Background: Neuropathic pain is one of the most common problems in patients with diabetes mellitus (DM). In this study, the effect of botulinum toxin type A (BTX-A) on neuropathic pain, quality of sleep, and quality of life of diabetic patients with sensorimotor polyneuropathy was studied.Methods: This randomized placebo-controlled trial study was carried out in a double-blind (patient-researcher) method. The study was performed on 32 patients with type 2 DM. Neuropathy was confirmed by Douleur Neuropathique 4 (DN4) Questionnaire and nerve conduction study (NCS). The patients were randomly assigned to two intervention and control groups based on the random numbers table. After selecting the subjects, we used 36-Item Short Form Health Survey (SF-36), Neuropathic Pain Scale (NPS), Visual Analogue Scale (VAS), and Pittsburgh Sleep Quality Index (PSQI) questionnaires before and after 3 months of 100 units BTX-A injection (as intervention group) or same amount of chloride sodium (as control group) to the subjects' feet. The data were analyzed by SPSS software using independent two-sample t-test, chi-square test, and one-way repeated measures analysis of variance (ANOVA).Results: 12 male and 20 female patients participated in this study. There was a significant difference in the mean VAS, PSQI, physical dimension of the SF-36, and some NPS indices over time (12 weeks) (P < 0.001).Conclusion: The results of this study showed that BTX-A reduced neuropathic pain and improved the quality of life and sleep in people with diabetic neuropathy. In the majority of cases, the term ‘pain’ refers to tissue damage caused by external stimuli (nociception). The other category, referred to as ‘neuropathic pain’, occurs due to damage to the peripheral nervous system (PNS) and the central nervous system (CNS), or because of the disturbances in signal transduction along the nerves.2-4 These types of pain attack extremities, thereby disrupting sleep, reducing the quality of life, creating anxiety, interfering with routine activities, and increasing living costs.5-7Neuropathic pain is one of the most prevalent problems associated with diabetics.7,8 Pain, the numbness of organs, and sensory impairment, especially in the lower limbs with a stocking-glove distribution pattern developing towards proximal parts, are the main symptoms of the disease.1,9,10Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent cause of peripheral neuropathy. This condition is developed in 30%-90% of diabetic patients.11,12 In Iran, the prevalence of this disorder has been reported to be 28% in Khoramabad, 45.6% in Hamadan, and 51.7% in Yazd.13-15The prevalence of DSPN has been reported to be different in various studies, depending on the related diagnostic criteria. Approximately 20 to 30 million people around the world suffer from this condition.16 Drugs, such as carbamazepine, opioids, and antidepressants were developed and used to reduce the rate and extent of neuropathic pain; however, due to the non-long-term pain relief, increased treatment costs, and side effects of these drugs, they have turned into challenging issues.17,18Finding efficient treatments for this disease has always been a serious challenge, with about 39% of the patients with DSPN reported to have been unresponsive.19Neuropathic pain has recently been treated with lidocaine, botulinum toxin type A (BTX-A), and capsaicin. Although the effects of these drugs have not so far been confirmed, they are likely to be used, given the limited number of side effects they may generate in patients.20 Research has also shown that BTX-A’s analgesic effects are independent of reducing muscle disorders, and the dose needed to relieve pain is less than the one necessary to improve the movement.21 Paterson et al. found out that BTX-A could block pain receptors; in addition, they observed that the intra-cutaneous injection of BTX-A reduced the sensitivity of mechanical pain and inhibited pain.22 In the same vein, other studies reported that BTX-A reduced neurogenic inflammation.23BTX affects both motor neurons and all other nerves.24BTX-A is injected in subcutaneous, intramuscular, and muscular forms as well as in the nerves.25Nam et al. reported that the severity of neuropathic pain decreased significantly in a patient aged 62 years with brain tumors after the injection of a 100-unit dose of BTX; the resulted pain relief lasted for 12 weeks.26Park and Park investigated the impact of BTX on neuropathic pain; they referred to the 40-year use of BTX in medicine and reported that treatment with BTX was effective in patients with diabetes mellitus (DM), trigeminal neuralgia (TNG), herpes, as well as intolerable types of neuropathic pain, such as the pain caused by spinal cord injuries as well as post-stroke pain.27Han et al. studied the effects of BTX-A on the treatment of 40 patients with neuropathic pain due to spinal cord injuries. Their study which was a randomized, double blind, and placebo-controlled study showed that BTX-A reduced neuropathic pain caused by spinal cord injuries.The present study was conducted to compare the effects of BTX-A on lower limb neuropathic pain among two groups of patients with DM, one as an intervention group and the other as control group receiving a placebo, who referred to the Diabetes Clinic of Ali ibn Abi Talib Hospital in Rafsanjan, Iran.The present study was a double-blind clinical trial with the design shown in the flowchart .In order to meet ethical criteria, while obtaining the code of ethics from the Ethics Committee (IR.RUMS.REC.1395.116), written informed consent was obtained from the participants. This trial was registered in the Iranian Registry of Clinical Trials (IRCT) system under code of IRCT20190129042540N1.Patients: Firstly, 50 patients with sensory and motor complaints were evaluated. In fact, 38 patients with type 2 DM aged 40-70 years, who were admitted to the Diabetes Clinic of Ali Ibn Abi Talib Hospital in Rafsanjan, were selected based on the inclusion and exclusion criteria to be listed in the following sections.The neuropathy (sensory and motor polyneuropathy) of the patients was confirmed by a neurologist using Douleur Neuropathique 4 (DN4) Questionnaire and nerve conduction study (NCS).Inclusion criteria: The main inclusion criteria included having type 2 DM for at least 3 years, aging 40-70 years, giving positive answers to four or more questions in DN4,28,29 and showing the evidence of diabetic neuropathy in the lower limb electrophysiological examination,30 as well as suffering from mild to severe neuropathy according to the Toronto Clinical Neuropathy Score (TCNS).31Exclusion criteria: Initially, subjects allergic to BTX-A, those who used other drugs to reduce neuropathic pain, the ones with a history of myasthenia gravis (MG), subjects with the distal muscle weakness, kidney dysfunctions, and a history of alcohol use, post-operative patients, those who started taking medicines after the beginning of the study, and the ones who developed aminoglycosides or the obstructive airway disease concurrently, were excluded from the study.32Method of injection: All patients were asked to attend the Diabetes Clinic of Ali ibn Abi Talib Hospital on a specific day. All preparations for the injection of the toxin were made by an expert on the same day and at the same location in the hospital, with necessary measures adopted concurrently by other colleagues. For the patients in the intervention group, 100 units of BTX-A  were dissolved in 1.2 ml of normal saline and according to the grid pattern of 12 points (3 × 4) on the foot surface : The SF-36 standard questionnaire is used to measure the health-related quality of life. Montazeri et al. confirmed, using Cronbach’s alpha, the reliability and validity of the Persian version of the SF-36 standard questionnaire at 0.65. In this questionnaire, 8 physical activity scales, including the variables of physical role functioning, physical pain, general health, vitality, physical functioning, social role functioning, emotional role functioning, and mental health are assessed. The first five scales are used in assessing the physical condition, with the three other scales used to examine mental status.34Visual Analogue Scale (VAS): It includes a questionnaire in which a straight line is drawn, being used to compare the patient’s pain scores at various stages. This questionnaire has been used in numerous studies, with its validity and reliability having been confirmed by Cronbach’s alpha at 0.99.35,36Neuropathic Pain Scale (NPS): This questionnaire assesses the feeling and quality of pain in patients. It consists of 10 questions, with two questions being related to the severity of pain in general, and 8 questions being connected with the quality and location of pain, including hot sensation, dull sensation, cold sensation, unpleasant sensation, deep sensation, surface sensation, and pain intensity. The validity and reliability of the NPS questionnaire have been confirmed by Jensen et al. using Cronbach’s alpha at 0.78.37Pittsburgh Sleep Quality Index (PSQI): PSQI is a questionnaire for the assessment of the sleep quality of people, being composed of 18 questions, with a scoring scale of 0 to 3. In this questionnaire, 7 subscales of sleep quality, sleep latency, sleep time, sleep efficiency, sleep disorders, sleep deprivation, and daily functional disorders are considered. The scores of these seven components constitute the total score of the questionnaire, ranging from 0 to 21; the higher the score is, the lower an individual’s sleep quality will be. A score over 6 alludes to an undesirable sleep quality. The validity and reliability of this questionnaire was confirmed by Farrahi et al. using Cronbach’s alpha at 0.77.38The independent two-sample t-test and the chi-square test were used to compare demographic and primary features of the patients. In addition, one-way repeated measures analysis of variance (ANOVA) was used to assess the changes to the outcome indices in the intervention and placebo groups in 1, 4, 8, and 12 weeks after the intervention. The data were analyzed using SPSS software . The significance level was considered at 0.05. The patients were assigned randomly to two intervention and control groups based on random numbers and completed SF-36, NPS, VAS, and PSQI questionnaires. The patients were referred back to the clinic one week later and were required to return again in weeks 4, 8, and 12 after the injection to collect the data required for NPS, VAS, SF-36, and PSQI questionnaires, which were used at the beginning of the injection .According to the inclusion and exclusion criteria, 32 patients (12 men and 20 women) were divided into two intervention and placebo groups in the present study, with 16 subjects in each group.According to the results of One-way repeated measures ANOVA was used to compare the mean changes in the outcome variables in the two groups over time. In all cases, due to the significance of the Mauchly’s Test of Sphericity, the results of the non-parametric test for Greenhouse-Geisser correction were reported. The only case where the spherical assumption was confirmed using the Mauchly probe (P > 0.050) and sphericity-assumed test results, was the cold sensation variable.There was no significant difference in the VAS between the two groups (P = 0.270) at the beginning of the study, and the two groups were homogeneous. There was a significant difference in the mean VAS over time (12 weeks) (P < 0.001); in addition, there was a significant correlation between the mean VAS in the intervention and control groups, which resulted in a change in the mean VAS. The time was not the same in the two groups, and the decrease in pain intensity was significantly higher in the intervention group than the placebo group during the follow-up period (from the beginning to the end of week 12) .PSQI measured at different times for