Oral mucositis (OM) in patients receiving cancer therapy is thus far not well managed with standard approaches. We aimed to assess the safety and effectiveness of methylene blue (MB) oral rinse for OM pain in patients receiving cancer therapy.n = 15), MB 0.05%+CTx (n = 14), MB 0.1%+CTx (n = 15), or CTx alone (n = 16). Intervention groups received MB oral rinse every 6 h for 2 days with outcomes measured at days 1–2; safety was evaluated up to 30 days. The primary outcome measured change in the pain numeric rating scale (0–10) from baseline to day 2. Secondary outcome measured change in oral function burden scores from baseline to day 2, World Health Organization OM grades, morphine equivalent daily doses, and adverse events. The trial was registered with ClinicalTrials.gov ID: NCT03469284.In this randomized, single-blind phase 2 clinical trial, patients were randomized to one of four arms: MB 0.025%+conventional therapy (CTx)  completed the study. Compared with those who received CTx alone, those who received MB had a significant reduction of pain scores at day 2 of treatment (mean ± SD); 0.025%: 5.2 ± 2.9, 0.05%: 4.5 ± 2.9, 0.1%: 5.15 ± 2.6) and reduction of oral function burden scores . No serious adverse events were noted, but eight patients reported burning sensation of the oral cavity with the first dose, and this caused one patient to discontinue therapy.MB oral rinse showed significant pain reduction and improved oral functioning with minimal adverse effects.ClinicalTrials.gov ID: NCT03469284.The online version contains supplementary material available at 10.1186/s12916-022-02579-8. Oral mucositis (OM) is a debilitating condition that can occur in patients receiving oncologic therapy. OM initially manifests as oral mucosal erythema and mild pain. Still, it may progress to oral mucosal ulcerations and severe pain that affects oral intake, thus increasing morbidity, disrupting the quality of life, and adding to the cost of care. Risk factors for OM include the prior use of etoposide to mobilize peripheral blood progenitor cells, prior oropharyngeal radiotherapy, renal failure, poor performance status, and malnutrition .2+ (PO4)2 both showed benefit in preventing and treating OM, but their effect in patients receiving stem cell transplantation appeared to be weak [Several agents have shown benefits for the prevention or treatment of OM. Intravenous palifermin showed effective prophylaxis compared with placebo in patients receiving cyclophosphamide/etoposide/total body irradiation  but not  be weak , 8. Oral be weak . Laser t be weak .In contrast, many interventions, some of which remain commonly used, are unproven or ineffective .Although many efforts aim to resolve the histologic manifestations of OM, the biggest challenge in clinical practice is pain control . TherefoThe purpose of this prospective, randomized trial was to determine the effectiveness and the safety of methylene blue oral rinse (MBOR) in the management of OM related to oncologic treatment.This was a prospective, randomized, single-blind, phase 2 clinical trial. Eligibility criteria included age of at least 18 years, a cancer diagnosis, receiving systemic chemotherapy, a current clinical diagnosis of OM, pain and oral dysfunction associated with OM despite conventional therapy (CTx), and voluntary written consent. Conventional therapy was defined as any intervention aimed at controlling oral pain, that included oral hygiene, analgesic rinses , and opiate analgesics. Exclusion criteria included known allergy to MB, pregnancy or breastfeeding, cognitive impairment and inability to consent, known history of G6PD deficiency, asymptomatic OM, and concomitant use of pro-serotonergic drugs. Patients undergoing radiation therapy were excluded due to the unknown ionization effect of MB on the radiating tissue.The protocol met the criteria for an investigational new drug and was subject to federal regulations under the US Food and Drug Administration requirements. Therefore, specific parameters of safety report were imposed, and the use of a placebo was not allowed in this trial. It was also requested to test different concentrations of MB to find the lowest efficient dose. The protocol was approved by the institutional review board at The University of Texas MD Anderson Cancer Center, Houston, Texas. Trial registration: ClinicalTrials.gov ID: NCT03469284; protocol number: 2016-1051.The study was conducted at The University of Texas MD Anderson Cancer Center involving adult patients with intractable pain associated with OM secondary to cancer therapy. Patients were enrolled between March 1, 2019, and December 01, 2020, and were randomized into one of four intervention arms: CTx alone (control arm) or 0.025%, 0.05%, or 0.1% MB solution in addition to CTx. Randomization allocation was downloaded from the institution’s clinical trial conduct website. All team members and patients were blinded to the concentration of MB used in each arm. MB was provided by the compound research pharmacy, responsible for the undisclosed dilution assigned. During the trial, three patients dropped out because they were disappointed at being assigned to receive CTx alone , which ranged from 0 (no pain) to 10 (worst possible pain). Secondary endpoints included oral functioning burden , morphine equivalent daily dose, and the incidence of adverse events after MB administration up to 30 days after the first dose of MB.Once eligible, patients were randomly allocated to one of the MB treatment arms stratifying for baseline NRS and baseline OFB; the research pharmacy delivered a 100-mL solution bottle to the bedside. A research team member was present to provide final instructions and supervise the use of the first dose. Patients were instructed to take one mouthful (6–10 mL) of the MB solution and hold it at the painful sites for 5 min. Swishing and gargling were encouraged to reach all anatomical corners of the oral cavity. Patients were then instructed to spit and pause a few minutes before rinsing or ingesting meals. The same steps were repeated every 6 h . Pain NRS and OFB scores were measured after each use and recorded at baseline and day 1, and day 2, after starting the treatment.F test with a 0.05 significance level in a one-way ANOVA test. The size of the variation in the means is represented by their standard deviation which is 1.14 . The common standard deviation within a group is assumed to be 2.5.For the primary outcome (OM pain reduction from baseline to 2 days after entering the study), we expected the mean pain reduction of 0, 2, 2.5, and 3 points for CTx alone, CTx + MB 0.025%, CTx + MB 0.05%, and CTx + MB 0.1% arms, respectively. The total sample of 60 subjects (15 in each arm) achieves 83% power to detect differences among the means versus equal means using an P-value less than 0.05 indicated statistical significance. SAS 9.4  was used for data analysis.Patient demographics and baseline characteristics, including baseline pain NRS scores and OFB scores, were summarized using descriptive statistics and compared by treatment group, utilizing Fisher’s exact test or chi-square test for categorical variables and Kruskal-Wallis test for continuous variables . Changes in NRS and OFB scores from baseline to day 2 were compared among treatment arms using ANOVA. According to ANOVA test, pairwise comparisons (by Tukey method) were performed if the overall group showed significant differences. A n = 43, 72%), followed by systemic chemotherapy alone . Most common therapeutic agents included carmustine/etoposide/cytarabine/melphalan combined, melphalan alone, vorinostat/gemcitabine/busulfan/melphalan mix, cyclophosphamide/etoposide combined, gemcitabine/docetaxel/melphalan/carboplatin combined, and etoposide alone.Of 112 patients screened, 43 did not meet all inclusion criteria, 69 were enrolled, and 60 completed the trial ; the clinical severity of the OM was documented only at enrollment point to the study. All patients were actively receiving oral rinses and concomitant systemic opiate analgesics, with a median morphine equivalent daily dose (MEDD) of 113.75 . Most patients had severe OFB at baseline, with a median score of 5  on the 0–6 scale. No patients were reported to be receiving total parenteral nutrition.The mucositis-related pain had lasted a median of 6 days  before the patient joined the trial. All patients had a clinical diagnosis of mucositis related to cancer therapy; per World Health Organization criteria, most patients had grade 3 mucositis  were suspected to have esophageal compromise; the oral mucosa was the most reported location .All patients had painful lesions in multiple areas of the oral cavity. Many : mean ± SD changes in pain NRS scores at day 2 were 5.2 ± 2.81 for CTx+MB 0.025%, 4.54 ± 2.93 for CTx+MB 0.05%, and 5.15 ± 2.64 for CTx+MB 0.1%, compared with 1.69 ± 3.09 for CTx alone : mean ± SD changes in OFB scores on day 2 were 2.47 ± 1.55 for CTx+MB 0.025%, 2.79 ± 1.72 for CTx+MB 0.05%, and 2.87 ± 1.60 for CTx+MB 0.1%, compared with 0.81 ± 1.11 for CTx alone , almost all patients required several doses—up to 6 (48 h)—to achieve sustained pain relief. Similarly, in more than half of the patients who received MB , pain recurred between 4 and 8 h . However, the intensity of recurring pain was reported at lower scores than at the baseline. The trial had sponsored only 100 mL of the MB solution, but we found that more than half of the patients who received it  requested to continue the MB oral solution after day 2. Two patients required only one dose of MB for complete pain relief.Although the maximum pain relief was reported within minutes of the first dose in most patients who received MB . Similarly, the reduction in pain NRS scores on day 2 was not statistically different between three concentrations of MB .The main reduction in pain NRS and OFB scores was evident within the first 2 days, with the most substantial effect observed on the first day of use of MB. Although the MB concentration of 0.1% appeared to improve OFB more effectively than the 0.05% and 0.025% concentrations, there was not a statistically significant difference between each pair of these groups . Transient mouth and teeth discoloration were reported, but this resolved with oral hygiene or after meals. No permanent stain or other side effects were reported at the 30-day follow-up.Our phase 2 randomized clinical trial showed that MBOR led to significantly better pain reduction and improved OFB than CTx alone, with minimal, transient, and self-resolved adverse events. No events were reported at 30-day follow-up.MB has been used to treat various painful syndromes, including postoperative pain, discogenic pain, and neuropathic pain –22.More than 75% of patients reported analgesia within minutes of the first dose in our study. Although most patients required several doses, a significant reduction in pain NRS scores and improvement in OFB was observed in the first 24 h, with additional improvement at 48 h. After 2 days, 59% of patients still required treatment. But no patients required treatment after 7 days. The time course of MB analgesia seems to support a neurolysis mechanism. MB seems to be a long-term inhibitor of peripheral axons by denaturation of free nociceptive nerve endings. A typical peripheral nerve injury initially leads to acute axonal degeneration within 30 min . The degOther proposed mechanisms of MB analgesia are anti-inflammatory, by inhibition of nitric oxide inflammatory pathway–via induced guanylate cyclase –29. MiclWhereas several therapies for the treatment of oral pain associated to mucositis have their shortcomings, even a diluted topical MB solution (0.025%) can be highly effective as it can readily reach the target nerves with a minimum barrier. We observed no statistical difference in analgesia between the three MB concentrations, our results support using the most diluted solution initially to further reduce the transient discoloration and perhaps the burning sensation.Unlike other oral rinses currently used in clinical practice, MBOR does not result in local anesthesia of the oral cavity; it therefore does not change the perception of the taste or inhibit the gag reflex. In addition, MB demonstrated an accumulative analgesic effect after multiple doses. Although the present showed good results, the trial was limited in that it was not a placebo-controlled study. The study recruited a relatively small number of patients. We acknowledge that not discontinuing CTx in patients assigned to receive MB could result in a co-intervention bias.This clinical trial demonstrated effectiveness in pain relief and improving OFB using MB + CTx compared with CTx alone. This trial of MBOR supports its use as a low-risk, efficient, and easy-to-use treatment for refractory oral pain due to OM from cancer therapy. Whereas MBOR is not commercially available, it must be compounded individually, that in some cases led to costs too great for some individuals that remains a challenge to overcome. However, the low cost and wide availability of MB makes it potentially accessible to patients of all socioeconomic backgrounds widely worldwide. Further studies are needed to evaluate the possible effect of MBOR in OM severity and healing time.Additional file 1.


