) and nurses (n = 200) in this study, we consider that this limitation may have not significantly affected the study findings.Despite the interesting observations of this study, there are some limitations worth mentioning. First, this is a single-center study performed on Chinese patients. A multicenter setting and a larger cohort of patients are needed to verify our findings. Also, considering that ethnicity, race, and population might lead to different pain tolerance level, multiethnicity and population data would be useful to further validate the applicability of the study protocol to more countries. Lastly, the patients were not separated by their disease or surgery types, which may have affected the study results to a certain extent. However, considering the large number of patients (In summary, the reported nurse-led neurosurgery pain management model based on the Precede-Proceed model was associated with improved satisfaction, reduced usage of analgesic drugs, and lower incidence of delirium in ICU patients. These findings suggest that this management model could be worthy of clinical application. However, since this study was only performed in one hospital, further studies using larger cohorts of data from multiple hospitals should be performed to validate our findings.


Up to 80% of Alzheimer’s disease (AD) patients in nursing homes experiences chronic pain and 97% develops fluctuant neuropsychiatric symptoms (NPS). Agitation, associated with unrelieved pain, is managed through antipsychotics and may increase the risk of death. Evidence is accumulating in favor of analgesia for a safer, effective therapy of agitation. The Italian version of Mobilization–Observation–Behavior–Intensity–Dementia, I-MOBID2, recently validated in the Italian setting, shows: good scale content validity index (0.89), high construct validity (Spearman rank-order correlation Rho = 0.748), reliable internal consistency (Cronbach’s α coefficient = 0.751), good-excellent inter-rater  and test-retest (ICC = 0.902) reliability, and good inter-rater and test-retest agreement (Cohen’s K = 0.744) with 5.8 min completion time. This study intends to identify the responsiveness of the I-MOBID2 based on COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) recommendations, assessing the a priori hypotheses of (1) the efficacy of painkillers administered to severe AD patients after proper pain assessment and (2) the effect of reduction of the Cohen-Mansfield Agitation Inventory (CMAI) score and of agitation rescue medications. This protocol is approved by Calabria Region Ethics Committee protocol No. 31/2017 and follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Despiariables , i.e., pa priori hypotheses to test are the following: (i) I-MOBID2 overall and a decrease in the first and second part pain scores after 8-weeks of analgesic treatment; (ii) where the CMAI score decreases after 8-week analgesic treatment, the duration needed for a stepwise protocol for pain treatment to reduce agitation [The protocol for the present clinical study intends to identify: (1) the efficacy of the painkillers administered to patients suffering from severe AD ; (2) thegitation  and paingitation  in demengitation , recommegitation . Patientgitation . As previously occurred during the I-MOBID2 validation study, the nurses will receive a 2-h training and will perform a baseline 1-week observation of the patients to familiarize themselves with them and to assess pain using the I-MOBID2. According to the instructions for the use of the tool, they will explain clearly to the patients what will happen, asking “Mrs., can you please open and close your left hand? I will help you!” . For theIn agreement with the instructions manual of the CMAI, it is a caregivers’ rating questionnaire consisting of 29 agitated behaviors: each frequency of presentation will be rated on a 7-point scale based on the two weeks preceding its administration. In particular, the frequency of behavior occurrence is rated as follows: never; less than once a week; once or twice a week; several times a week; once or twice a day; several times a day; several times an hour. Since each behavior can include a wide spectrum of disorders, the raters and the respondents will be provided with a detailed description of behaviors, explaining that it is necessary to pay attention and include also similar but not exactly cited behaviors in the closest related item. In this case, the rater will be provided with appropriate training and will conduct the interview with the caregiver familiar with the patients. He will explain the importance of making this assessment and what is going to happen, providing the respondent with a copy of the scale several days before, reading aloud each item and doing the face-to-face interview without influencing him, in a quiet room, avoiding interruptions. Moreover, a