the two intervention and control groups showed that there was no significant difference between the two groups at the beginning of the study in terms of this specific criterion (P = 0.678). A significant difference was discovered in the mean PSQI variation over time (12 weeks) (P < 0.001); besides, the assessment of the interaction of the PSQI index over time in both groups showed that the drop in the sleep quality score of the subjects in the intervention group was significantly higher than that of the placebo group over time (from the beginning to the end of week 12) .The lower the score of the questionnaire was, the higher the quality of sleep would be.In addition, there was no significant difference between the two groups in terms of the mean score of the psychological dimension of the quality of life (P < 0.050). Regarding the physical aspect of the quality of life, there was no significant difference between the two groups at the beginning of the study (P = 0.678). However, a significant difference was identified in the mean changes of the physical dimension of the quality of life in the questionnaire over time (12 weeks) (P < 0.001); therefore, our results showed a significantly higher and more noticeable progression of the quality of life's physical dimension in the interventional group compared to the subjects of the placebo group .The results of the NPS questionnaire  are summarized in 39 In DM, the involvement in peripheral vasculature is high, yet there is no correlation between this type of involvement and diabetic neuropathy; thus, the cause of this disease remains unknown.40-44DM is the most prevalent disorder of endocrine glands, and many people with DM have a type of the nervous system involvement called DSPN.41Blood glucose control and normalization can relieve the symptoms of neuropathy and prevent the progression of the disease. However, there is evidence that even in case of controlling blood sugar, neuropathy signs are developed.42 Recent studies have confirmed the effects of BTX-A on the long-lasting reduction of neuropathic pain in diabetics, compared to previous treatments.43,44Over 20% of diabetics suffer from the painful disease of DSPN. It affects the general health level and quality of life even after receiving prescription drugs, including antiepileptic drugs, opioids, and non-steroidal anti-inflammatory drugs.45The score of the VAS questionnaire obtained by comparing the patient’s pain score at each stage with the next stage showed that there was a significant decrease in pain in the first week after the BTX-A intervention, implying the positive effect of BTX on treating pain of DSPN. This finding was consistent with results of a meta-analysis conducted by Lakhan et al. who examined the effects of BTX-A on the treatment of DSPN pain. The review results of various studies confirmed the reduction in the VAS test score after the injection of that toxin.32 On the other hand, we studied quality of life and sleep with other aspects of sensory abnormality more than investigated objects in that study.In Iran, a study by Ghasemi et al. showed that patients have experienced a drop in pain and the VAS score after receiving BTX-A, which was consistent with the results of the present research.31Yuan et al. performed a study similar to the present one, reporting that VAS scores decreased in weeks 1, 4, 8, and 12 after the intervention.46In the same vein, Ding et al. reported that the administration of BTX-A reduced the VAS score in weeks 4, 8, 12, and 24 after the injection.47 Our study approved this effect in adult patients.The results of the present study showed that the sleep quality in patients with DM improved after the BTX-A injection; this effect was significant in weeks 4 and 8, implying that the medication effect peaked on day 28 after the intervention. The results of the study by Binay Safer et al. implied a direct correlation between treatment with BTX-A and the improved sleep quality in children.31 The difference between two studies in the results of week 8 could be due to the difference in the toxin dose because 100 units of BTX-A were used in the present study, yet 50 units of it were administered to the patients in the mentioned study. Another difference between the two studies was the number of the participants, where 18 subjects were divided in two intervention and control groups in the study by Yuan et al.,31 but the present study was conducted on 32 subjects. According to the results of the study by Yuan et al., the PSQI score showed a significant difference in week 4. Although the sleep quality score decreased compared to the pre BTX-A injection period in week 8 and this decremental response implied that the sleep quality increased in the subjects, this was insignificant.47In addition, the physical and psychological dimensions of quality of life in both groups were assessed using the SF-36 questionnaire in the present study. In the present study, the psychological dimension of the subjects remained fixed at different times, indicating that BTX-A was psychologically ineffective; nevertheless, the individuals’ level of physical capacity in quality of life improved. This result is very important because a major problem of people with diabetic neuropathy is the poor quality of life and the debilitating complications of their body.31In the study by Yuan et al., no significant correlation was found between treatment with BTX-A and the subjects’ quality of life in both psychological and physical aspects. They attributed the lack of correlation to the impact of the quality of life on various factors, implying that the improvement in neuropathic symptoms alone could not improve the patients’ quality of life.46In the same vein, Ding et al. found out that the injection of BTX-A increased the SF-36 score and the patients’ quality of life in weeks 4, 12, and 24 after the injection.Considering the NPS questionnaire, the scores of dull, cold, sensitive, deep, and surface sensations decreased from week 4 after the BTX-A injection until the last week, which is another issue to be discussed in the present study. In addition, the scores decreased after weeks 4 and 8 after the injection in the fields of hot, unpleasant, and sharp sensations.32 The difference in the result concerning the sensation parameter could be due to the differences in the ways the two studies were conducted, including the number of patients and the time of monitoring the status of patients after the injection. The present study included 32 patients, while the aforementioned one was conducted on 40 patients; in addition, the present study evaluated patients in weeks 4, 8, and 12 after the injection, while the other one evaluated the patients just once after the injection.The results of the study by Ghasemi et al. indicated that the score of the NPS questionnaire decreased in all sections, except the cold sensation; therefore, this study was consistent with the results of the present research in all sections apart from the cold sensation.46In the same way, Ding et al. reported that NPS scores decreased after treatment with BTX-A in weeks 4, 8, 12, and 24 after the injection.The present study showed that the administration of BTX-A could help relieve the pain of diabetic patients with polyneuropathy and help them get rid of the constant suffering from anticonvulsants and sedatives. Changing the dosage of BTX-A produced more desirable outcomes than the former studies; hence, using other doses is likely to produce more optimal results in the future.


The number of patients having a postprocedural pain score of at least 3 was significantly greater in the MR group compared with the DR group . The number of patients with hypotensive episodes was higher in the DR group , which could all be restored with ephedrine. The use of dexmedetomidine in conjunction with remifentanil may be a safe option that provides excellent patient satisfaction while potentially attenuating postprocedural pain.Anesthesia for percutaneous transluminal angioplasty (PTA) involves a high-risk population having a broad spectrum of pain character and intensity. This study delved the anesthetic efficacy of dexmedetomidine versus midazolam, when used with remifentanil. Seventy patients scheduled for femoropopliteal PTA were randomized into two groups receiving either intermittent midazolam boluses (0.03–0.05 mg/kg) (MR group) or dexmedetomidine 0.2–0.7 μg/kg/h after a loading dose of 1.0 μg/kg for 10 min (DR group), both with remifentanil. The primary endpoint was the patients’ satisfaction . Secondary endpoints included postprocedural pain scores  and adverse events. The satisfaction level of patients was significantly greater in the DR group compared with the MR group (4.0  versus 4.0   Confronting an ageing society, the prevalence of peripheral artery disease (PAD) and its related morbidities continue to escalate . AccordiDexmedetomidine is a highly selective alpha 2 agonist that possess unique properties as it is able to provide both sedation and analgesia whilst preserving the respiratory function . PreviouThe primary aim of this randomized, controlled study was to compare the anesthetic efficacy of dexmedetomidine versus midazolam in PTA by comparing the patients’ satisfaction. Secondary endpoints were interventionists’ satisfaction, pain intensity and postprocedural analgesic requirements up to 24 h after the procedure, and the occurrence of drug-related adverse events.http://clinical trials.gov (NCT 02929095) and followed CONsolidated Standards of Reporting Trials (CONSORT) 2010 guidelines. After acquiring informed consent from each patient, 70 patients with American Society of Anesthesiologist physical status I to III, aged 20–80 years, who underwent PTA for femoropopliteal lesions under MAC between October 2016 and March 2018 were enrolled. We excluded patients with psychiatric disorder, cognitive impairment, myocardial infarction and/or stroke, hepatic dysfunction, or congestive heart failure. Patients were randomly and evenly assigned to either midazolam plus remifentanil  group or dexmedetomidine plus remifentanil  group by a computerized randomization table. Blinding of the group designation was maintained to the patients and the attending anesthesiologists and interventionists, while the studied drugs were prepared by an anesthesia nurse who was not involved in patient care or assessment.The current trial was approved by the institutional review board of the Yonsei University Health System, Seoul, South Korea and then enlisted in 2), and respiratory rate were monitored in all patients. Before starting MAC, all patients received oxygen at 5 L/min through an oxygen mask. Then, MAC was initiated using either MR or DR regimen and procedural draping and local anesthesia with 1% lidocaine to the ipsilateral and/or contralateral inguinal area were followed after 10 min of commencing MAC.After entering the hybrid operating theatre, ECG, non-invasive blood pressure, pulse-oximetry  .In all patients, continuous infusion of remifentanil at 1.2 μg/kg/h remifentanil using a syringe pump was started concomitantly with the bolus placement of midazolam or dexmedetomidine. The infusion rate of remifentanil was adjusted according to the pain score evaluation . The remifentanil infusion rate was increased by 0.6 μg/kg/h and up to 7.2 μg/kg/h to maintain the pain score ≤3. Remifentanil infusion rate was decreased by 0.6 μg/kg/h until reaching 0.6 μg/kg/h when the pain score was between 0 and 1.2 < 90%) occurred, patients were given a verbal awakening stimulation  followed by a gentle squeeze at the trapezius muscle if unresponsive. If respiratory depression persisted despite these stimulations, the rate of remifentanil infusion was reduced by 0.6 μg/kg/h and head extension with or without jaw thrust was performed, while preparing for further advanced airway management.If hypotension occurred , 4–8 