This secondary analysis of a randomised controlled patient-blinded trial comparing effectiveness and side effect briefings in patients with chronic low back pain (CLBP) investigated the association between patients’ pre-treatment expectations about minimal acupuncture treatment and pain intensity as outcome during and after the end of the treatment.Chronic low back pain patients with a pain intensity of at least 4 on a numeric rating scale from 0 to 10 received eight sessions of minimal acupuncture treatment over 4 weeks. The primary outcome was change in pain intensity rated on a Numerical Rating Scale (NRS 0–10) from inclusion visit to treatment session 4 and to the end of the treatment. Patients’ expectations about the effectiveness of acupuncture were assessed using the Expectation for Treatment Scale (ETS) before randomization. Linear regression was applied to investigate whether patients’ pre-treatment expectations predicted changes in pain intensity during and after treatment.b = -0.264, p = 0.002), but not after the end of the treatment. This association was found in females and males.A total of 142 CLBP patients  were included in our analysis. Patients’ pre-treatment expectations about acupuncture treatment were associated with changes in pain intensity after four sessions of minimal acupuncture treatment (Our results imply that higher pre-treatment expectations only lead to larger reductions in pain intensity in the initial phase of a treatment, with a similar magnitude for both females and males. As the treatment progresses in the second half of the treatment, adapted expectations or other non-specific effects might play a more important role in predicting treatment outcome. Patient expectations in the context of medical treatment have received increasing attention in research in recent years, with a growing body of literature suggesting their influence on clinical outcomes. Associations of patient expectations and treatment outcomes have been shown for a variety of medical conditions including heart disease , post-chAcupuncture is part of Chinese Medicine, and data from a large patient data meta-analysis suggests that acupuncture is statistically significantly superior to sham acupuncture and no acupuncture control conditions. The differences between real acupuncture and sham acupuncture, however, were not clinically meaningful . The autThose non-specific contextual factors are complex sets of internal, external or relational elements, including patient’s expectations, history, baseline characteristics, type of treatment, treatment setting, and clinician’s behaviour ,21. ContPrevious studies investigating the effect of expectations on outcomes of acupuncture were heterogeneous in terms of study design, pain condition, outcome measures, and measurement of expectation, which makes it difficult to draw definitive conclusions. Some studies found strong effects ,25; otheTo expand our understanding of the association between patients’ pre-treatment expectations and treatment outcome, we performed this secondary data analysis based on the data from a randomised controlled clinical trial . The triWith this analysis, we wanted to answer the questions whether patients’ pre-treatment expectations about acupuncture treatment predict changes in pain intensity (a) after four treatment sessions and (b) after the end of the treatment. We hypothesised that patients with higher expectations about the effectiveness of acupuncture treatment were more likely to experience reductions in pain intensity than patients with lower expectations at both time points independently of sex.This secondary analysis is based on the data from a randomised controlled patient-blinded trial comparing a regular expectation briefing with a high expectation briefing (factor effectiveness) and a regular side effect briefing with an intense side effect briefing (factor side effects) using a 2 x 2 factorial design in patients with chronic low back pain (CLBP).All patients received eight sessions of minimal acupuncture treatment within 4 weeks. The standardised briefing intervention with the study physician took place before the first acupuncture session (lasting approximately 30 minutes) and before the third acupuncture session (lasting approximately 15 minutes). Two booster emails were sent after the third and sixth acupuncture session. Because there were no significant differences between the two expectation briefing groups in expectation and pain outcomes, all patients were pooled for this analysis . The samhttps://www.drks.de (DRKS00010191).The trial was conducted in accordance with the Declaration of Helsinki  and the Patients were recruited via email newsletters directed to the staff of the University Hospital Zurich and other university institutions; by posters and flyers in university buildings, fitness gyms and practises of physicians; and via the institutes´ website. First patient was recruited May 5, 2016, and last patient completed the study December 6, 2017. Individuals interested in study participation received information about the study and underwent a preliminary telephone screening regarding location, duration, and intensity of their back pain.We included male and female patients between 18 and 65 years of age with clinically diagnosed CLBP  with an All patients gave written informed consent before they were randomised into the trial. All randomised patients who received at least four sessions of acupuncture treatment were included in the analysis.All patients received the same standardised minimal acupuncture treatment, which had been used successfully before in a trial and was shown to be more effective than no treatment . The trePatients were allowed to treat chronic low back pain with non-steroidal anti-inflammatory drugs if required. The use of pain medication had to be documented in a medication diary. All patients were informed that they would receive a treatment that was shown to be beneficial for chronic low back pain.Patients’ expectations about acupuncture treatment effectiveness were assessed using the Expectation for Treatment Scale (ETS)  before rThe ETS is a well-validated scale consisting of 5 items, each rated on a 4-point scale ranging from 1  to 4 (definitely agree). The total score ranging from 5 to 20 is the sum of all responses, and higher values indicate higher expectations about acupuncture treatment. The scale showed acceptable internal consistency (α = 0.77) in our patient population, and the ETS score was normally distributed.Pain intensity during the previous 7 days was assessed at the inclusion visit, after acupuncture session 4, and after the end of the treatment using an 11-point NRS ranging from 0 (no pain) to 10 (worst imaginable pain) –41. Our Data on patient demographics, including age, sex, education, and employment status, were obtained via the baseline questionnaire.Optimism and pessimism were assessed using the German version of the Life Orientation Test—Revised (LOT-R) . The 10-www.nihpromis.org). The PROMIS Profile-29 combines the 4-item short forms from the seven PROMIS domains  and a single item on pain intensity [Self-reported health was assessed at baseline using the 29-item short-form of the Patient-Reported Outcomes Measurement Information System®  to 10 (worst imaginable pain). The duration of pain was assessed at the inclusion visit by asking patients about the onset (month and year) of chronic low back pain and calculated by subtracting the date of the onset of pain from the date of the inclusion visit.The analysis followed a prespecified analysis plan which was finalised and signed prior to starting the analysis. Descriptive statistics, including frequencies and percentages (%) for categorical variables and mean and standard deviation (SD) for continuous variables, were used for patient characteristics and measures of interest. To assess the differences between females and males, Chi-square test was used for categorical variables and one-way ANOVA was used for continuous variables. No adjustments for multiple comparisons were done.An independent t-test was used to compare patient pre-treatment expectations between patients who previously received acupuncture treatment and those who did not have acupuncture treatment before. A dependent t-test for paired samples was used to investigate the differences between pain intensity at the inclusion visit, after four sessions of acupuncture, and after completion of the treatment. Cohen´s d for repeated measurements was calculated to measure the effect size between pre- and post-treatment scores .Pearson correlations were used to test for the associations of the sociodemographic (sex and age), previous experience , pain , self-reported health (PROMIS), personality traits (LOT-R), and briefing group variables with the primary outcome change in pain intensity and patient expectations.b) to determine whether expectations were associated with a change in pain intensity after four acupuncture sessions or after the end of the treatment. Because our primary focus was the unadjusted analysis, adjusted regression models were only run if any of the variables included in the Pearson correlations were found to have an association with change in pain intensity with a p-value of ≤ 0.10. Analyses were performed for the total sample and stratified by sex.Unadjusted linear regression was used to estimate standardised beta coefficients . Patient pre-treatment expectations were significantly higher in patients who had a previous acupuncture treatment compared to patients who did not have acupuncture treatment before (13.1 ± 3.7 (n = 65) versus 11.5 ± 3.5 (n = 77), p = 0.003). Additional factors associated with higher patient pre-treatment expectations were pain intensity , pain bothersomeness  and fatigue .The mean pain intensity (NRS 0–10) significantly decreased by 1.20 points  after four acupuncture sessions and by 1.62 points  after the end of treatment, resulting in a pre-post Cohen’s d of 0.72 and 0.71, respectively see .b = -0.258, SE = 0.101, p = 0.013) and males . After adjusting for baseline pain bothersomeness and anxiety, the standardised estimate of beta of the total sample decreased to -0.219 (SE = 0.083), meaning that for each 1-point increase in patients’ expectations, there was a 0.219-point improvement in pain. This value, however, retained statistical significance (p = 0.01). This significant association was also found in females  but the association was not significant in males. Even after adding the remaining variables to our analysis  patient expectation still had a significant impact on change in pain intensity for the total sample . No significant associations were found between patients’ expectations and improvement in pain intensity between inclusion visit and the end of the treatment at the end of week four.As displayed in This analysis shows that in patients with chronic low back pain, patients’ pre-treatment expectations about acupuncture were predictive of improvements in pain intensity after four treatment sessions but not after the end of the treatment. This effect was found in females and males. Pain intensity decreased over the course of treatment. The observed pre-post pain intensity reduction was approximately 30%, which is usually regarded as clinically meaningful –50.The inconsistent findings of the previous studies analysing the relationship between patient expectations and acupuncture treatment outcomes in patients with low back pain might be due to differences in how expectations and outcomes were defined and measured and how patients were recruited. Laferton et al.  pointed Only two studies used pain intensity as an outcome, which was measured