rating of disruptiveness of the observed behaviors will be performed, asking for every behavior that has occurred and if it is disruptive to the staff: Not at All; A little; Moderately; Very Much; Extremely. The numeric rating scale corresponding is as follows: 1 = Never; 2 = Less than once a week but still occurring; 3 = Once or twice a week; 4 = Several times a week; 5 = Once or twice a day; 6 = Several times a day; 7 = Several times an hour. The scores will average the frequency of occurrence within the two previous weeks considered. For the I-MOBID2, about 5–6 min will be needed for completion, whereas 20 min for CMAI. The protocol for agitation assessment through the CMAI is shown in No intervention drugs out of usual care will be used. The patients meeting the inclusion criteria will be enrolled and randomly allocated to two groups: (1) usual care and (2) analgesic treatment based on the WHO analgesic ladder according to the assessment of intensity. In particular, oral non-steroidal anti-inflammatory drugs (NSAIDs) including naproxen, ibuprofen, and diclofenac will be considered for inflammatory musculoskeletal pain and celecoxib in case of chronic osteoarthrosis, after the failure of acetaminophen, only for short periods as recommended by the American Geriatric Society (AGS) panel ,56, to rThis is a multicentre trial involving nursing home consecutive patients. The inclusion criteria are the following: age ≥ 65 years; MMSE ≤ 12; informed consent signed by a legal representative. In particular, since GDS  and FASTThis study protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines ,73. Thist-test and the correlations with the CMAI and psychotropic drugs identified through Pearson’s correlation [Patients are considered in pain when the I-MOBID2 items or the overall pain intensity are scored ≥ 3 and suffering from agitation with a CMAI score ≥ 39 . Descriprelation . No sampThe high prevalence of pain in elderly persons in nursing homes (over 65 and with a mean of 83 years of age ) has bee


Objective. Clavicle fracture fixation is commonly performed under general anesthesia due to the complex sensory innervation in this region which poses a challenge for anesthesiologists applying regional anesthetic (RA) techniques. In part 1 of this two-part study, we summarized the current literature describing various RA approaches in clavicle fractures and surgery. In our earlier scoping review, we surmised that a superficial or intermediate cervical plexus block (CPB) may provide analgesia for this procedure and, when combined with an interscalene brachial plexus block (ISB), can provide anesthesia to the clavicular region for surgical fixation. We performed a retrospective study, consolidating assumptions that were based on the results of our earlier scoping review. Methods. A retrospective study was conducted on 168 consecutive patients who underwent clavicle fixation surgery at a tertiary healthcare system in Singapore. We used a standardized pro forma to collate perioperative data from the electronic health records of both hospitals, including anesthetic technique, analgesic requirements, pain scores, and adverse events, up to the second postoperative day or up until discharge. Results. In our study, patients who received RA had significantly reduced pain scores and opioid requirements, compared to general anesthesia (GA) alone. Through subgroup analysis, differences were found in postoperative pain scores and opioid requirements in the following order: GA alone > GA with local infiltration analgesia > CPB > CPB plus ISB. All patients who received combined CPB and ISB had upper limb weakness in recovery, compared to none with CPB alone (p < 0.001). Of those who received an ISB either in isolation or combined with a CPB, four (9.3%) were reported to have dyspnea (within 24 h) and motor weakness that persisted beyond 12 h, compared to none for patients that received CPB alone. Conclusions. Addition of a CPB to GA for clavicle fracture fixation surgery is associated with reduced pain scores in the early postoperative period, with a lower opioid requirement compared to GA alone. In patients undergoing GA, the combination of a CPB with an ISB was associated with a small, although statistically significant, reduction in pain scores and opioid requirements compared to a CPB alone. Clavicle fractures are a common upper extremity injury that can be associated with significant perioperative pain ,2,3. SurGiven the lack of studies that directly investigate the impact of a CPB in patients who receive clavicle surgery under GA, and to make our earlier scoping review more complete, we thus conducted a retrospective medical records study in order to consolidate the assumptions based on the findings in our scoping review. Furthermore, in our earlier scoping review, we also noted that the effect of surgical local anesthetic (LA) infiltration as a supplement to patients undergoing clavicle fracture fixation under GA has not been well articulated. In our study, we retrospectively compared patients who had a CPB or ISB alone or in combination, compared to patients who did not receive any regional anesthesia/analgesia technique in the case of clavicle surgery under GA. We also made comparisons between patients who received GA alone versus those who received GA with local infiltration analgesia (LIA) without regional anesthesia (RA).We conducted a retrospective review of patients who underwent clavicle fixation surgery within a tertiary healthcare cluster in Singapore. Approval for the study was obtained from the institutional review board prior to commencement of the study (reference number: DSRB 2021/00596). Data collection. Data were extracted from the electronic health records of 176 consecutive adult patients undergoing clavicle fixation surgery at 2 hospitals within a tertiary healthcare system, from August 2015 to April 2021. Data were recorded using a standardized pro forma, and included demographic data, such as age, gender, and ethnicity, relevant anesthetic and surgical data such as anesthetic technique , postoperative pain scores in recovery, opioid requirements (intraoperative and in recovery), non-opioid analgesic regimen, and pain scores up to the 2nd postoperative day, or up to discharge. Documentation from medical, nursing, anesthetic, acute pain services, and surgical records, as well as electronic medication administration charts, were all examined.Pain scores were expressed as a numeric rating scale from 0–10/10. We reported total opioid requirements from the intraoperative period up to the point of discharge from recovery, as oral opioids are not typically prescribed in recovery at our institution. Total opioid requirements were expressed as milligrams of oral morphine equivalents (OME). We also collected data on block-related complications, and opioid-related adverse effects. Data were manually collated and cross-checked by 2 individuals to ensure accuracy.Inclusion and exclusion criteria. All patients aged 18 years and above who underwent isolated clavicle fixation surgery were considered eligible for inclusion, regardless of the site of the fracture. We excluded 12 patients who either (1) underwent concurrent surgical procedures, or (2) had concomitant non-clavicular injuries due to the potential for distracting pain that would confound the pain assessment. A total of 170 patients were eligible for inclusion into the study.Statistical analysis. Analyses were performed using R statistical software  and R studio . The Kolmogorov–Smirnov test was applied to assess the distribution of continuous variables for normality. Continuous, normally distributed data were expressed in terms of the mean and standard deviation. Pain scores were presented in terms of median and interquartile range. Categorical data were described in terms of numbers and proportions. When multiple hypotheses are tested simultaneously, there is a propensity for type I error, and methods to control the family-wise error rate or false discovery rate are required [p-value using a Bonferroni correction for quantitative, normally distributed data. In the case of non-parametric data, we applied the Kruskal–Wallis test across groups, and performed post hoc pairwise comparisons using the Wilcoxon rank sum test, controlling the family-wise error rate with Holm’s step-down procedure for multiple testing correction. For statistical significance, we used a threshold of p < 0.05.required . When pePatient characteristics. Patient characteristics are presented in p = 0.186) (= 0.186) .p = 0.648). Amongst patients who received RA, 38 (46.9%) patients received a CPB, 32 (39.5%) patients received a combination of a CPB and an ISB, and 11 (13.6%) patients received an ISB alone. A further two patients received a supraclavicular brachial plexus block ; there were no differences in the type of airway device used (intubation vs. supraglottic airway) between the group that received regional anesthesia and the group that did not  and volumes  of LA have all been used at the discretion of the primary anesthetic team. No additives such as dexamethasone, clonidine, or dexmedetomidine were added into any of the nerve block injectates. We found that patients who received RA had a small reduction in median pain scores in the post-anesthetic care unit , and on the first postoperative day  compared to those who did not receive a regional block (p < 0.001), as well as a need for rescue analgesia in recovery . There were no differences in the incidence of pain that affected sleep . We did not analyze postoperative opioid use in our institution, as patients are generally not prescribed strong opioids for this procedure postoperatively, and only six patients were administered