mg of ephedrine was given intravenously. If bradycardia (heart rate < 45 bpm) occurred, 0.1–0.2 mg of glycopyrrolate was given intravenously. If bradycardia persisted, 0.5 mg of atropine was given intravenously. If respiratory depression (respiratory rate < 10/min) and/or hypoxia , the patients were asked to choose their satisfaction score about their given MAC using a 5-point numerical rating scale  before being transferred to the general ward.After the end of procedure, the interventionists were asked to choose their satisfaction score using the same 5-point numeric rating scale. In the PACU before being transferred to the general ward, patients were asked for the overall pain score during the procedure using the above described 11-point numeric rating scale. They were also asked for the overall pain score during the 24 h of the post-procedural period. Patients were also asked for the frequency of having a pain score ≥3 during the study period. The number of patients requiring rescue analgesics, and the total amount of analgesics administered to the patients in morphine equivalent dose was recorded.Sample size calculation was calculated based on the patients’ satisfaction score. In a previous study, the level of satisfaction by MR regimen in catheter ablation for atrial fibrillation was 2.9 ± 0.6 . Assumint-test (mean ± standard deviation [SD]). Skewed data were tested using Mann-Whitney U test (median [interquartile range]). Intergroup comparisons of categorical variables were tested using Chi-square test (n [%]). For pain scores that were assessed at 3 time points, post hoc Bonferroni correction was applied. Thus, the p values for the pain scores were considered statistically significant when <0.017. Otherwise, p < 0.05 was considered statistically significant.All statistical analyses were performed with the SAS 9.4 and Rx64 program. Intergroup comparisons of satisfaction and pain scores were done by Mann-Whitney U test. Continuous variables were assessed for their distribution (Shapiro-Wilk test). Intergroup comparison of other variables that showed normal distribution were tested using the independent A total of 105 patients were screened, and 70 among them were enrolled and evenly randomized into either the MR or DR group. There was one dropout among the 70 enrolled subjects .p = 0.021) (p = 0.046).Patients’ characteristics and procedural data are displayed in = 0.021) , Table 22 were all within clinically acceptable ranges and showed no intergroup differences throughout the procedure , while the total amount of administered rescue analgesics in morphine equivalent dose showed a trend towards being lower in the DR group compared with the MR group   .Anesthetic care for PTA can be challenging as patients with PAD comprise a high-risk group for cardiovascular events ,15. ThusFor MAC during cardiovascular procedures, continuous infusion of remifentanil has become the mainstay of anesthesia with the intermittent use of sedatives as necessary. Opioids have their advantages in that they are potent analgesics able to cover diverse pain characters and they lack direct myocardial depressant effects except for their central vagotonic influence . HoweverDexmedetomidine is a potent and selective alpha 2 agonist exerting sedative and analgesic effects at the same time without compromising respiration. Accordingly, emerging evidence supports its beneficial influence in critical care and MAC involving conscious sedation for cardiovascular procedures , while iN-methyl-d-aspartate receptor activation via suppression of NR2B subunit phosphorylation [As our results indicate, patients receiving dexmedetomidine were more satisfied with their anesthetic care than those receiving midazolam with none of the patients in the DR group reporting a satisfaction score of less than 3  confirming our primary hypothesis. This beneficial effect of dexmedetomidine was even more evident in patients with considerable resting pain (Rutherford category ≥4). In terms of its efficacy on pain scores, we could only observe trends towards lower procedural and postprocedural pain scores in the DR group compared with the MR group. Interestingly, there were a significantly lower number of patients in the DR group who experienced a significant postprocedural pain (pain scores of ≥3) than the MR group, despite receiving a lower amount of rescue analgesics. Thus, per our hypothesis, the experimentally proven anti-inflammatory property of dexmedetomidine attenuating oxidative stress may have been responsible for the reduced incidence of intense pain after reperfusion in the current study. Also, concerns have been raised regarding a potential hyperalgesic phenomenon after discontinuation of remifentanil infusion that is not clearly understood . Dexmederylation , which mIn terms of drug-related adverse events, use of dexmedetomidine was associated with more frequent episodes of hypotension, which could all be rapidly restored by a single ephedrine bolus. This result agrees with our previous report involving patients undergoing catheter ablation of atrial fibrillation . By beinIn terms of opioid sparing effect and respiratory function, we could not observe any significant favorable influence of dexmedetomidine over the conventional use of midazolam, which may be attributable to the following. The chosen MR regimen has been used and adjusted in our institution over the past 5 years for PTA to provide safe conscious sedation, which yielded acceptable patient satisfaction as well.The limitations of the current study are as follows. Although there are solid experimental backgrounds, we did not measure markers of oxidative stress or inflammation, and thus, we can only speculate about the favorable influence of dexmedetomidine on post-reperfusion pain. Also, the sample size may be insufficient for validating our secondary endpoints, especially in terms of pain scores as they showed only statistical trends towards being lower in the DR group. Lastly, due to the nature of the disease, the inclusion of male patients was predominant, limiting the extrapolation of these results to female patients.In conclusion, MAC for a high-risk group requires special attention balancing the safety and the patients’ satisfaction. Also, a proper anesthetic regimen should be tailored to cover the disease- and procedure-specific pain characteristics that are unique to patients with PAD undergoing PTA. In line with these needs, the current study provides primary evidence that the use of dexmedetomidine in conjunction with remifentanil may be a safe option that provides excellent patients’ satisfaction while potentially attenuating postprocedural pain as well.


Acute pain during weekly radiotherapy (RT) to the head and neck is not well characterized. We studied dose-volume metrics and clinical variables that are plausibly associated with throat or esophageal pain as measured with a weekly questionnaire during RT.We prospectively collected weekly patient-reported outcomes from 122 head and neck cancer patients during RT. The pain score for each question consisted of a four-level scale: none (0), mild (1), moderate (2), and severe (3). Univariate and multivariate ordinal logistic regression analyses were performed to investigate associations between both esophageal and throat pain and clinical as well as dosimetric variables.In multivariate analysis, age was significantly associated with both types of pain, leading to odds ratio (OR) = 0.95 (p = 0.008) and OR = 0.95 (p = 0.007) for esophageal and throat pain, respectively. For throat pain, sex , with females at higher risk, and fractional organ at risk (OAR) mean dose  were significantly associated with throat pain.A fractional OAR mean dose of 1.1 Gy seems a reasonable cutoff for separating no or mild pain from moderate to severe esophageal and throat pain. Younger patients who received RT experienced more esophageal and throat pain. Females experienced more throat pain, but not esophageal pain. Treatment-related pain results from radiation damage to the mucosal epithelium, causing thinning, atrophy, inflammation, and resulting ulceration A qualitative study noted that all participants viewed effective pain management as a key facet of their RT treatment for head and neck cancer, previous pain experienced influenced current perceptions of pain, forewarning of potential pain did not reliably improve pain experiences, and participants preferred and benefited from pain management by a specialist team Tumor, dental extraction, neoadjuvant chemotherapy, or head and neck surgery-related pain may be present prior to the initiation of radiation, thereby complicating the patient’s pain experience during radiation. Chang et al. have found that transdermal fentanyl reduced pain during RT, but with increased nausea and vomiting Acute pain during weekly RT is not well characterized or understood, despite the resulting significant impact on quality of life. Given this knowledge gap, we studied dose-volume metrics and clinical variables that are plausibly associated with throat or esophageal pain as measured with a weekly questionnaire during RT.2We prospectively collected weekly patient-reported outcomes (PROs) from 122 consecutive head and neck cancer patients during RT who were treated at Washington University School of Medicine in St. Louis between 2010 and 2012. The study was approved by institutional review board. After removing patients who received multiple RT and who did not have target RT structures analyzed in this current study, 96 patients were evaluable. The majority of patients (N = 94) were treated with intensity-modulated RT (IMRT); only two patients were treated with 3D conformal RT (3DCRT). The questionnaire was designed to measure the degree of pain in 16 anatomical structures: gums/gingiva, lip, lymph node(s), ear, eye, face, food pipe/esophagus, mouth, neck, scalp, sinus, skin, throat, tongue, tooth/teeth, and voice box/larynx. Patients were asked: “Do you have pain in the:”. The pain score for each question consisted of a four-level scale: none (0), mild (1), moderate (2), and severe (3). The current study focused on 2 of the 16 anatomical locations: the “food pipe/esophagus” and the “throat”. The organ at risk (OAR) contouring was standardized. The esophagus was contoured inferiorly from the level of the sternal notch to its superior extent. The throat was contoured inferiorly from the inferior border of the mandible superiorly to the hard palate and encompassed the oral cavity.Patients were treated in the supine position while immobilized using a thermoplastic mask. Fusion of PET/CT and/or MRI scans to the planning CT helped define the clinical tumor volumes (CTVs) as well as clinical and pathologic information. Up to two CTVs  were defined. In general, for surgical patients, the CTV1 encompassed the high-risk volume which consisted of the pre-operative primary gross tumor volume (GTV) with a 0.5–1 cm margin and any involved lymph node levels. For non-surgical patients, the CTV1 encompassed the primary GTV with a 1–1.5 cm margin and involved lymph nodes plus a 0.5 cm margin. For both types of patients, the CTV2 corresponded to electively treated lymph node levels. Planning target volumes (PTVs) were defined by adding 0.5 cm to the corresponding CTVs and subtracting 3 mm from the skin. Depending on the treatment, CTV1 and CTV2 received 70 and 56 Gy , 66 and 54 Gy , or 60 and 52 Gy , respectively. Patients receiving chemotherapy received: either induction or concurrent chemotherapy. Concurrent chemotherapy consisted of either cisplatin, carboplatin, or cetuximab. Induction chemotherapy included TPF , ACCF , or carboplatin and etoposide. In general, pain medications were prescribed as needed starting with “magic mouthwash” , followed by an opioid prescribed on an as-needed basis, and finally, a combination of a fentanyl patch for baseline pain and oxycodone