after 8 weeks  or 24 moOf note were the relatively low baseline expectations about the effectiveness of acupuncture to treat chronic low back pain in our patient population, which can potentially be explained by the fact that most of our patients were recruited through flyers and not referred from their general practitioner. They may not have chosen acupuncture specifically because of their expectations about this treatment but rather because they coincidentally became aware of the possibility to try it. The 46% of the patients who had a previous acupuncture treatment had significantly higher expectations than the acupuncture-naïve patients. Although previous acupuncture treatment is an important predictor of further acupuncture usage and might therefore yield higher expectations , the higPatient expectations predicted the clinically non-meaningful improvements in pain intensity after four sessions but not the clinically meaningful improvements in pain intensity after eight sessions, the end of the acupuncture treatment. Thus, patients with higher expectations improved more compared to patients with lower expectations in the first half of the treatment; however, the overall improvements from the treatment were independent of patients’ expectations. Although not clinically meaningful, most improvements in pain occurred during the first half of the treatment. The additional improvements in the second half of the treatment were comparatively small. This is in line with results presented by Pach et al. , who fouPatient pre-treatment expectations can be regarded as meaningful in the initial part of the treatment, but factors other than expectations might be more relevant in predicting long-term improvements in pain intensity. The assessment of patient expectations could be valuable for clinicians who wish to predict their patients’ prognoses for a specific treatment since both sides might have different views on expected benefits . Future Our analysis had several strengths: It used a validated scale to measure patient expectations with good internal validity; it used data from a trial with a highly standardised setting, high adherence to treatment, and high follow-up rates; it used common pain outcomes; and it had approximately equal proportions of patients with and without previous acupuncture experience. One potential limitation of the study is that patients were mostly recruited via posters and flyers, and these patients might differ from patients seeking treatment by an acupuncturist in a usual care setting. Also, we did not assess the interventions used by patients as non-pharmacological usual care intervention. They might, however, also have an impact on pain intensity during and after the treatment. Eventually, the study was a single-centre study conducted in the metropolitan area of Zurich, and the sample was well-educated. Our patients might therefore not be representative of the general back pain population of Switzerland.Findings from this analysis add further insight into the association between patients´ pre-treatment expectations and pain intensity as outcome in patients with chronic low back pain. We have not been able to show that pre-treatment expectations enhance treatment outcomes after the end of the treatment. Our results imply that higher pre-treatment expectations only lead to greater reductions in pain intensity in the initial phase of a treatment with a similar magnitude for both females and males. As the treatment progresses, adapted expectations or other non-specific effects might play a more important role in predicting treatment outcome.S1 Fig(TIF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 TableSignificant results are marked in bold. Negative sign indicates an impact of expectations on an improvement in pain intensity. *Analysis was adjusted for pain bothersomeness, anxiety, expectation briefing group, side effect briefing group, PROMIS, LOT, PSM and side effect score.(PDF)Click here for additional data file.


Up to 70% of limb amputees develop chronic postamputation neuropathic pain (CPANP) which includes phantom pain and residual limb neuropathic pain due to neuroma formation. CPANP often requires invasive procedures aimed at neuroma ablation. Five amputees received 6 noninvasive magnetic resonance‐guided high‐intensity‐focused ultrasound MRgHIFU treatments ExAblate®, Insightec, Tirat‐Carmel, Israel). Although ablative temperature (>65°C) at the neuroma was reached in only 1 patient, pain intensity dropped from 5.7 at baseline to 4.3 and back to 5.6 at 3 and 6 month follow‐up. Post‐treatment bone necrosis was demonstrated in 1 patient. Although no firm conclusion about the effectiveness of MRgHIFU for CPANP could be drawn, further studies are warranted. CPANPchronic postamputation neuropathic painHIFUhigh‐intensity‐focused ultrasoundMRmagnetic resonanceMRgHIFUmagnetic resonance‐guided high‐intensity‐focused ultrasoundMRImagnetic resonance imagingNPSnumerical pain scaleUSultrasoundIn 2005, 1.6 million people were estimated to be living with limb loss in the United StatesMRgHIFU is utilized for painful metastatic bone tumors and osteid osteoma in the extremities. It has been studied in other painful conditions, for ablating small, localized sensory nerves in patients with knee osteoarthritis and facet joint arthropathy. It is also used for nonpainful condition including tremor , uterine fibroids, and ablation of prostate tissue  of MRgHIFU in limb amputees with CPANP.The study was approved by Rambam Health Care Campus Ethics Committee (RMB 0180‐16). Patients with CPANP who met the following inclusion criteria were recruited to the study: men and women aged 18 and older, suffering from CPANP for at least 3 months; able and willing to give informed consent; average pain intensity (when present) ≥4 on a 0–10 numerical pain scale (NPS) during 3 days prior to enrollment, irrespective of medication used; not more than 3 targeted neuromas, clearly visible by noncontrast MRI and located deeper than 10 mm from the skin; and temporary pain relief following a local anesthetics injection to the targeted neuroma(s) or to the relevant peripheral nerve(s). Patients were excluded from the study if they had: any acute or unstable medical condition that was expected to hinder them from completing this study; standard contraindications for contrast MRI or for sedation; and unwillingness to undergo the procedure under prolonged sedation (approximately 3 hours).Patients were prescreened by a comprehensive medical and pain history, recording of current symptoms and a general physical and a detailed neurological examination of the stump. After signing an informed consent form, eligible patients were referred to a contrast MRI of the stump (unless a MRI scan was performed within 6 months prior to enrollment in the study). Subsequently, an US‐guided local anesthetic injection was performed to either the identified neuroma(s) or the involved nerve(s), proximal to the neuroma(s). A 50% pain relief was considered a successful injection.2 monitoring under the care of a certified anesthesiologist throughout the procedure. Nerve block was added to 1 patient (001) prior to the procedure. Treatment was performed using the ExAblate MRgHIFU system . Patients were positioned on the MRgHIFU table with the targeted neuroma centered above the ultrasound transducer. The treated limb was fixated to the ExAblate table with adhesive plasters. Position, clear ultrasound pathway, and target neuroma's location and size were verified by MRI .The procedure was mostly performed on an outpatient basis. Patients received sedation (midazolam and fentanyl) with heart rate and pOImages were loaded to the ExAblate workstation, and the target area was marked. A patient‐specific treatment plan was generated covering the targeted neuroma optimizing the number of sonications, location, and energy levels to avoid damage to surrounding tissue. After verifying correct positioning using low‐energy sub‐therapeutic sonications, treatment began at full energy, attempting to reach ablation temperatures of 65°C–85°C. During each sonication, real‐time MR thermometry and anatomical images were acquired Figure , Table 2Change from baseline in the average daily pain intensity (when present), measured for 3 consecutive days on the NPS was considered the primary outcome measure. Secondary endpoints included changes from baseline of the followings: 1) maximum daily pain intensity, measured for 3 consecutive days, on the NPS (0–10); 2) minimum daily pain intensity, measured for 3 consecutive days, on the NPS (0–10); 3) Short‐Form McGill Pain Questionnaire score (0–45); 4) Pittsburgh Sleep Quality Index (0–21); 5) quality of life measured by the EQ‐5D questionnaire (0–15); 6) Brief Pain Inventory (0–70); 7) MRI findings in the treated neuroma(s); and 8) treatment complications.Telephone follow‐up visits were completed at 1 and 3 days, and 2 weeks post‐treatment and clinic visits at 1 week and 1, 3, and 6 months post‐treatment. A follow‐up MRI to assess the effects on the treated neuroma(s) was performed 4 months after treatment.Twenty‐one amputees were prescreened between April 2017 and October 2018. Thirteen of them were excluded from further procedures for the following reasons: reluctant to undergo the procedure,Altogether, 6 neuromas were treated. In 4 patients, a single tibial neuroma was treated. One patient p001) had 3 neuromas ; the tibial neuroma was treated twice and the peroneal once. Due to safety hazards, full energy treatment of the sural neuroma was not initiated. The number of sonications ranged from 7 to 29. Despite of repeated sonications over relatively long treatment times (between 3:00 and 4:20 hours), ablation temperatures of 65°C was reached in only 4 of 107 administered sonications, all in 1 patient (p010). Overheating off adjacent tissues, mainly bone, was the reason for avoiding higher sonication energy levels. Table  had 3 neThree of the 5 treated patients  completed the entire 6‐month follow‐up. An additional patient p012) completed the 2‐week telephone follow‐up but was unwilling to comply with the scheduled follow‐up clinic visits due to worsening of his phantom pain following the procedure. Another patient (p018) passed away from lung cancer and missed her 6‐month follow‐up visit. Figure  completeFollow‐up MRI scans were performed 1–6 months after treatment in all 5 treated patients, and were compared to the baseline findings in term of neuroma size, signal, and enhancement with gadolinium. No changes in any of these parameters were noted in all treated neuromas Table .Although all procedure lasted considerable time (hours) and required prolonged sedation, no safety hazards were recorded in any of the patients. Patients' safety or comfort did not require stopping any procedure prematurely. One patient (p012) reported aggravation in his pain 2 weeks after treatment. He declined further follow‐up clinic visits but made his follow‐up MRI scan available for our review. In another patient (p018) an MRI scan 1 month after the procedure showed findings consistent with post‐treatment bone and soft tissue infarction in the posterolateral facet of the tibia and the adjacent soft tissue, close to the stump neuroma. Nonetheless, the patient reported dramatic pain relief at that time. Unfortunately, she passed away so no additional follow‐up MRI was performed.The aim of the present feasibility study was to provide initial information on the effectiveness (pain reduction) and safety of MRgHIFU treatment directed at ablating stump neuromas in amputees with CPANP. As often happens in studies with well‐defined inclusion criteria, only 5 of 21 prescreened amputees were