morphine or oxycodone in the early postoperative period after leaving the operating theatre, hence precluding any meaningful statistical comparison. We also found a statistically significant reduction in postoperative nausea and vomiting in the group that received RA . There were no reports of oversedation or acute urinary retention that required urinary catheterization.al block . This waCervical plexus block vs. combined cervical plexus and interscalene block. We also compared patients who received a cervical plexus block against those who received a cervical plexus block and ISB combination (bination . p = 0.045) on the basis of linear regression analysis. However, we did not find any statistically significant differences in pain scores  in patients who had the block performed under ultrasound guidance compared to the landmark technique.During data extraction, we encountered difficulties in nomenclature for cervical plexus blockade, with a near-universal label of superficial cervical plexus block used in clinical documentation. Given the retrospective nature of the study, it is difficult to ascertain if a superficial or intermediate cervical plexus block was performed, particularly in the context of ultrasound guidance; thus, we applied a generic label of CPB for this study. Nonetheless, for the group which received a CPB alone, the landmark technique was associated with a higher opioid requirement (p = 0.150). Compared to patients who only received a CPB, patients who received an ISB in combination with a CPB had lower median pain scores in recovery and on the first postoperative day  (p < 0.001)  , and low< 0.001) . FurtherCervical plexus block vs. general anesthesia with local infiltration analgesia. In addition, given the lack of studies investigating a CPB and GA compared to GA alone, we compared patients who received a CPB alone to patients who did not receive a RA technique. Furthermore, most studies did not make a comparison between GA with CPB and GA with LIA. In our data set, LIA was typically performed by the surgical team with 10–20 mL of 0.25% or 0.5% bupivacaine with adrenaline. Patients who received a CPB had a small but significant reduction in pain scores during recovery  that was achieved with lower opioid requirements , and a lower need for rescue analgesia  (= 0.042) . General anesthesia vs. general anesthesia with local infiltration analgesia. We also performed comparisons between patients who received GA alone and those who received GA with LIA. We found that LIA was associated with improved pain scores in recovery , which was achieved with lower opioid requirements  (p = 0.006). However, there were no statistically significant differences in pain scores on the first (p = 0.942) or second (p = 0.810) postoperative day.< 0.001)  and a reInterscalene brachial plexus block. Only a small number of patients received an isolated brachial plexus block (n = 11), which made it difficult to carry out meaningful comparative analyses. Median pain scores were 5.0 (IQR = 6.0), 2.0 (IQR = 1.0) and 2.0 (IQR = 1.0) in the post-anesthetic care unit on the first and second postoperative days, respectively. Mean oral opioid requirements (OME) were 15.4 mg, with a wide 95% confidence interval from 9.8 mg to 21.0 mg. Nonetheless, linear regression analysis showed that a fracture involving the middle third of the clavicle was significantly associated with higher total opioid requirements (p = 0.001) compared to lateral third fractures, although this was not statistically significant for pain scores in recovery, or on the first or second postoperative days. Block-related complications. In our data set, all patients who received an ISB were documented to have upper limb motor weakness in recovery or on arrival to the ward, with four  patients having motor blockade that persisted beyond 12 h, postoperatively. None of the patients who received a CPB alone had documented motor blockade. Lastly, four (9.3%) of all patients who received an ISB were documented to experience dyspnea postoperatively within 24 h of the block; this may have been related to phrenic nerve involvement, although none required oxygen supplementation postoperatively beyond the post-anesthetic care unit. All patients who received an ISB  had postoperative motor blockade in recovery. As this was a retrospective study, the exact time or duration of resolution of the motor block could not be ascertained. No patients had a residual upper limb motor or sensory blockade that persisted beyond the first postoperative day.No other recorded block-related complications were found during our retrospective data collection. We did not find any differences in the incidence of postoperative nausea and vomiting or pain affecting sleep between patients who received RA and those who did not. However, our study was not powered to identify these differences. Lastly, due