or morphine as needed for breakthrough pain.2.1Univariate and multivariate ordinal logistic regression analyses were performed to investigate associations between both esophagus and throat pain and clinical as well as dosimetric variables. Dosimetry data was extracted from the esophagus and oral cavity planning volumes using CERR  3Weekly completion rates of PROs were 79%, 82%, 83%, 80%, 81%, 79%, and 64% for esophageal pain and 81%, 84%, 88%, 82%, 80%, 77%, and 70% for throat pain. For this cohort, maximum pain scores were averaged for each treatment week as shown in In univariate ordinal logistic regression using Dx (minimum dose to the x% highest dose volume), mean dose, and maximum dose in esophagus, mean dose showed the highest odds ratio (OR) associated with esophagus pain: OR = 2.40 (p = 0.027) see . For thrMultivariate ordinal logistic regression analysis was performed using clinical variables with p < 0.05 in the univariate analysis and fractional OAR mean dose. Age was significantly associated with both types of pain, leading to OR = 0.95 (p = 0.008) and OR = 0.95 (p = 0.007) for esophagus and throat pain, respectively. This implies that, other factors being equal, younger people tend to experience more pain during RT. For throat pain, sex , with females at higher risk, and fractional OAR mean dose  were significantly associated with throat pain. In addition, ordinal logistic regression analyses were performed on dosimetric and clinical variables for surgical and non-surgical groups, separately. The results are shown in the It was observed that surgical patients had more unilateral neck radiation than non-surgical patients with more bilateral neck radiation . There was a statistically significant difference of fractional mean dose in the oral cavity with p = 0.015 using the Wilcoxon rank-sum test between the surgical  and non-surgical groups whereas fractional mean dose of the esophagus was not statistically different between the two groups (p = 0.159) .Fig. 4Co4To our knowledge, this is the first published evidence of dosimetric predictors associated with pain during head and neck RT, using a substantial cohort of 96 patients. Based on our analyses, we propose that a fractional OAR mean dose of 1.1 Gy is a reasonable cutoff that separates esophageal and throat pain scores of 0–1 from those of 2–3 see . It is iThe data raise several questions. First, should the mucosal surface be an IMRT optimization structure? A clinically practical way of doing this could entail the following steps: autocontouring the air inside the head and neck , expanding this volume by 3–4 mm, and subtracting the initial autocontoured air volume. An IMRT goal where the fractional dose to this volume is less than 1.1 Gy could be specified. Depending on the PTV, this fractional OAR mean dose goal may not be feasible. However, knowing the fractional OAR mean dose may be useful for counseling the patient about the level of pain that he or she may experience, and for alerting the physician that more aggressive pain management may be necessary.Secondly, should elective node prescriptions be reconsidered (CTV2)? As previously described, the CTV1 fractional dose for the surgical and non-surgical scenarios was 2 Gy. However, the fractional dose for the elective CTV2 was 1.6 (56 Gy in 35 fractions) Gy, 1.63 (54 Gy in 33) Gy, and 1.73 (52 Gy in 30) Gy for the non-surgical, surgical p16−, and surgical p16+ scenarios, respectively. Although the total dose decreases in each scenario (which is desirable), the fractional OAR dose actually increases, which, as shown, tends to result in increased acute pain. One could hypothesize that further reducing the fractional dose to consistently deliver 1.6 Gy or less to the CTV2 without compromising clinical outcomes would be desirable .This is the first study to our knowledge that shows that younger patients receiving RT experience more esophageal and throat pain, but the reason for this is unclear. We believe that perceptual, pharmacological response, or biological differences influenced by aging could be responsible. This is in contrast to the current evidence from a study by El Tumi et al. that suggests old adults may be more sensitive to mechanically evoked pain There was a statistically significant difference of fractional mean dose in the oral cavity between the non-surgical and surgical patients as a result of treatment policies. Surgical patients had a lower fractional OAR mean dose. This is likely because surgical patients had more unilateral neck radiation than non-surgical patients, resulting in a smaller volume of the mucosa receiving radiation. Although the univariate analysis suggested that patients receiving unilateral radiation experienced less pain, the multivariate analysis did not.Pain increased from week 1 to week 3 during RT see , reachinThis study has some important limitations. In particular, the first questionnaire was given after up to 4 treatment fractions. However, most patients received the questionnaire before the third fraction. From clinical experience and the lateness of the pain peak, it is unlikely that this would result in any significant increase in the baseline pain score. Also, the patient population includes both surgical and non-surgical patients, with surgical patients receiving two different fractionation schemes. Although anatomical regions were as specific as possible, the descriptor ‘maximum pain’ fails to address the extent of the painful tissue volume. For example, although we suspect that treating the oral cavity unilaterally versus bilaterally may result in a similar maximum pain experience for a patient, the mucosal surface experiencing pain is probably reduced in the former with a corresponding reduction in overall pain experience. Another limitation is that some patients may have difficulty in distinguishing between throat and esophageal pain.Finally, patients did not keep pain medication diaries, which may have helped to better understand the effect of pain medications. The pain management strategy was fairly homogeneous among patients because they were managed by the same physician, which should minimize this as a confounding factor.5A fractional OAR mean dose of 1.1 Gy seems a reasonable cutoff for separating no or mild pain from moderate to severe esophageal or throat pain. Younger patients receiving RT experienced more esophageal and throat pain. Females experienced more throat pain, but not esophageal pain. Further studies, including mucosal dose as an IMRT optimization goal, may help reduce the pain experienced by patients, resulting in improved quality of life during treatment.6None to disclose.


Multiple myeloma (MM) represents approximately 15% of haematological malignancies and most of the patients present with bone involvement. Focal or diffuse spinal osteolysis may result in significant morbidity by causing painful progressive vertebral compression fractures (VCFs) and deformities. Advances in the systemic treatment of myeloma have achieved high response rates and prolonged the survival significantly. Early diagnosis and management of skeletal events contribute to improving the prognosis and quality of life of MM patients. The management of patients with significant pain due to VCFs in the acute phase is not standardised. While some patients are successfully treated conservatively, and pain relief is achieved within a few weeks, a large percentage has disabling pain and morbidity and hence they are considered for surgical intervention. Balloon kyphoplasty and percutaneous vertebroplasty are minimally invasive procedures which have been shown to relieve pain and restore function. Despite increasing positive evidence for the use of these procedures, the indications, timing, efficacy, safety and their role in the treatment algorithm of myeloma spinal disease are yet to be elucidated. This paper reports an update of the consensus statement from the International Myeloma Working Group on the role of cement augmentation in myeloma patients with VCFs. Several skeletal events over a patient’s lifetime result in substantial morbidity, mortality5 and increased healthcare costs.Multiple myeloma (MM) is a haematologic malignancy characterised by infiltration of the bone marrow by plasma cells which can be associated with lytic bone disease causing severe bone pain, pathological fractures and neurological compromise including cauda equina/spinal cord compression. Up to 90% of the myeloma patients develop osteolytic lesions during the course of their disease7. Patients with myeloma are living much longer because of improved treatment of the primary disease. Haematological medical management aims at improving the survival of these patients and maintaining their quality of life (QoL). It is thus especially important to treat the osteolytic bone disease and vertebral compression fractures (VCFs) of the spine in a timely manner. Historically, haematologists treated the pain associated with VCFs with radiotherapy and strong opioids. However, these treatments have their own side effects and do not stabilise the fracture. In many cases, pain remains disabling and some patients develop progressive deformities. Some of the fractures also fail to heal and may result in significant chronic pain.The introduction of new targeted therapeutic agents in combination with stem cell transplantation has led to a remarkable evolution in the management of myeloma over the last 2 decades8. Following a spinal fracture, there is an exponential risk of a subsequent one due to an abnormal sagittal balance that ensues and the additional compressive forces on the anterior aspect of the spine11. Moreover, the patients adopt a kyphotic posture to minimise pain from their VCFs and to compensate for the weakness of the spinal musculature14. Patients with multiple fractures have reduced activities of daily living, pulmonary and gastric problems and have increased morbidity and mortality13. The kyphotic posture significantly reduces lung function15 and pulmonary disease is the commonest cause of death in women with VCFs17. Another major consequence of the spinal deformities is the psychological impact to these patients who often suffer from depression, anxiety and low self-esteem, with accompanying loss of QoL20.Treatment of the spine is directed towards keeping the patient pain free, ambulatory and continent. A secondary aim should be to minimise any progressive kyphotic deformity which can lead to a poor QoL. Vertebrae that are severely compressed can lose more than 50% of their original height33.The introduction of minimally invasive procedures such as balloon kyphoplasty (BKP) and percutaneous vertebroplasty (PV) has enabled the vast majority of the treated patients to return to a near normal level of function within a very short period of time with excellent pain relief34. The aim of this paper is to update the previous recommendations by the IMWG considering new published data.In 2008, a consensus statement was published by the International Myeloma Working Group (IMWG) on the role of vertebral augmentation with cement in MM40. Kallmes et al. had a simulated surgical procedure as control group without cement augmentation, and in the study by Buchbinder et al., the patients had a sham procedure which entailed injection of a local anaesthetic into the periosteum over the lamina and pedicle. Some of the criticisms of these two studies, the patients most in need of cement augmentation and therefore potentially the ones with the maximum amount of benefit, were possibly excluded from the studies on the basis that they would not allow themselves to be randomised into one of the two groups. The patients enrolled in the studies may have had facet joint-related pain and not the severe pain that one would usually associate with an acute VCF. This may explain why the patients did not show improvement following VP. It is