eventually treated. Of them, only 3 completed the 6‐month follow‐up period. Nonetheless, with the exception of 1 patient, in whom pain escalated soon after the procedure, at least some pain relief was noted by the others for at least 3 months. Similar improvement was reported in additional, secondary outcome measures.pulsed radiofrequency treatment (with only a sub‐ablative temperature of ~42°C rather than true ablative temperature) was administered. Nonetheless, decrease in pain intensity was reported by 18 of 20 treated patients.Due to previously mentioned technical challenges, ablative temperature was reached only in a small minority of administered sonifications. Thus, not surprisingly, no changes in the size, signal, or gadolinium enhancement could be detected in any of the treated neuromas. As such, the study team decided against performing further procedures with the ExAblate apparatus, even though pain intensity declined in 4 of the 5 treated patients. Whether the noted decline in pain intensity can still be attributed to the administered treatment is a valid question. A possible answer to this question may come from a different ablative technique—the radiofrequency. Several reports on the effect of ablative radiofrequency treatment (where target temperature far above 65°C has been reached) yielded positive results,From the safety standpoint, no serious adverse events occurred in any of the patients. However, 2 safety concerns should be considered. First, the MRI findings suggesting post‐treatment bone and soft tissue infarction in patient 012. Although this finding was unlikely of clinical significance since the patient reported dramatic pain relief for 3‐month following the procedure, the MRI findings still suggest that even under careful, real‐time temperature control, surrounding tissues can get affected. Second, the procedure required a long sedation time, which is not entirely free of potential hazards. Additionally, the cost of the procedure should be considered and compared to alternative ablating techniques, especially in light of the long and costly scan—and treating team—time required for the MRgHIFU procedure.As already mentioned, the main treating challenge originated from the technical aspects of the MRgHIFU device (ExAblate), which did not allow reaching an ablative temperature at the target site in a safe manner in the majority of the sonifications. The leading reason for that is that in this device, the US beams came from a relatively narrow angle, below the sedated patient. This considerably limited the options of aiming the beam to the required target zones while assuring a clear ultrasound pathway. Additionally, the ExAblate device only allowed the use of a whole body MR coil rather than a limb coil. This reduced the scan resolution to a degree where it was at times difficult even for an experienced musculoskeletal radiologist to visualize the neuromas during the procedure. Conclusively, we suggest that a modified device, perhaps with a dome‐shaped transducer placed around the stump edge, compatible with a limb coil, will likely allow overcoming some of these technical challenges.Taken together, no firm conclusion regarding the effectiveness and safety of MRgHIFU for CPANP can be drawn from this feasibility study. Nonetheless, the authors still believe that noninvasive HIFU techniques aimed at ablating neuromas and safely relieving CPANP should not abandoned. Further studies with properly adjusted technologies in a larger sample size should be carried on.Appendix S1 Supporting Information.Click here for additional data file.Appendix S2 Tables.Click here for additional data file.


Chronic pelvic pain is a common and disabling condition in women living with endometriosis. Pharmacological and surgical treatments are not always effective at controlling pain and present important restrictions. Digital therapeutics (DTx) are emerging as major nonpharmacological alternatives that aim to extend the analgesic therapeutic arsenal of patients.In this randomized controlled trial (RCT), we aimed to measure the immediate and 4-hour persisting effects of a single use 20-minute DTx (Endocare) on pain in women experiencing pelvic pain due to endometriosis.A total of 45 women with endometriosis participated in a randomized controlled study comparing the analgesic effect of a single use of a virtual reality digital treatment named Endocare  to a 2D digital control . Perceived pain and pain relief were measured before the treatment and 15, 30, 45, 60, and 240 minutes after the end of the treatment.P<.01). Endocare was significantly more effective than the control group . Endocare decreased the mean pain intensity from 6.0 (SD 1.31) before the treatment to 4.5 (SD 1.71) posttreatment, while the control only decreased it from 5.7 (SD 1.36) to 5.0 (SD 1.43). When comparing each posttreatment measures to the pretest, Endocare significantly reduced pain perception for all points in time up to 4 hours posttreatment. The differences did not reached significance for the control group. Moreover, Endocare was significantly superior to the control group 15, 30, and 45 minutes after the treatment . The mean perceived pain relief was significantly higher for Endocare at 28% (SD 2%) compared to the control, which was 15% (SD 1%) for all the posttreatment measurements .The clustered posttreatment pain was significantly reduced compared to the pretreatment for both Endocare and the control group (all Our study aimed to test the effects of a single use of a DTx treatment on reported pain at different time points in women diagnosed with endometriosis experiencing moderate-to-severe pelvic pain. Importantly, our results support that Endocare, a virtual reality immersive treatment, significantly reduce pain perception compared to a digital control in women living with endometriosis. Interestingly, we are the first to notice that the effect persisted up to 4 hours posttreatment.ClinicalTrials.gov NCT04650516; https://tinyurl.com/2a2eu9wv Endometriosis is characterized by lesions occurring outside the uterus whose appearance and behaviors are close to those of the endometrium mainly on the pelvic peritoneum, ovaries, and rectovaginal septum . It mighThe mean prevalence of endometriosis in women with CPP has been estimated at 70% (SD 3%) , but it Current management of endometriosis pain involves pharmacological  and surgical treatments -11. The Hormonal therapies or surgeries are not adapted for women willing to get pregnant. Therefore, the development of nonpharmacological alternatives for the management of endometriosis pain is critical to extend the treatment arsenal for women with pelvic-perineal pain and endometriosis . Among tIn the past few decades, the emergence of digital therapeutics (DTx) aimed at the use of informatic tools to aid the diagnosis and therapy of various pathologies has led to the creation of many new therapeutic devices . RecentlOn these bases, a new digital therapeutic approach, Endocare, was created by combining various therapeutic procedures based on several modalities in a VR environment, individually known to reduce pain -27. EndoThis was a randomized, controlled, comparative, open-label, 2-parallel-group interventional study comparing the effect of Endocare and a digital control on endometriosis-related pain after a single use. This RCT was conducted between December 2020 and May 2021 at the Franco-European Multidisciplinary Endometriosis Institute (IFEMEndo), Clinic Tivoli-Ducos in Bordeaux, France.This study was conducted in compliance with good clinical practice guidelines, the principles of the Declaration of Helsinki, and French laws and regulations. It was reviewed and approved on November 6, 2020, by the Comité de Protection des Personnes. All participants completed and signed the informed consent form before inclusion in the study and before any study-related procedure began. Before commencing participant enrollment, this study was registered on ClinicalTrials.gov (NCT04650516).Standard operating procedures were applied for the conduct and analysis of the clinical investigation. This study was monitored regularly according to the specifically designed monitoring plan. Furthermore, data were captured following the double entry procedure in the dedicated case report form and compared. Discrepancies were reviewed and corrected by a third entry clerk. A data validation document specifically written for this study aimed to list all data checks to be performed. A data manager programmed the checks with Ennov Clinsight, and the sponsor validated the checks. In case of inconsistencies, a query was edited during the quality analysis beyond data entry. The investigator or another authorized person from the clinical staff was asked to answer the query by confirming or correcting the data.The selection criteria were women over 18 years old with a magnetic resonance imagery (MRI) diagnosis of endometriosis who were willing to participate in the study and signed the informed consent form. All patients were recruited from a highly specialized center . These patients experienced mostly severe pain related to their chronic pain condition and presented a long medical history concerning their endometriosis, which was often deep endometriosis.To be included in this study, the screened participants who met the selection criteria had to be living with moderate-to-severe endometriosis-related pain with a score ≥4 on an 11-point numerical rating scale (NRS) at the time of inclusion, a criterion shared among various studies .The exclusion criteria were women who (1) were pregnant or breastfeeding; (2) had consumed painkillers within 8 hours prior to inclusion; (3) were participating in an interventional study or had participated in an interventional study within 30 days before enrolment; (4) were employed by the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator; and (5) had a contraindication to Endocare or the digital control, such as severe visual, hearing or cognitive impairments, color blindness, photosensitivity, epilepsy, or motion sickness.This study aimed to evaluate the short-term pain evolution after a single use of Endocare compared to a digital control in participants experiencing endometriosis-related pelvic pain. The primary end point was the mean pain intensity 60 minutes after the beginning of treatment . Gerlinger et al  determinWith a 2-sided 95% CI, the study achieved 81% power to detect a difference between the group means at the last time of 20 mm on a 100-mm VAS with a 25-mm standard deviation. The correlation between measurements within a participant was estimated at 0.500. A test based on a mixed-model analysis was anticipated at a significance level of 5%. Assuming that about 25% of women would not experience an endometriosis-related pain ≥4 on NRS at time of inclusion, we planned to screen 50 women. Consequently, at least 40 women were planned to be included in the study.Finally, 46 participants were screened, of which 45 were included and randomized; 1 was a screen failure because she never went back for the study visit . A totalPain medications were stopped at least 8 hours prior to participation. If pain persisted after treatment (Endocare or control), the patient could take their pain management rescue treatment, thus ending the data collection at that time.We developed the Endocare treatment  specifically for this study . It was The digital control was also developed by Lucine specifically for this study . The dig, a clinic that specializes in endometriosis. All patients were diagnosed with endometriosis by specialized gynecologists and medical procedures . Recruitment was done when the patients came for