to the limits of retrospective data collection in terms of electronic health records, we were unable to collect sufficient quantitative or qualitative data on motor blockade or block duration for meaningful analysis. We conducted this retrospective study to elucidate the efficacy of CPB with or without the addition of an ISB in the early postoperative period, compared to patients who underwent surgery without regional anesthesia. We also made pairwise comparisons between these groups and with patients who received general anesthesia, with or without LIA. General anesthesia versus regional anesthesia. Our findings demonstrate that early postoperative pain scores and opioid requirements ranked in the following order: GA alone > GA with LIA > CPB > CPB plus ISB. However, this difference became less significant beyond the first postoperative day (p = 0.045), likely due to reduced opioid use. Compared to patients who underwent clavicle fixation under GA with LIA, patients who received a CPB had a small but statistically significant reduction in pain scores  in the immediate postoperative period, which was achieved by significantly lower opioid doses  and reduced requirements for rescue analgesia during recovery (p = 0.045), although we did not find any significant differences in pain scores. This has to be interpreted on the basis of nomenclature difficulties, similarly to those that were highlighted in our earlier scoping review. In our data set, virtually all CPBs were labelled as a superficial cervical plexus block; however, it is possible that some of these were actually intermediate cervical plexus blocks, with deposition of LA beneath the theoretical fascial barrier that may have dichotomized the two blocks by preventing deeper LA spread—although studies have not consistently demonstrated any difference in efficacy between the two [tive day . Regionarecovery . Based o the two ,16,17. Superficial cervical plexus plus interscalene block. There was a statistically significant, but small further reduction in pain scores and opioid requirements with the addition of an ISB (p = 0.001). This was congruent with the sensory blockade produced by this technique, since the subscapular, lateral pectoral and axillary nerves that innervate the lateral aspect of the clavicle receive contributions from the fifth to seventh cervical nerve roots, which were targeted in this approach [f an ISB . In addiapproach . We opinp < 0.001), in a proportion of patients who received an ISB with a blockade persisting beyond 12 h. This could be undesirable for patients who are candidates for ambulatory surgery, as the insensate upper limb may prolong a return to function. Our retrospective data are limited in terms of describing the extent of motor weakness, and no single method was used to quantify the degree of motor blockade; this is an issue that warrants consideration for future studies. Early studies associated the incidence of phrenic nerve involvement with an ISB to be as high as 100%, albeit with a paresthesia technique [Unsurprisingly, all patients who received a combined CPB and ISB had limb weakness in recovery, compared to none with CPB alone ; considering that this can be achieved with reduced opioid requirements (p = 0.006), this simple intervention should be given due consideration whenever possible. However, our data could not be used to examine the efficacy of adding LIA to RA, either pre-emptively or as a rescue procedure, which could be examined in future studies. e fibers . Supplemirements , and redIn part 1 of our publication, we discussed the complexity of sensory innervation to the skin over the clavicle, and the clavicle periosteum itself ,6,7. In Unanswered questions. In this retrospective study, we noted the frequent use of high-concentration amide LAs in relatively large volumes. This carries a risk of spread to the recurrent laryngeal and phrenic nerve; furthermore, high concentrations of LAs carry an increased potential for neurotoxicity [toxicity . Thus, ttoxicity ,21. FurtStudy strengths and limitations. Our study involved a reasonable sample size (n = 168) compared to similar studies [ studies . HoweverAddition of a CPB to GA for clavicle fracture fixation surgery is associated with reduced pain scores in the early postoperative period, with a lower opioid requirement compared to GA alone. In patients undergoing GA, the combination of a CPB with an ISB is associated with a small, although statistically significant reduction in pain scores and opioid requirements, compared to a CPB alone. However, the magnitude of the reduction is likely clinically insignificant, especially considering the propensity for motor blockade and hemidiaphragmatic paresis that are associated with an ISB. Further observational and randomized studies are required to determine the efficacy and safety of the various RA techniques.