recognised clinically that the severe pain due to an acute VCF subsides if the fracture starts to heal but patients can experience residual pain related to a resultant deformity. The deformity alters the facet joint mechanics and facet-related pain can ensue. Wilson et al. reported that a third of the patients technically suitable for VP for an osteoporotic fracture, responded beneficially to a facet joint injection alone. In this study, the percentage of the enrolled patients may had facet-related pain rather pain from the original fracture42. Significant reduction in mortality and morbidity using cement augmentation with BKP or VP versus nonsurgical management was reported in retrospective analyses43.The PV and BKP have been extensively used in the treatment of painful osteoporotic and cancer-related VCFs. The value of these modalities in treating osteoporotic VCFs was questioned because of the results from two prospective randomised trials that showed no benefit when compared with a sham procedure in relieving pain49. The prospective randomised controlled trial Cancer Patient Fracture Evaluation (CAFE), provided evidence for the superiority of BKP versus non-surgical management (NSM) of painful VCFs. 134 cancer patients were enrolled, of whom 49 had MM. Of these, 22 were randomly assigned to BKP and 27 to NSM33. BKP was found to be significantly more favourable than NSM offering rapid and sustained pain relief at 1 year, as well as improved back function, QoL, activity, reduced use of analgesics and bed rest days. Similarly, other studies have reported beneficial results of BKP and PV in rapid pain control, functional and QoL in MM patients with VCFs52.However, these studies reported outcomes on osteoporotic and not on cancer patients. In the cancer population, prospective and retrospective analyses reported favourable results in the treatment of painful metastatic cancer and myeloma-related VCF’s with PV and BKP44. It is very important that we do not deny treatment in MM patients that may be very effective in relieving the pain from their acute VCF. They may require VCP (VP or BKP) to give them rapid relief of their pain and return them to function as soon as possible. The pain relief from cement augmentation has been sustained over long post-operative periods in patients with MM54. Many patients with myeloma who get over the acute fracture pain may benefit from facet joint injections for facet-related pain due to the kyphotic deformity.Additional kyphoplasty was more effective than additional radiation or systemic therapy in terms of pain relief, reduction of pain associated disability and of fracture incidence of the entire thoracolumbar spine55. Splinting of fractures and thermoplastic bracing of spinal deformities has been used for many years to treat disability and pain. Bracing for 8–12 weeks has also been used for the treatment of VCF’s related to myeloma52. This may be all that is needed to give the patients pain relief from their acute fracture pain. The thermoplastic brace may also give temporary stability to a fractured spine and to patients with sternal fracture56 while chemotherapy is initiated. The most important treatment modality is the systemic anti-myeloma therapy to get the myeloma under control. After one or two cycles of systemic anti-myeloma therapy, cement augmentation (PV and BKP) can be performed if in fact the acute fracture pain is still present. Often these patients have had relief of their acute fracture pain with the thermoplastic brace alone or with the addition of 4–6 weeks of medical/conservative treatment. This means that the patients may not need cement augmentation. Instead if they have chronic pain of a lower intensity over their kyphotic deformity they may benefit from some facet joint injections.The evidence on bracing in the management of osteoporotic VCFs is conflicting and the role of the use of external supportive devices including rigid thoracolumbar spinal orthosis (TLSO) or hyperextension braces is yet to be defined57 thereby preventing further collapse of the vertebral body. Further collapse, particularly into kyphosis, may lead to spinal cord compromise because of the deformity.A small group of myeloma patients present with a soft tissue myelomatous mass within the spinal canal that can result in spinal cord or cauda equine compression. These patients often present with neurological deficits and each case needs to be assessed individually. MRI scanning is clearly imperative but a CT scan with soft tissue windows will help to delineate whether the neural compression is due to bone or soft tissue. If the compression is due to a soft tissue mass with associated neurological impairment, then this may be amenable to steroids/chemotherapy and immediate radiotherapy. Patients with cord compression and no neurological deficit may not need radiotherapy because chemotherapy and steroids have been shown to result in excellent resolution of the soft tissue myelomatous mass. Ideally, if patients can be treated with steroids, radiotherapy and chemotherapy and have a very good resolution of their symptoms in 24 h, then they may not need surgical decompression and stabilisation. All decisions regarding patients with spinal cord compression need to be taken into conjunction with an experienced spinal surgeon. Clearly, if a patient has spinal cord or cauda equina compression and has significant neurological sequelae then they may require urgent surgical decompression and associated fixation. The aim however in patients with haematological malignancies should be to try and avoid placement of screws/fixation of the spine. The metalwork has a higher than normal risk of failure because the bone is very weak due to MM causing secondary osteoporosis. In addition, there is a higher risk of metalwork infection because the patients are immunosuppressed during their conventional chemotherapy, immunotherapy and stem cell transplantation. After resolution of the intraspinal mass with chemotherapy, radiotherapy and steroids the fractured vertebra may need to be augmented with cement to treat the acute fracture pain but also to give mechanical support to the anterior and middle columns of the spine59. This appearance is similar to diffuse idiopathic skeletal hyperostosis60. It is a phenomenon that may be accelerated by or the result of treatment with bisphosphonates. This is a very interesting finding and warrants further research to see whether patients with myeloma present a completely different clinical problem than patients with osteolytic metastases due to solid tumours.Patients that present with no intraspinal soft tissue mass, but overt bony destruction and dubious spinal stability are another important group of patients. A posterior vertebral wall defect or pedicle/facet fracture may lead one to question the spinal stability in this patient group. Often all that is needed is a spinal brace to keep them out of pain while the spine confers itself stability by producing bridging bony osteophytesThe following is the consensus statement for recommendations for spinal support and cement augmentation from the International Myeloma Working Group. MM patients with significant pain at a fracture site should be offered a BKP or PV procedure and the procedure should be performed within 4–8 weeks unless there are medical contraindications Tables .Table 1I61. Patients with acute fracture pain should be considered and not the patient with facet joint-related pain. The clinical picture should be confirmed with MRI scanning. The most useful MRI images to show an acute or on-going painful fracture are the sagittal STIR and T1 weighted sequences. The T1 weighted images may be more helpful in diagnosing a VCF in a MM patient than the STIR images. In addition, T1 images may also show the fracture line.Careful assessment to determine the severity and site of the painMRI is crucial to document any radiological nerve root/cauda equina or spinal cord compression.CT scan with sagittal and coronal reconstructions may be needed to assess if there is spinal instability. A SINS classification can be helpful when determining the stability of the spine. If there is a posterior wall defect or pedicle/facet joint involvement, then CT can determine the safety of cement placement within the vertebral body. If patients get a recurrence of pain after a successful cement augmentation, then sagittal T1 and STIR images of the spine should be repeated to see if there is a new fracture that could develop following myeloma treatment.Assessment of myeloma disease status and therefore risk related to anaesthetic and any cement augmentation procedure. This includes potential anti-myeloma treatment requirements and risk for infection and bleeding. Coordination of procedure with treating haematologist/oncologist to avoid anaemia, leukopaenia and/or thrombocytopaenia related to systemic anti-myeloma therapy.63 of VCF’s with cement augmentation not only treats the pain associated with the fracture but in addition improves clinical outcome and QoL52  was superior for the patients having BKP in the 1st month compared to the patients who received non-surgical treatment. The patients in the BKP group showed a marked reduction in back pain and required less pain relief. This is important for myeloma patients since most of them have a degree of renal impairment. In addition, improvement of function and mobility can reduce thrombotic and infection risk. Therefore, early intervention within 4–8 weeks31. This is also the consensus of the panel.For patients with multiple VCF’s and significant pain, the maximum number of levels that should be augmented at a time should be determined by the operator. There is no upper limit for total number of vertebrae that should be treated in one intervention. The panel’s recommendation is that it is appropriate to treat up to 3 levels at a time and any decision treating more levels than this should be taken with caution. The reason for this is that cement embolus to the lungs may occur compromising respiratory function. Cement augmentation without cement leakage into the disc above or below should not increase the risk of adjacent vertebral body fracture. Cement leakage rates with BKP are reported to be less than with VP66 or percutaneously if the experience is available. The thoracic and lumbar vertebral bodies can be augmented with cement in the standard transpedicular or extrapedicular approach. Pain due to fractures from T1 to T4 rarely needs to be treated with cement augmentation because the pain usually settles with conservative management. Sarcroplasty can be performed if there is evidence of sacral insufficiency fractures.Cement augmentation of the spine is possible at all spinal levels. The C2 vertebral body can be augmented via a trans-oral or submandibular route. The C3–C7 vertebral bodies can be accessed and augmented through a standard open anterior cervical approach71. Although there has been a change in emphasis from VP to BKP, the evidence for one procedure over the other is debatable. A meta-analysis of randomised and non-randomised trials of VP, BKP and NSM in patients with VCF due to osteoporosis31 has found that BKP was better than VP or NSM in reducing disability. Both BKP and VP were better for reducing pain (mostly during the first 8 weeks) and subsequent fracture risk (by about 50%) when compared to NSM. There was no difference between BKP and VP for these parameters. Cement leakage into the canal, lungs or other major organs was less for BKP than for VP. BKP was better in restoring mid-vertebral height and in changing kyphotic angle than VP and was also associated with less incidence of refracture. BKP, which involves inflation of a balloon tamp to create a void in the vertebral body, controls the delivery of cement better than PV. Patients with multiple VCF’s may become very kyphotic in the thoracic and lumbar regions