their medical examination and were informed about this study. If the patients expressed interested in participating in this study, the research team offered them a new appointment at the clinic to receive the study treatment.Women living with endometriosis pain were recruited from IFEMEndoWhen patients returned to the clinic on the day of the inclusion visit, their pain level needed to be at least 4 on an 11-point numeric pain rating scale to participate in this study. Patients reporting a pain of <4 on this scale were considered as screen failures and withdrawn from the study. This pain intensity evaluation represented the pretreatment evaluation just before the use of Endocare or control and is considered the baseline (T0).If the patient consented to participate and met the inclusion criteria, they were randomized to 1 of the 2 groups, Endocare or control. The treatment (either Endocare or control) consisted of a single use of the VR headset on the day of the visit, as presented in The research team accompanied the patient to distinct isolated rooms and then handed them either the headset  or the tablet . Patients were then guided orally by the investigator for up to 5 minutes until the beginning of the treatment .Once the treatment was completed, each participant was asked to rate on a paper questionnaire their pain perception on an 11-point NRS  and their perceived pain relief on a 5-point categorical scale 15 minutes (T15), 30 minutes (T30), 45 minutes (T45), and 60 minutes (T60) after administration of the allocated study treatment. During the first hour, participants remained under the direct supervision of the study site staff. After the first hour, and if cleared by the study site staff, participants were free to leave the study site and go home to complete next assessment 240 minutes (T240) after the end of the treatment. Adverse events (AEs), if any, were collected during the entire duration of patients’ participation. Before leaving the clinic, participants underwent a general health status check to ensure they were not experiencing any AEs and were able to go home.At home, patients were asked to rate on a paper questionnaire their pain relief on a 5-point categorical scale and pain intensity based on the 11-point NRS at T240 or at the last time point if the participant dropped out the study or began taking a rescue medication before the end of the follow-up period.Pain intensity was evaluated on an 11-point NRS at T0, T15, T30, T45, T60, and T240. This scale is the reference tool to assess pain in most clinical trials, and it has been used in various recent studies, including those related to endometriosis -31. NotaPain relief was evaluated on a 5-point categorical scale  at T0, T15, T30, T45, T60, and T240.If rescue medication was needed, the participant was asked to rate their pain intensity or pain relief just prior to the intake of the rescue medication. Study follow-up was terminated upon the intake of rescue medication.Patients who dropped out before the end of the 240-minute follow-up period were not replaced.A linear mixed-model framework was used for statistical analysis . The selected covariance matrix of the repeated measurements that better fitted the data based on the Akaike Information Criterion was the first-order ante-dependence. There were 3 explanatory fixed factors: group , time , and group*time, as well as a random effect on the intercept of each participant. In the first analysis, time (fixed effect) was parametrized as baseline (T0) versus all other times (T15 to T240). The analysis consisted of comparing T0 with the 5 posttreatment data clustered for both groups and looking at the interaction term (group*time). A contrast analysis was also performed to verify the difference between baseline (T0) and posttreatment times (clustered) in the 2 separate groups. In the second analysis, time was parametrized as T0, T15, T30, T45, T60 and T240. A contrast analysis was also performed to test the difference between T0 and all other times (separated) in both groups. Bonferroni corrections were applied for multiple comparisons.For pain relief, data were analyzed using R software. Because data did not satisfy to normality when assessed with the Shapiro-Wilk normality test, Wilcoxon unilateral unpaired tests corrected for multiple comparisons with a false discovery rate (FDR) were used.Of the 45 women that participated in the study, 1 (2%) did not return the questionnaire. Among the patients included, 1 (2%) from the treatment group and 4 (9%) from the control group took rescue medication after T60 but before T240. Therefore, in accordance with the study design, no results at T240 were collected for these 5 patients. Participants from both groups were comparable in terms of age, height, and weight , as wellAll participants were recruited from a clinic that specializes in endometriosis and were living with severe endometriosis-associated symptoms . Of the Most of the patients were taking different classes of medications for their endometriosis condition, including hormones, analgesics, and antidepressants . Since t40,712F=.060; P=.807), but we did observe an effect of the time . Moreover, we found an interaction for group*time , indicating that the mean reduction of pain through time (T0) was significantly different between each group . Contrast analysis revealed that the mean reduction of pain was greater in the Endocare group  than in the control group .We first analyzed the differences between the baseline pain (T0) and the 5 clustered posttreatment measurements covering 15 minutes to 4 hours after the treatment  in both groups using a linear mixed model . We did 41,122F=0.716; P=.402), but we did observe an effect of the time . Moreover, we did not find an interaction of group*time , likely due to a weak statistical power. Contrast analysis revealed group*time interactions at T15 , T30 , and T45 , a tendency for T60 , and none for T240 . This indicates that the mean reduction of pain through time was significantly different between each group  from T15 to T45, but it was not significantly different from T60 to T240. For the Endocare group, the pain perception reduction was significant in each of the 5 posttreatment measurements (P<.05). For the control group, except for a tendency at T15 , no significance was reached relative to the pain perception reduction in each of the 5 posttreatment measurements .We then aimed to analyze the differences between the baseline (T0) and each of the 5 posttreatment measurements separately  in both groups using a mixed model . We did 41,800F=.009; P=.924) nor adenomyosis  changed the results. This indicates that the effect of the treatment on pain was independent of these 2 conditions.A total of 31 (70%) participants had surgery related to endometriosis (14 in the Endocare group and 17 in the control), and 11 (25%) suffered from adenomyosis (6 in the Endocare group and 5 in the control). Thus, we introduced 2 covariates, surgery and adenomyosis, into the linear mixed model. Neither surgery (P<.05).At each posttreatment measurements, participants were asked to measure their perceived pain relief on a 5-point numerical scale from no relief to total relief . The meat-test, P=.004).Finally, we analyzed the maximum reduction of pain intensity in both groups. The mean maximum effect was 42% (95% CI 30.82-53.18) for Endocare and 22% (95% CI 15.38-28.53) for the control group. The maximum effect was significantly higher for the treatment group  participants reported mild-to-moderate AEs, of which 4 (8%) were evaluated as probably unrelated and 3 (6%) as possibly related to the Endocare treatment. The 3 possibly related events were within the treatment group and described as a mild headache and nausea related to motion sickness.In this RCT, we aimed to measure the immediate and 4 hours persisting effects of a single use of a 20-minute DTx (Endocare) on pain in women living with pelvic pain related to endometriosis. We showed that Endocare was able to significantly reduce the overall pain perception when comparing the pain at baseline (T0) with the combined 5 posttreatment measurements from 15 minutes (T15) to 4 hours (T240).We found that our digital control was also able to significantly reduce the overall pain perception but significantly less than the Endocare treatment. Next, we wanted to evaluate whether the pain reduction was significant at each posttreatment measurement  compared to baseline (T0) in each group. We showed that this was the case for the Endocare group but not for the control group, thus confirming the analgesic effect of the Endocare treatment. To our knowledge, our study is the first to demonstrate an effect on pain reduction in women living with moderate-to-severe pelvic pain due to endometriosis by using a nonpharmacological treatment that combined VR with visual and auditory stimuli.Numerous studies have shown that VR is an effective way to reduce acute pain intensity, especially pain experienced during medical procedures, by burn victims, or by women during childbirth ,33-36. TThus, the combination of these stimulations potentialized with the VR experience could lead to the decrease in pain observed in the Endocare group immediately after and up to 4 hours posttreatment.In the field of VR research, while some studies do not use a control group ,42, otheIn this study, we chose to use a digital control program displayed through a 2D tablet with a headset, allowing us to control for the Endocare treatment and not solely the VR apparatus or the stimuli. Indeed, our digital control contained the same composition as the Endocare treatment  without the immersive aspect of VR or the auditory and visual stimuli of the treatment. However, to preserve an immersive-like session, we chose to keep a soundtrack composed of nature sounds related to the projected image in the control group, which could potentially explain the positive outcome observed. This slight decrease in pain intensity observed in the control group indicates that our control is relevant.One limitation of our study may be the population, as we decided to work with patients living with mostly severe pain related to a complex and chronic pain condition, which could represent a selection bias. We likely could have had slightly better treatment results with less severe pain conditions. However, to assess this potential selection bias and analyze whether the beneficial effect would be lessened in populations with complex pathologies related to endometriosis, we covariated for surgery and adenomyosis, 2 conditions with potentially more pain and less responses to the treatment. We found that the results were equivalent, suggesting a similar effect in all subpopulations, including those with a more complex pathophysiology. Nevertheless, an effect in the range of 30% for Endocare can ultimately be considered moderately significant according to the IMMPACT guidelines . This caIn conclusion, this pilot study on the Endocare treatment shows encouraging results for developing a digital therapy to relieve patients of pelvic and perineal pain associated with endometriosis. Moreover, Endocare treatment can be a great alternative to hormonal treatment or surgery for women who wish to get pregnant. These results will be further investigated in a second study evaluating the analgesic effects of the repeated use of Endocare at home with a larger population of women living with chronic pelvic pain associated with endometriosis. In the future, Endocare could benefit patients diagnosed with endometriosis during their everyday life to reduce the acute and chronic pain encountered in this pathology, thus improving their quality of life.