of the spine. A hyperkyphosis results in a positive sagittal alignment also termed sagittal imbalance. Patients with a positive sagittal balance find it more difficult to stand in the upright posture and in attempting to do so expend more energy. Poor sagittal alignment has been shown to be a strong predictor of disability72. There has been debate as to the potential for BKP and PV to restore vertebral body height following a VCF. Some papers however report an improvement in the Cobb angle (degree of kyphosis) following BKP74 for VCF’s related to MM. Similar outcomes of KIVA implant to BKP vertebral augmentation were reported in patients with VCFs secondary to cancer and osteoporosis79. More research is needed to answer this question definitively. In addition, direct comparison of the complications of NSM, VP and BKP and the optimal timing for VCF treatment in MM patients are questions that could be answered in a prospective randomised, controlled clinical trial.Published studies report contradicting results for cement augmentationThe use of radiotherapy for local disease control and palliation should be used judiciously and sparingly depending on the patient’s presentation, need for urgent response, and prior treatment history and response. MRI and CT scans are crucial to differentiate between a soft tissue myelomatous mass in the spinal canal from bony encroachment. The reason for this is that radiation therapy is very effective in reducing the size of a soft tissue myelomatous mass but not effective if there is bony neural compression and does not stabilise the VCF.Patients with a soft tissue mass or plasmacytoma that has not resolved with systemic therapyPatients who cannot receive systemic therapyRelapsed refractory patientsPalliative approach for poor performance status patientsWhen mass is associated with severe painLocation of plasmacytoma precluding use of BKP or PV; e.g. tumour impacting posterior part of the vertebral body close to spinal cord and nerves.Radiotherapy should be limited as much as possible to spare the patient’s marrow function. Current systemic combination therapies of steroids with novel agents work rapidly and should decrease the need for palliative radiotherapy. Radiation therapy may be appropriate for:Receiving radiotherapy and the dose of previous radiotherapy are not contraindications for cement augmentation (PV or BKP) if it is needed. The need and timing of a cement augmentation procedure for patients that have been irradiated depends on the patient’s pain Fig. . The cemOverall, the proposed algorithm for spinal support in myeloma presenting with VCFs or spinal cord compression is summarised in a flow diagram in Fig. The prognosis of patients with myeloma has improved considerably over the last 15 years because of the advances in Haematological Oncology. We therefore need to become more proficient at treating the associated medical/surgical complications related to the disease. One such complication is one or more VCF’s of the spine. Patients may present with significant spinal fracture pain or neurological compromise. These signs and symptoms may present at the time of the index procedure or when there is a relapse of the disease. Essentially, myeloma patients that present with spinal symptoms and signs need to be assessed to establish the source and nature of their pain and presence/absence of neurological compromise and spinal instability.Those that present with neurological compromise may have spinal cord, cauda equina or nerve root compression. It is imperative, in patients with neurological compromise, to get not only an MRI scan with STIR and T1 weighted images but also a CT scan (with soft tissue windowing) to delineate whether it is bone or soft tissue compromising the neurological structures. Soft tissue in the spinal canal due to a myelomatous deposit is usually very sensitive to treatment with chemotherapy/radiotherapy/steroids and therefore the neural compression can be treated by these modalities without the need for surgical decompression. Ideally, one would like to avoid any instrumentation in myeloma patients if possible because of the risk of subsequent metalwork/deep spinal infection during periods of immunocompromise. However, if there is significant spinal cord compromise/cauda equina compression then surgical decompression may be needed as an emergency and an immediate spinal surgical consultation should be sought on all such patients. Once the spinal cord/cauda equine compression has been treated with steroids/chemotherapy/radiotherapy, cement augmentation may be needed to alleviate the pain associated with the fracture or to restore spinal stability. It is uncommon for a myeloma patient to present with neurological compromise because of bony encroachment but if it occurs, radiotherapy/chemotherapy/steroids will not be an effective treatment. Surgery may be needed in this cohort of patients.80. A brace may be all that is needed in patients with a spinal fracture if they can mobilise without significant pain. The external orthosis will also keep the patients in the upright posture  while their fractures heal. Patients who present with spinal pain and have a new diagnosis of myeloma may need, depending on systemic symptoms, to have their disease controlled with chemotherapy prior to any consideration for cement augmentation. The chemotherapy immune-compromises the patients and therefore the correct timing of cement augmentation should be a multi-disciplinary decision. Antibiotic prophylaxis in the peri-operative period is strongly advised to avoid infection. The orthotic brace can be a very useful tool to control the pain to an acceptable level while the disease is being treated with the first couple of cycles of chemotherapy.Patients who present with spinal pain, but no neurological compromise should have an MRI scan performed with STIR and T1 weighted images to detect any spinal fractures. The T1 weighted images may be better than the STIR images in highlighting the fracture line in vertebrae infiltrated with a myelomatous deposit. If one has concerns about the spinal stability because of a posterior wall defect or pedicle/facet joint/pars involvement, then a CT scan with sagittal and coronal reconstructions can be very helpful. Patients can have quite significant bony defects but still be structurally stable in an orthotic brace81 in patients with myeloma, may decrease the need for spinal fixation in patients otherwise thought to be at risk of spinal instability because of involvement of all three bony spinal columns57.Another important aspect of the treatment in myeloma patients involves bisphosphonate therapy. This drug treatment clearly helps to stabilise the bone density in patients with myeloma but, in addition may have a positive effect in producing an external scaffold of bone around the vertebral bodies to confer them extra stability. This external scaffold, which has been described as DISH in prior publicationsThe prognosis of MM is continually improving due to medical advances. The treatment of myeloma with chemo- immunotherapeutic agents and autologous stem cell transplantation renders the patient immunocompromised for periods of time, exposing them to infection. Spinal fixation has been employed traditionally to treat myeloma patients when decompression and stabilisation were deemed to be essential. However, it is well established that in situ instrumentation is at risk of getting infected when the patients are in an immunocompromised state. If the metalwork gets infected, then the consequences can be catastrophic. Cement augmentation is a very effective way of stabilising the anterior and middle spinal columns without the need for metalwork fixation. It is an excellent way to relieve the pain from a VCF. The myeloma spine treated with bisphosphonates appears to produce an external scaffold of bone that stabilises even the most moth-eaten spinal elements once the disease process is under control. An external orthosis can be very effective when trying to achieve pain relief from a fracture. It also helps to maintain the correct sagittal balance in patients with multiple fractures while they heal or before they are treated with cement augmentation. The development of radiofrequency ablation in combination with cement augmentation procedures is currently under investigation with encouraging results.


Background and purposeLower back pain is an extremely common health problem and causes more global disability than any other condition. Moreover, it causes an enormous economic burden in both developed and developing countries. The aim of this study is to determine the frequency of different risk factors for lower back pain in a tertiary care centre in Islamabad.MethodsA cross-sectional study was conducted at Shifa International Hospital’s neurosurgery and neurology outpatient department from September 2016 to February 2017. A total of 375 patients with lower back pain were interviewed regarding risk factors.ResultsAmong the 375 patients, the majority were men . The mean patient age was 42.05 ± 15.35 years (mean ± standard deviation); most of the patients belonged to the 21- to 40-year-old age group . The majority (78.4%) had chronic back pain. Lower back pain was found to be predominant in housewives , followed by those with office jobs , private jobs  , and healthcare workers . In terms of work schedule, 51.2% of patients reported working around 41–50 hours per week. The major risk factors identified were lack of exercise , use of soft foam mattress , prolonged sitting , lifting heavy weight , bending or twisting , sleep disorder , anxiety , hypertension , and depression .ConclusionsOur study concludes that lower back pain is a multifactorial phenomenon. Age, gender, profession, working hours, comorbid conditions, trauma, lifestyle, and stresses in life all play a role in its causation. Increasing physical activity and modifying lifestyle are suggested to prevent this major health issue. Lower back pain (LBP) is an extremely common health problem -4. LowerLower back pain is defined as a nonspecific condition that refers to complaints of acute or chronic pain and discomfort in the area between the lower posterior margin of the ribcage and the horizontal gluteal fold .There are numerous diverse causes of lower back pain including occupational, behavioural, socio-economic, and metabolic. Although there are some studies regarding this subject, there is still a need for more studies in developing countries like Pakistan, so that the frequency of different risk factors associated with lower back pain can be determined. This will eventually help the clinicians manage the patient as a whole instead of merely prescribing analgesics or advising exercise.A cross-sectional study was conducted at the Shifa International Hospital's neurosurgery and neurology outpatient department (OPD) from September 2016 to February 2017. All patients above the age of 18 years presenting to the neurosurgery and neurology OPD with a complaint of lower back pain were included in the study. An informed consent was obtained from all participants. Those who refused to give consent were excluded from our study. The patients were selected using non-randomized convenient sampling. A sample size of 375 was estimated, using an anticipated population precision of 58% , with anThe selected patients were interviewed regarding their occupation, working hours, hostile job environment, job insecurity, sleep disorders, depression, anxiety, and comorbidities like obesity, hypertension, coronary artery disease, smoking, and alcohol consumption. A data collection form, in English, was prepared and used to document the patient’s age, sex, duration of symptoms, and risk factors for lower back pain mentioned above. The results were analyzed using Statistical Package for Social Sciences  software version 21. A descriptive