Surgical stress and pain result in activation of hypothalamus-pituitary-adrenal axis. The aim of this study was to establish the effects of postoperative pain and various modalities of analgesic administration on salivary and serum cortisol levels, as well as to establish the validity of salivary cortisol as a stress indicator in surgical patients.A randomized controlled trial involved 60 patients scheduled for elective abdominal aortic aneurysm surgery. Patients were randomly divided into two groups depending on the model of postoperative analgesia. The first group (MI - morphine intermittently) included patients given morphine doses 0.1 mg/kg/6h s.c. intermittently. The second group  included patients who received morphine via the PCA system - intravenous administration of morphine adjusted to a dose of 1 mg per shot and a lockout interval of 6 minutes. Abdominal aortic aneurysm (AAA) is a vascular pathology characterized by dilatation of the aorta with a diameter of >3 cm or 50% greater than the normal diameter, which poses a risk of aortic rupture. Ultrasound screening among the population over 65 revealed that 4–7% of males and 1–2% females suffer from AAA The surgery causes postoperative pain, which should be managed as soon as possible and with a highest possible efficacy in order to reduce suffering, provide adequate recovery and prevent complications Surgical stress and pain result in activation of hypothalamus-pituitary-adrenal (HPA) axis The aim of this study was to investigate and compare the efficacy and safety of PCA compared to intermittent administration of bolus doses of morphine after AAA repair surgery, to establish the effects of postoperative pain and various modalities of analgesic administration on salivary and serum cortisol levels, as well as to establish the validity of salivary cortisol as a stress indicator or predictive biomarker in surgical patients.The study protocol complied with the Declaration of Helsinki. After obtaining approval from the Institutional Ethics Commission and informed written patient consent, a total of 60 patients of both sexes scheduled for elective AAA repair were included in this prospective study. The study was conducted at the Clinic for Anesthesia, Intensive Therapy and Pain Management of the University Clinical Center of Vojvodina. The patients with Cushing’s syndrome and patients on corticosteroid therapy were not included in the study. Patients on prolonged mechanical ventilation as well as those who were non-cooperative were excluded from the study.Depending on the postoperative analgesia model the patients were distributed into two groups by the method of random selection. The first group (MI) included patients given morphine doses 0.1 mg/kg/6h s.c. intermittently. The second group (MPCA) included patients who received morphine via the PCA system – intravenous administration of morphine adjusted to a dose of 1 mg per shot and a lockout interval of 6 minutes. In case of need for additional analgesia, the patients received metamizole sodium and acetaminophen.All patients were operated under general balanced anesthesia. Anesthetic premedication was done using midazolam 0.05 mg/kg i.m. Propofol 2 mg/kg and rocuronium bromide 0.6 mg/kg were used for induction to anesthesia. The anesthesia and analgesia were maintained applying sevoflurane and fentanyl, respectively. Muscle relaxation was provided by continuous infusion of rocuronium bromide 0.4 mg/kg.The operations were performed by open surgical repair, with a transperitoneal approach through a midline laparotomy. Repair of the aorta was carried out in a systematic fashion that involves clamping the aorta to stop blood flow, the aneurysmal segment is removed and suturing a synthetic graft to replace the diseased arterial segment.The intensity of pain has been assessed using Numerical rating scale (NRS) at one-hour intervals starting from the hour 3 post-surgery during first 12 hours, and then at hours 15 and 18 post surgery. NRS values were defined on an eleven-point scale with a range 0–10 . The patient was asked to encircle the number corresponding to his/her pain intensity. Score 1–3 was interpreted as mild pain, score 4–6 as moderate, and score 7–10 as severe pain.The patient satisfaction with postoperative analgesia was assessed 24 hours after surgery by asking the patients to evaluate the quality of postoperative analgesia using the grading scale 1 to 10.The following data were registered: age, sex, and comorbidities. One day post-surgery, in all patients, salivary cortisol and serum cortisol levels were measured at 6:00 am and 8:00 am, respectively. Salivary cortisol was sampled before serum cortisol to avoid the influence of venipuncture stress on salivary cortisol values. Abstaining from any food, drink, chewing gum, tooth brushing or using dental floss for minimum of 60 minutes before sampling is the prerequisite for a successful collection of saliva samples. The saliva samples were collected into salivettes  according to the prescribed procedure as following: The top cap of the tube was removed to expose the swab. The swab was introduced into the mouth and rolled in the mouth  for approximately two minutes. After two minutes, the tampon was spitted back into the tube; the tube cap was put back and screwed on tightly and immediately sent to the laboratory for testing. Serum cortisol was determined applying CMIA (Chemiluminescent Micro particle Immunoassay) method, whereas ECLIA (Electro-Chemiluminescence Immunoassay) was used for determining salivary cortisol. Both techniques are innovative serological methods of new generation, fully automated, showing superior specificity and sensitivity than the ELISA. These methods are effective tools for determining supernatant or serum levels of hormones, tumor markers and other biomarkers.Statistical analysis was performed applying the R software (Version 3.4.0). The following descriptive statistic measures were used: arithmetic mean, standard deviation, frequency and percentages. A t-test for independent samples and a Mann-Whitney test were used to compare the mean values of the variables of the two populations. Correlation was determined using Spearman’s correlation coefficient. A p < 0.05 value was taken for statistical significance of the test.Both groups consisted of 30 patients. The group MI included 27 male and 3 female patients, whereas MPCA group consisted of 26 males and 4 females. The average age in group MI was 68.1 and 64.5 in MPCA group. The average weight and height of MI-patients was 82.6 kg and 172.3 cm, and 85.3 kg and 176.1 cm in group MPCA. The groups did not differ with respect to the identified comorbidities .The average NRS pain intensity according to groups is displayed in Hemodynamic instability is defined as a deviation greater than 30% in relation to the basal values of blood pressure and heart rate, and it was more prevalent in the MI group .Patients’ satisfaction after the investigation period was equal . None of the patients experienced side effects of morphine analgesia, and we believe that morphine administered by any of these methods is absolutely safe after abdominal aortic aneurysm surgery.Serum cortisol levels were almost identical in both groups  . Higher In spite of most recent trend of using non-opioid anesthesia and analgesia as well as oral and regional analgesia, opioids are still the most commonly used analgesics for the management of post-operative pain. When opioids are indicated, PCA is the method of choice For this study, we selected patients who underwent AAA surgery because it is considered one of the most painful procedures, and we thought it would be a good indicator of surgical stress. This pathology is much more common in male patients; thus, using homogenous groups prevented the influence of gender on the results.Neuroendocrine response to stress and activation of hypothalamic-pituitary-adrenal axis result in elevated secretion of catecholamines and glucocorticoids Salivary cortisol is a valuable potential marker of vulnerability to stress disorder. Biochemical presentation of hypercortisolemia, that is, increased concentration of salivary cortisol, reflects the enhanced »capacity« of the central adrenergic system. The measure ment of salivary cortisol concentration has several advantages over the conventional determination of total blood concentrations. The sampling procedure for salivary cortisol measurement is simple, non-invasive and stress-free, whereas blood sampling might be stressful and thus cause consequent increase in cortisol levels The first day post-surgery is still the period when the highest level of stress is expected, especially after major surgery such as AAA, which is due to high intensity of pain despite therapy, as well as to stress associated with hospitalization. The results of our study revealed that, on the first postoperative day in the morning, serum cortisol levels were within reference range, close to the upper reference limit. The values were almost identical in both groups. However, the values for salivary cortisol were several times higher in both groups, yet without statistically significant differences between the groups. During the night, the intensity of pain was higher in MPCA-group, which resulted in increased levels of salivary cortisol in the morning being 116.3 nmol/L as compared with 47.1 nmol/L in MI-group.Considering the precisely and strictly defined criteria for qualifying a parameter as a biomarker, a longitudinal study which would compare the preoperative and postoperative values might offer some guidelines for salivary cortisol as a candidate for »state« or »trait« biomarker. Anyway, salivary cortisol could be considered as a marker for overall vulnerability to psychopathological manifestations occurring during perioperative period, which is in compliance with literature data Our study has several limitations. It is a single-center study, and the number of participants was relatively small. Both the pain evaluation according to NRS and the evaluation of patients’ satisfaction with analgesia are subjective methods, which might affect the results.According to our results study demonstrate that opioid analgesic morphine proved excellent for managing the acute postoperative pain after AAA repair treatment and because of that our next study planned to give surgical patients various anti-stress medicine as adjuvant therapy and examine their effects on acute postoperative pain after surgical interventions. Both analgesic techniques using morphine, with all their advantages and drawbacks, are acceptable and legitimate choice for postoperative analgesia. Our study confirmed that salivary cortisol is a more sensitive stress biomarker in surgical patients as compared to serum cortisol. Nevertheless, further studies are needed to provide additional evidence.MI, morphine intermittently;
MPCA, morphine patient-controlled analgesia;
AAA, abdominal aortic aneurysm;
PCA, patient-controlled analgesia;
HPA, hypothalamus- pituitary-adrenal;
CRF, corticotrophin-releasing factor;
NRS, numerical rating scale;
CMIA, chemiluminescent microparticle immunoassay;
ECLIA, electro-chemiluminescence immunoassayAll the authors declare that they have no conflict of interest in this work.