analysis was performed on the variables.Among the 375 patients, majority were male  and 181 (48.3%) were female. The mean patient age was 42.05 ± 15.35 years (mean ± standard deviation). While most of the patients, 296 of 375, were 21–60 years old (78.9%), the majority of the patients belonged to the 21–40 years old age group  as shown in Figure The majority (78.4%) had chronic back pain as shown in Figure Regarding work hours per week, 51.2% of patients reported working around 41–50 hours per week. Figure Lower back pain was found to be predominant in housewives , followed by those with office jobs , private jobs  , and healthcare workers  as shown in Figure The major risk factors were lack of exercise , use of soft foam mattress 52%, n = 195), prolonged sitting , lifting heavy weight , bending or twisting movement , sleep disorder , anxiety , hypertension , and depression . The frequency of risk factors correlating with back pain is shown in Table 95, proloLBP is one of the most common causes of doctor visits and has a global prevalence estimated at 9.4% . We deciWe noticed that 121 of 375 patients (32.3%) in our sample with LBP also had associated hypertension, defined as systolic blood pressure ≥ 140 mmHg and diastolic blood pressure ≥ 90 mmHg. In the literature, hypertension has been associated with a low prevalence of back pain; this is possibly due to hypalgesia .LBP with comorbid coronary artery disease (CAD) was present in 33 of 375 patients (8.8%) while LBP with dyslipidemia was present in 68 of 375 patients (18.1%). While it is believed that there is no etiological link between LBP and CAD , dyslipiLBP with a history of lower back trauma was seen in 98 of 375 patients (26.1%). There is a lack of literature establishing a correlation between lower back trauma and LBP in Pakistan.Among the patients, 189 of 375 (50.4%) reported LBP with a history of prolonged unsupported sitting. This is believed to be due to changes in the L4–L5 vertebra that may contribute to symptoms . In PakiWe found that 286 of 375 patients (76.3%) with LBP did not exercise. Exercise is generally believed to decrease the prevalence of LBP . We obseIt was noted that 62 of 375 patients (16.5%) with LBP also smoked. We did not differentiate current from former smokers. It is believed that smokers have a higher incidence and prevalence of LBP compared to people who have never smoked . We founHeavy weight lifting was reported by 182 of 375 patients (48.5%). However, the weight, duration and nature  of the heavy weight lifting was not defined.The most common risk factors in the psychosocial category were sleep disorder, seen in 156 of 375 patients (41.6%), anxiety in 148 of 375 patients (39.5%), depression in 108 of 375 patients (28.8%), family disputes in 82 of 375 patients (21.9%), stress at the workplace in 72 of 375 patients (19.2%), and job insecurity in 48 of 375 patients (12.8%).On the basis of our results, we believe that patients complaining of LBP should have a detailed social history work up that asks about their work and how often they sit unsupported. Likewise, homemakers should be given particular attention as the lack of ergonomic support as they go about their daily routines may be contributing to LBP. Similarly, exercise should be offered as a suggestion as good practice, even to otherwise healthy patients, owing to its protective role in the development of LBP and other problems later on. Similarly, smoking status should also be inquired about, and patients counselled to quit owing to its range of disastrous effects including LBP. Heavy lifting related LBP can be avoided by physicians advising patients on correct lifting techniques to prevent LBP.When it comes to psychosocial problems, it can be seen that sleep disorders require careful analysis and management by the physician. Anxiety and depression should also be kept in mind as they may manifest as LBP.Our study concludes that lower back pain is a multifactorial phenomenon. Age, gender, profession, working hours, comorbid conditions, trauma, lifestyle, stresses in life all play a role in its causation. It is suggested to increase physical activity and modify lifestyle to prevent this major health issue.


Dementia produces major clinical and social problems that have catastrophic consequences for patients and their families. Dementia also complicates clinical care for other co-existing medical conditions. Magnetic Resonance Imaging (MRI) utilization is increasingly used for diagnostic purposes, such as early diagnosis of dementia and special examination of dementia. This study analyzed the utilization status and factors affecting use of MRI examination of patients with dementia using the Charlson Comorbidity Index (CCI). We used data from the Korean National Hospital Discharge In-depth Injury Survey (KNHDS) for three years, from 2013 to 2015, investigated by Korea Centers for Disease Control and Prevention (KCDC). The subjects of the study were 643 patients whose primary diagnosis code according to the International Classification of Disease (ICD) is F00–F03 . As independent variables, we used sex, age, type of insurance, the admission route, length of stay, result of treatment, number of hospital beds, and the hospital’s location. In this study, the independent variables affecting MRI examination of dementia patients were length of stay, hospital location, and CCI. The ratio of MRI examination of patients with dementia in which the CCI was 1, was significantly higher by 1.757 times than in cases where the CCI was 0. Hence, it can be used to provide basic data for formulating health care policy for dementia patients by studying their overall situation. The prevalence of dementia is increasing worldwide and is predicted to double every 20 years . DementiIn this study, we analyzed the utilization status and factors affecting MRI examination of patients with dementia by using the CCI. Our results suggest essential data for the establishment of health care policy for improvement of quality medical care.We used data from the Korean National Hospital Discharge In-depth Injury Survey (KNHDS) for three years, from 2013 to 2015, investigated by Korea Centers for Disease Control and Prevention (KCDC). In February 2018, to acquire the data for the present study, the researchers went through the procedure for consent, including the application form for the use of raw materials and the pledge of information security through the injury Monitoring Business Homepage of the Center for Disease Control and Prevention . The Korean National Hospital Discharge In-depth Injury Survey (KNHDS) contains data collected from about 150 hospitals nationwide, each with more than 100 beds [The subjects of the study were 643 patients whose primary diagnosis code by the International Classification of Disease (ICD) was F00–F03 . Among the patients admitted to the hospital, we targeted patients whose primary diagnose was dementia. So, whether the diagnosis of dementia was given during the hospitalization or if the patients had pre-existing dementia is not clear. However, during the hospitalization period, the presence or absence of an MRI examinations was investigated, and the same patient may be hospitalized twice or more with dementia during the investigation period.The dependent variable was the presence or absence of MRI examinations, and the brain MRI code 88.91 was utilized according to the International Classification of Disease 9th revision Clinical Modification (ICD-9-CM) code . As indeStatistical analysis was conducted using the SPSS Statistics for Windows, version 24.0 . Chi-squared analyses were conducted to ascertain the difference of MRI examination rate according to socio-demographic characteristics, CCI, and medical use characteristics of dementia patients. Logistic regression analysis was conducted to determine the factors that affect MRI examination of patients with dementia.Results of MRI examination rate according to the CCI of patients with dementia were 15.6% at CCI 0, 22.5% at CCI 1, 24.5% at CCI 2, and 16.7% at CCI 3 or more . p < 0.05). The rates of MRI examination according to the length of stay were 26.5% at 5–9 days, 18.6% at 1–4 days, 18.3% at 10–25 days, and 9.0% at 26 days or longer. The rates of MRI examination according to the results of the treatment were at 28.6% in the case of diagnosis only, 20.0% at improved and 7.9% at not improved. The rates of MRI examination by hospital bed size were 28.4% at 500–999 beds, 14.4% at 100–299 beds, 12.8% at 1000 or more beds, and 9.1% at 300–499 beds. MRI examination rates according to location of hospital were the highest at 36.2% in the case of the Gyeonggi region , therefore the null hypothesis of “regression coefficient equals zero” was rejected  of length of stay at 26 days or longer was 0.432 (95% CI = 0.209–0.896). In the case of 26 days or longer, compared with length of stay of 1–4 days, the ratio of MRI examination was significantly lower by a factor of 0.432. The ratio of MRI examination of patients with dementia in which the CCI was 1, was significantly higher by 1.757 times (95% CI = 1.070–2.884), compared to cases where CCI was 0. In the case of hospitals in the Gyeonngi area, compared with hospitals in the Seoul area, the ratio of MRI examination of patients with dementia was significantly higher by 2.645 times (95% CI = 1.278–5.474). These results suggest that the number of medical institutions in Seoul is higher than that in Gyeonggi area, but that the number of general hospitals and hospitals in the Gyeonggi area is larger than that in Seoul. Result of the likelihood ratio test was 536.081 . These results are due to the fact that minor diseases  are not included in the CCI score. Our study showed that the ratio of MRI examination of dementia patients with a CCI 1 was significantly higher than for CCI 0 in the logistic regression analysis. With CCI 2 and 3+, the frequency of MRI was higher than seen with CCI 0, but the differences were not statistically significant. These results may be due to the small number of cases, and CCI weight and MRI frequency may be closely related as well.Elderly patients may develop dementia that is associated with chronic diseases, mainly including chronic obstructive pulmonary disease, cerebrovascular accident, and heart failure . MRI scaThis study has several limitations. Our study was a cross-sectional study, not a cohort study, and the subjects of the study, dementia patients, included both patients who were diagnosed with dementia before admission and those who were diagnosed with dementia. In addition, the data used in this study showed the presence of MRI during hospitalization and there was a limit to clarifying the causal relationship between diagnosis of dementia and MRI findings. However, it is considered to be meaningful data for the use of MRI according to the accompanying diseases of dementia patients, because it is based on the representative data collected from hospitals with over 100 beds in the Korea Centers for Disease Control and Prevention (KCDC).In this study, there was a significant difference in the use of MRI among dementia patients according to the CCI. Except for the high-risk group, which is inappropriate for testing, the presence of comorbidity means that the diagnostic utility through MRI is higher. In addition, the higher utilization of MRI in a certain area (Gyeonggi) may reflect a large concentration of medical institutions in that area. In order to increase the utilization of MRI diagnosis and prediction through MRI, a separate program for early diagnosis of dementia that reflects these variables and appropriate distribution of medical resources by age, comorbidity, and region should be planned. Furthermore, the results of this study can be used as a basic data for programs for early diagnosis of dementia or for national health policy for the proper distribution of medical resources.