Pain is unpleasant sensory and emotional experiences associated with actual and/or potential tissue damage. It is the most common and prevalent reason for emergency departments (ED) visits with prevalence over 70% in the world.The study aimed to assess the adequacy and appropriateness of pain management at Aabet Hospital, Addis Ababa, Ethiopia.A hospital-based prospective cross-sectional study was conducted at Aabet hospital from December 1, 2020 to March 30, 2021. Adult trauma patients having pain  with Glasgow Coma Scale score > 13 were eligible to participate in the study. The pain intensity was evaluated at the time of admission (o minute) and then at 60, 120, 180, and 240 minutes. The time of the first analgesics was registered. The adequacy and the appropriateness of the pain management were calculated through pain management index (PMI).Two hundred thirty-two (232) participants were included in this study of which 126 (54.3%) were admitted due to road traffic accident followed by fall 44(19%). Only 21 (9.1%) study participants received the first analgesic treatment within 30 minutes while 27(11.6%) participants had no treatment at all within 240 minutes. The mean pain intensity score at admission was 5.55 ± 2.32 and reduced to 4.09 ± 2.69. Nearly half 110 (47.4%) of the study participants were treated inadequately (PMI (-) score). There was a weak and negative correlation between PMI and time to analgesia . The type of analgesia used, the time to analgesia, and the degree of pain may predict 65% of the variance in PMI score .From the results of this study, it can be concluded that acute pain in trauma patients was under and inappropriately treated. Pain is “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual and potential tissue damage” . It is tAcute trauma pain has been the most neglected but yet the most deleterious to the health and well-being of injured patients . It’s toGuidelines and experts recommend the management of acute pain in less than 30 min  but the mean time for most setting in ER was 78 minutes in the US and greater in low-income countries , 7–10. AThe right pain management requires knowledge about pharmacological properties of non-opioids and opioids analgesics as well as, the assessment of risks related to opioid diversion, abuse, and misuse , 7. A syThis study was therefore aimed at assessing the pain intensity of trauma patients, time to analgesia of the trauma patients, adequacy and appropriateness of the pain management. It would be an important milestone in informing all concerned bodies to device interventions and conducting further research regarding the acute pain management practice in an emergency setting in Ethiopia.This study was conducted at the triage of emergency medicine and critical care department of Aabet hospital in Addis Ababa, Ethiopia. AaBET Hospital is a part of St. Paul’s Hospital Millennium Medical College. It is an emergency dedicated center with level 3 trauma care. It provides emergency and critical care services, orthopedic, neuro-surgery, general surgery, and plastics surgery services. The emergency department has 60 beds and the overall hospital bed is 300. The hospital serves about 400,000 populations in Addis Ababa and surrounding. The rate of admission at the hospital’s ED is 41–55 patients per day  .The primary objective of this study was to assess the adequacy and appropriateness of pain management at Aabet Hospital, Addis Ababa, Ethiopia and the secondary objectives of this study were to assess time to analgesia for trauma patients, to assess pain intensity before and after analgesia administration to trauma patients and to assess the adequacy of acute pain management in accordance with the WHO pain management ladder among trauma patients admitted to Aabet hospital.A hospital-based prospective cross-sectional study design was employed. The data were collected for a period of four months  and data from patients’ medical chart and pain outcome questioners were used for the study.All adult patients admitted to triage of emergency Aabet Hospital during the study period fulfilling eligibility criteria were included. The inclusion Criteria were patients presented with injuries due to trauma, patients ≥ 18 years of age, stable patients , Glasgow Coma Scale score > 13 , patients having pain (at least score 1) according to verbal rating scale, and patients willing to participate in the study. The exclusion criteria were cognitive and mental disabilities , patients who require cardiopulmonary resuscitation, endotracheal intubation, or transferring to intensive care units during data collection and patients who were addicted, alcoholic and had opiate abuse. The dependent Variables were adequacy and appropriateness of pain management.2 pq/ E2) and the assumption is that the prevalence of the patients reporting pain in the ED is 80.1% [The sample size required was calculated by using single proportion sample size formula  with a confidence interval of 95% and a = 0.05, P = prevalence of pain in emergency department in Ethiopia (80.1%)  and d = f =In the past three months there were N = 1542 trauma patients admitted to the triage of the Aabet Hospital which was < 10,000 for which correction formula was used and the sample size calculated to be (nA carefully designed data collection tool that was derived from American Pain Society Patient Outcome Questionnaire (APS-POQ-R) for Quality Improvement of Pain Management in hospitalized patients was used to meet the designed objective , 20. NumThe time sections were derived from Emergency Severity Index (ESI) of the triage category where severe cases were admitted to Red area (should be treated immediately), Orange area (treat the patient in less than 10 minutes), moderate to Yellow (treat the patients in less than 60 minutes) and mild cases to Green area (treat the patient within 240 minutes). The data collectors rated and recorded the pain intensity of the trauma patient. The time of the administration of the first analgesic was recorded; if the second dose of analgesia was administered, it should also be recorded. Any side effects correlated to the analgesic drugs delivered were recorded.The PMI has been proposed as an auditable measure of the appropriateness for analgesic therapy. The PMI is a tool that tries to correlate an individual patient’s pain intensity to the appropriateness of the prescribed analgesics according to the WHO pain management ladder. The PMI is calculated by first giving scores to both the patient’s pain intensity and the class of the analgesic prescribed. Based on previous studies, the cutoff points used for pain intensity were 0 for no pain, 1 to 4 for mild pain, 5 to 6 for moderate pain, and 7 to 10 for severe pain. Accordingly, the absence of pain was scored as 0, mild pain as 1, moderate pain as 2 and severe pain as 3. In a similar manner, different potency of analgesic drugs prescribed were categorized as 0 if no analgesic drug was prescribed, 1 if a non-opioid analgesic was prescribed , 2 if a weak opioid analgesic was prescribed , and 3 if a strong opioid was prescribed .The PMI was calculated by subtracting the pain intensity or score from the analgesic level and ranged from − 3  to + 3 (patient experienced no pain but was taking morphine). Negative scores on the PMI were considered as indicators of inadequate pain management, and scores of 0 and greater was labeled as conservative indicators of adequate pain management.Variables and database were coded, set and entered, cleaned, and analyzed using Statistical Package for Social Science (SPSS) version 26.0. Descriptive statistics included mean and standard deviation for continuous variables and frequency and percentage for categorical data were used to summarize socio-demographic and relevant characteristics of the study participants. The normality of data on pain intensity was measured by Kolmogorov-Smirnov tests. The pain intensity was analyzed in different sub-groups using one-way analysis of variance (ANOVA) repeated measures test. The pain intensity in different time sections will be analyzed by the repeated measure.Pearson correlations were conducted to check relationship between patients’ characteristics and adequacy of pain. Multiples linear regression Analysis of PMI as dependent variable and type of analgesia administered, time to analgesia and pain intensity at admission as independent variables were used to assess the adequacy of pain management (p < 0.05).The reliability of pain assessment scale was tested by Cronbach’s Alpha coefficient and found to be reliable with a value of 0.96. Prior to the actual data collection process, Pretest was done on 20 (in about 10% of the participants) trauma patients two weeks before the day of actual data collection and based on the results obtained from pre-test, amendment was made on the assessment tools and way of assessment based on the inputs found on pre-test. Eight data collectors (two pharmacists (B.Pharm), five BSc Nurses and one Clinical nurse), a supervisor  and four card room workers were hired and the principal investigator provided two day training to the data collectors and supervisor to familiarize them on data collection instruments and on how to collect the necessary data from patient medical charts and how to conduct patient interviews. The supervisor was supervising data collectors and facilitates the daily activities. All filled checklists were reviewed for completeness and consistency on daily basis by the supervisor and principal investigator.Prior to data collection, the full protocol of this study was submitted to Ethical Review Committee of AAU, School of Pharmacy, College of Health Sciences and received ethical clearance with reference number ERB/SOP/205/10/2020, and also permission for data collection was obtained from Aabet hospital. Each study participant was informed about the purpose of the study and its potential risk  and is reversible. It’s of sudden onset, occurs immediately after an injury which is usually severe in nature.scores of zero or greater on PMI or a decrease in pain score to < 4 and a decrease from triage pain score of ≥ 2 , 21.is a person older than or equal to 18 years of age.Pain that is persistent and has been experienced for more than three months.describe the lack