A classical approach to produce interscalene brachial plexus block (ISBPB) consistently spares the posterior aspect of the shoulder and ulnar sides of the elbow, forearm, and hand, which are innervated by the lower trunk of the brachial plexus (C8–T1). As an alternative to the classical approach, a caudal approach to ISBPB successfully produces anesthesia of the ulnar sides of the elbow, forearm, and hand. However, its beneficial effects on anesthesia in the posterior aspect of the shoulder have not been investigated. In addition, the C8 nerve root is not routinely selectively blocked during ISBPB. Therefore, we will compare the C5 to C7 and C5 to C8 nerve root blocks during a caudal approach to ISBPB to assess the clinical benefit of C8 nerve blocks for the surgical anesthesia of the posterior aspect of the shoulder.In this prospective parallel-group single-blind randomized controlled trial, 74 patients scheduled to undergo arthroscopic shoulder surgery under ISBPB are randomly allocated to receive the C5 to C7 or C5 to C8 nerve root block at a 1:1 ratio. The primary outcome is pain intensity, which is rated as 0 (no pain), 1 (mild pain), or 2 (severe pain), during the introduction of a posterior portal into the glenohumeral joint. The secondary outcomes are (1) the extent of the ipsilateral sensory, motor, hemidiaphragmatic, and stellate ganglion blockade, (2) changes in the results of a pulmonary function test, (3) incidence of complications related to ISBPB, (4) postoperative numerical pain rating scale scores, (5) patients’ satisfaction with the ISBPB, (6) dose and frequency of analgesic use, and (7) incidence of conversion to general anesthesia.This study is the first to evaluate the beneficial effects of the C8 nerve root block during ISBPB, which has rarely been performed due to the technical challenge in visualizing and blocking the C8 nerve root. It is expected that a C8 nerve root block performed during ISBPB will provide sufficient surgical anesthesia of the posterior aspect of the shoulder, which cannot be achieved by a classical approach to ISBPB.NCT03487874. Registered on 4 April 2018.ClicnicalTrials.gov, The online version of this article (10.1186/s13063-019-3624-9) contains supplementary material, which is available to authorized users. Since Winnie introduced the interscalene brachial plexus block (ISBPB) in 1970 , as a suTo block the lower trunk of the brachial plexus, a caudal approach to ISBPB guided by nerve stimulation , 9, ultrTherefore, we will compare pain intensity upon the introduction of a posterior portal into the subacromial space between patients receiving the C5 to C7 nerve root block and those receiving the C5 to C8 nerve root block during a caudal approach to ISBPB. Our primary hypothesis is that the C5 to C8 nerve root block will reduce the intensity of pain caused by the introduction of a posterior portal compared to the C5 to C7 nerve root block.The protocol of this prospective single-center parallel-group single-blind randomized controlled trial was approved by the institutional review board of Daegu Catholic University Medical Center CR-18-018) and was registered in ClinicalTrials.gov (NCT03487874) before patients were enrolled. This trial is being conducted in a tertiary university hospital  in Daegu, Republic of Korea. The protocol of this trial conforms to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines  those receiving the C5 to C7 nerve root block during ISBPB and 2) those receiving the C5 to C8 nerve root block. They will be allocated in a 1:1 ratio  performing ISBPB. The allocation will not be revealed accidentally to the participant because the block needle is introduced through the same area for both types of ISBPB. Moreover, the ultrasound monitor  is not within the participant’s line of sight and the participant’s head will be covered with a sterilized drape. If serious adverse events that significantly affect the safety of participants occur , the patients will be removed from the trial, the blinding will be removed, and the events will be reported to the institutional review board.Participants may withdraw from the study at any time. The investigators can also withdraw a participant if it is considered that their safety will be compromised by their continued participation. In addition, a participant will be withdrawn if unexpected changes in their surgical plan necessitate general anesthesia. The reasons for withdrawal will be recorded in the case report form.Participants’ private information, such as their name, social security number, phone number, address, family relationship, educational background, occupation, or chart number, will not be collected. Only the study code will be collected, which will be managed separately. The data collected will be kept confidential until they are required for analysis by the investigators. The principal investigator (JHK) will manage the final dataset. The data collected will be stored under encryption for 3 years after the completion of the study and subsequently discarded.-1 hr-1 via a peripheral intravenous line 1 hr before surgery. No premedication is administered to the patients. On arrival at the operating theater, electrocardiography, pulse oximetry, and noninvasive blood pressure monitoring are instituted. To facilitate the placement of ISBPB, patients’ heads are slightly rotated to the contralateral side to the block and their necks are extended in a supine position. The skin around the neck and clavicle is sterilized using povidone iodine and is then covered with a fenestrated drape.Patients fast from midnight before the day of surgery. The infusion of Plasmalyte is commenced at a rate of 5 ml kgBy placing a 5 to 13 MHz linear phased array transducer  on the supraclavicular fossa, the compact arrangement of the brachial plexus can be visualized lateral to the subclavian artery. The transducer is tracked cephalad to visualize the C8 nerve root lying on the first rib, the C7 nerve root or middle trunk, and the C5 and C6 nerve roots or upper trunk between the anterior and middle scalene muscles in the absence of a visible subclavian artery  or hypotension  , is treaWhen patients begin to feel postoperative pain, 10 ml of a solution containing 25 mg of bupivacaine and 10 μg of epinephrine is injected as a bolus into the operation site via the indwelling catheter, which is then removed. Intravenous tramadol (50 mg) is administered at more than 2-h intervals when patients report a numerical pain rating scale (NRS) score of more than 2 (0 represents “no pain” while 10 represents “the worst pain imaginable”). From the afternoon on the first postoperative day, 650 mg of extended-release acetaminophen and 2 mg of immediate-release hydromorphone are administered orally three times a day. From the second postoperative day, the dosage is changed to four times a day.the extent of the ipsilateral sensory, motor, hemidiaphragmatic, and stellate ganglion blockadechanges in the results of a pulmonary function testincidence of complications related to ISBPBat admission to the postanesthetic care unitat discharge from the postanesthetic care unitbetween 6 and 12 h after surgery24 h after surgeryNRS scores:the highest NRS score during the 24 h after surgerypostoperative hour when pain starts to be feltpatients’ satisfaction with surgical anesthesia and postoperative analgesiadose and frequency of intraoperative and postoperative analgesic useincidence of conversion to general anesthesiaAs the primary outcome, pain intensity during the introduction of a posterior portal is assessed. The secondary outcomes include:The primary and secondary outcomes will be assessed by EK and CHC.Pain intensity is rated as 0 (no pain), 1 (mild pain), or 2 (severe pain) during surgical incision and subsequent insertion of the blunt trocar and viewing cannula below the acromion. The sensory and motor blockade is evaluated 30 min after ISBPB. As an assessment of the sensory blockade, the response to the application of ice to the dermatomal areas of C5 to T1 of the shoulder  is gradeIpsilateral hemidiaphragmatic excursion, bilateral pupil sizes, and pulmonary function are measured in a supine position before and 30 min after the placement of ISBPB. By placing a 1.8 to 5.7 MHz convex phased array transducer  on the ipsilateral subcostal area, the hyperechoic line of the diaphragm, which moves with the respiratory cycle, is visualized using the liver or spleen as an acoustic window. By tracing the movement of the diaphragm under real-time M-mode ultrasonography, the hemidiaphragmatic excursion is measured as the peak amplitude caused by a deep and quiet inspiration from the resting expiratory position . HemidiaThe stellate ganglion block is confirmed by the development of Horner’s syndrome. As Horner’s syndrome is defined as an ipsilateral pupil diameter that is less than the contralateral pupil diameter by more than 5 mm , we measChanges in pulmonary function are determined by changes in the percentage of the predictive values of the measured parameters based on the equations from the European Community for Coal and Steel . Forced Complications related with ISBPB, which will be recorded prospectively, include accidental puncture of the common carotid, subclavian, dorsal scapular, or vertebral arteries, pneumothorax, hypotensive bradycardic event, epidural and intrathecal injections, local anesthetic systemic toxicity, and neurologic complications. Patients’ satisfaction with the surgical anesthesia and postoperative analgesia is measured using a five-point Likert scale consisting of “very dissatisfied,” “dissatisfied,” “unsure,” “satisfied,” and “very satisfied”.ncss.com/software/pass) was used to estimate the sample size.The primary outcome of this trial is pain intensity during the introduction of a posterior portal. In a pilot study using five subjects for each group, pain intensity was 0 in one patient from group C5–7 and three patients from group C5–8. A pain intensity of 1 was reported by four patients from group C5–7 and two patients from group C5–8. No patient reported a pain intensity of 2. Based on the above results, alternative multinomial distributions  were set as  and . Using 3000 Monte Carlo samples from the null multinomial distributions  and  and the alternative distributions, the sample size for this study was calculated to achieve a statistical power of 90% to detect a 0.4 difference in mean pain intensity between the two groups at a significance level of 0.05 using a two-sided Mann–Whitney–Wilcoxon test. Considering a dropout rate of 10%, 37 subjects are required in each group. PASS  by a statistician who is not involved in data collection.The primary outcome  will be compared between the two groups with a Mann–Whitney–Wilcoxon test. To compare the secondary outcomes between the two groups, independent-samples Student’s The two main side effects of ISBPB, which are ipsilateral hemidiaphragmatic paresis or paralysis and stellate ganglion blockade, do not have clinical significance because their symptoms, such as dyspnea, ptosis, facial flushing, or nasal stuffiness, are usually not noticed and do not cause significant discomfort in healthy patients , 28. HowOf the two major dermatome maps , the recruitment of subjects commenced in April 2018 and was completed in August 2019.Additional file 1:SPIRIT checklist. (DOC 122 kb)