of adequate treatment of pain in terms of dosages and rapidity of administration of analgesics for ED patients.the fear of the use of opioids by health care professional when the patient is eligible for the administration of opioids.the severity of pain in traumata patients, which would be assessed by numerical rating scale.a tool that tries to correlate an individual patient’s pain intensity to the appropriateness of the prescribed analgesics according to the WHO pain management ladder.any pain that goes on for longer than would be expected after an injury or illnessthe administration of the first analgesics within the observed 240 minutestime between admissions (0 hrs) of the patient to the hospital (from triage) and the first dose of analgesia.physical injury due to road traffic accident, burn, falls, gunshot wounds, fight, collision or any other emergency that results in physical injury.a specialized hospital facility that is designed to provide diagnostic and therapeutic services for patients with major trauma injuries. It’s an emergency department with specialized services.).From 1252 study participants encountered during the study period, a total of 232 study participants were included for analysis. Nearly three-fourth (69.8%) of the participants were males. The mean age of the study participants was 35.53 years and more than half (55.6%) of them were in the middle adulthood age (36–59 years). Majority (31.9%) of the participants were Oromo. Nearly half (45.26%) of the study participants had a primary level of education and nearly half (46.1%) of the study participants were civil servants  were admitted in the trauma center due to road traffic accidents followed by falling down accident 44 (19.0%) and fighting 22 (9.5%) while other causes of trauma were reported in 34 (14.7%) of the study participants. The type of trauma mainly found during this study was a fracture in 39.2% of the study participants, followed by contusion and stretching in 27.2%, laceration and wounds in 22.4%, burn in 9.9% and other injures in 1.3% of the study participants. Upper and lower limbs were the most parts of the body where the feeling of pain was observed in 126 (54.3%) of the participants followed by the trunk and head, 72 (31%) and 31 (13.4%) of the participants, respectively (Table Among the 232 patients participated in this study only 21 (9.1%) patients had received the first analgesic treatment within 30 minutes while 27(11.6%) had no treatment at all within the study duration (240 minutes). Furthermore, only 3 (1.3%) patients were treated non-pharmacologically. Most of the study participants 72 (31%) received non-opioids 59 (25.6%) participants received weak opioids, and 37 (15.9%) participants received strong opioids. With regard to dual treatment approach, only 25 (10.8%) of participants received non-opioids and weak opioids followed by 6 (2.6%) participants who were treated with non-pharmacologic pain management method with non-opioids, and 3 (1.3%) patients received non-opioids and strong opioids in the four hours follow up. As summarized in Table )On the other hand, 17 (7.3%) participants with mild pain and 13 (5.6%) participants with moderate pain received no analgesia, 55 (23.7%) participants with severe pain received weak opioids and 3 (1.3%) participants with moderate pain received strong opioids as depicted  participants were in severe pain while nearly a quarter 55 (23.7%) of the study participants were in moderate pain, and 81 (34.9%) participants were with mild pain and. At the end of follow up (at 240 minutes), only 21 (9.1%) participants were in pain free while 103 (44.4%) participants were in mild pain, 44 (19%) and 64 (27.6%) were in moderate pain and in severe pain, respectively as shown in Table One-way ANOVA repeated measure test compared means of pain intensity for each of analgesic type administered over 240 minutes. It showed that the mean pain intensity of those receiving no analgesia increased from 3.93 to 4.33 and those receiving non-opioids, weak opioids and strong opioids decreased from 3.97 to 2.81, 6.28 to 5.27 and 7.78 to 3.38, respectively as illustrated in the following diagram.Among the patients admitted in the ED of Aabet hospital, almost half (110 (47.4%)) of them were treated inadequately having a PMI (-) score, of which nearly two-third (37.9%) were in moderate or severe pain. Pearson correlations were conducted to check associations between patients’ characteristics and adequacy of pain management. Statistical significance was determined at p < 0.05. Table 2 = 0.65, Adjusted R2 = 0.651, p = 0.0001) while the types of treatment (non-pharmacologic and pharmacologic) and the number of analgesia used were not significant at p < 0.05. The type of analgesia administered, time to analgesia and pain intensity could predict 65% of the variance in PMI score. As the time to analgesia increases by 1 minute, the PMI decreases by -0.001 when all other independent variables are held constant and as the pain at admission increases by one unit, the PMI decreases by -0.191 unit when all other independent variables are held constant and as one unit increase unit in the type of analgesic used or as the patient switched from weak opioids to strong opioids, the PMI increase by .514 units.In this study, multiple linear regression analysis  from multiple linear regression analysis as depicted in the Table The type of analgesia administered, time to analgesia, pain intensity at 0 min(admission), and number of analgesia could predict 76.1% of the variance in the individuals’ pain score at the end of 240 minutes  followed by diclofenac 65 31.9%), paracetamol 41 (17.7%) and morphine 17(7.3%). Consistent with the findings of this study, other research conducted in Gondar, Ethiopia revealed that 39.9% of patients received tramadol, 19.7% received diclofenac and less than 4.5% of the patients received any strong opioids % followe. Likewis.9%, paraMultimodal pain management approach has the ability to better control pain and reduces opioid consumptions and complements opioid, thereby opioid sparing , 34, 35.The present study showed that nearly half (110 (47.4%) of the participants were treated inadequately though 88 37.9%) were in moderate or severe pain. Studies done in Gondar, Ethiopia had a comparable findings with the current study in that 57% of the patients reported that the analgesic was not adequate , 36, 37..9% were Psychometric evaluation of the American Pain Society Patient Outcome Questionnaire showed a reduction of approximately 30% in a Numeric Rating Scale in acute pain has been considered as a clinically important difference . AccordiThe inadequate pain management may emanate from several barriers in resource-limited setting. The limited availability and unaffordability of opioids are the major ones which pose a significant challenges to pain management . AccesseIt’s generally recommended that patients in ED should get their first analgesia within 30 minutes , 7, 9. HThe present study found that mean time of the first analgesia was 94.7 minutes which was much higher than studies done in US, Canada, Australia, Iran and Netherlands in which the mean time of analgesia for most setting in ER was 78 minutes , 40–42. Pain relief was not associated with time to analgesia but it had association with ED length of stay , 40, 41.2 = 0.65, Adjusted R2 = 0.651, p = 0.0001). As the time to analgesia increased by 1 minute, the PMI decreased by -0.001 units when all other independent variables are held constant. That means when the analgesics were given near the pain assessment minutes, the lesser the reports of pain but the overall pain management adequacy was improved as early as the first analgesia as shown on the PMI. This study had also addressed the gap that strong opioids were not administered as early as NSAIDs and weak opioids despite the patients were in severe pain. This might be due to misconception and the fear of strong opioids for addiction (opiophobia), the lengthy bureaucracy to get strong opioids, costs and availability of strong opioids [This study found that time to analgesia had negative and weak correlation with PMI . Multiple linear regressions also revealed that time to analgesia, the type of analgesia used, and pain intensity at admission could predict 65% of PMI  and trauma patients had higher probability of receiving early analgesia than non-trauma patients  .This study found that acute pain in trauma patient admitted in ED were undertreated and ignored as the fifth component of vital signs. Several studies in Ethiopia, confirmed that pain in cancer, in preoperative and postoperative, and in burn patients had not been treated adequately or had not received pain intervention , 28, 47This paper shed light on the importance of the time to analgesia and appropriateness of the pain management in trauma patients. Indeed, this study may help in filling the gaps in ED’s pain management practices through stimulating appropriate analgesic agent prescribing patterns and promoting adherence to good clinical practice set by the WHO.This study has some limitations. This was a single centered study, based on a nonconsecutive convenience sample of patients. As such, the results of this study were found from trauma patients admitted at the ED of trauma center and may not be generalizable to other ED settings with different staffing profiles and case mixes.Moreover, discharge pain medication information was unknown due to shortage of study period over a single patient and the patient were not completing the treatment in the hospital within the four-hour period which was helpful to know the length of hospital stay due to pain. Additionally, as the study was in trauma center, the trauma patient were most likely transferred to orthopedic surgical room, neurosurgery room, plastic and reconstructive surgery unit or intensive care unit after getting emergency medical service for longer stay and there may be loss to follow up in the process.From the findings of this study, it can be concluded that acute pain in trauma patients in the emergency department was undertreated and ignored as the fifth vital sign. Furthermore, this paper shed light on the significance of time to analgesia and the appropriateness of pain management in trauma patients.