Background and Objectives: This study aimed to examine the efficacy of tapentadol immediate release (IR) and morphine hydrochloride in the treatment of acute postoperative pain after total abdominal hysterectomy, as well as to examine the frequency of opioid-related side effects in observed patients. Materials and Methods: The prospective observational study was conducted over five months, and it included a total number of 100 patients. The two cohorts had different types of postoperative analgesia, and the effects were observed for 24 h postoperatively, by following the pain scores on NRS , contentment with analgesia, and opioid-related side effects. Results: Statistical significance was found when assessing pain 24 h after surgery while coughing, where patients in the tapentadol IR group had significantly higher mean pain scores (p < 0.01). The subjective feeling of satisfaction with postoperative analgesia was statistically significant in the tapentadol IR group (p = 0.005). Vertigo appeared significantly more in patients from the morphine group (p = 0.03). Conclusions: Tapentadol IR (immediate release) and morphine hydrochloride are both effective analgesics used in the first 24 h after total transabdominal hysterectomy. Overall satisfaction of patients with analgesia was good. The frequency of side effects was higher in the morphine group, with statistical significance regarding the vertigo. Every surgical procedure causes trauma and stress to the organism, and it is followed by different pain intensities that a patient experiences. Pain is caused by tissue damage and the placing of the different prostheses and drains, and it is worsened by surgical complications. The pain intensity that a person experiences depends on preexisting comorbidities, among other things. In the normal postoperative course, the pain intensity decreases with wound healing, and it is considered that this process takes up to 3 months. If the pain is still present after that period, it becomes chronic pain and it demands a different treatment approach . StudiesEven today, with all the advances in pain medicine, one cannot say that there is an ideal mode of analgesia in perioperative medicine. Intravenous opioids and other analgesics are the most frequently used drugs to alleviate postoperative pain in the first 24 h after surgery. The use of opioids for surgery patients is an especially challenging problem requiring clinicians to balance managing acute pain in the postoperative period and minimizing the risks of persistent opioid use after surgery . In the Morphine has been the archetypal analgesic for use in moderate and severe pain. It is also the gold standard against which other injected analgesics are tested. Morphine is an agonist at mu- and kappa-opioid receptors. Opioids appear to exert their effects by increasing intracellular calcium concentration, which, in turn, increases potassium conductance and hyperpolarization of excitable cell membranes. The decrease in membrane excitability that results may decrease both pre- and post-synaptic responses. Respiratory depression, nausea and vomiting, hallucinations, and dependence may complicate the use of morphine, especially after intravenous administration .Tapentadol is an analgesic with a double central mechanism of action . Tapentadol has a direct analgesic effect, without pharmacologically active metabolite ,14. The This study aimed to examine the efficacy of tapentadol IR in the treatment of acute postoperative pain after abdominal hysterectomy in comparison with analgesia provided by intravenously given morphine hydrochloride, as well as to examine the patient’s contentment with analgesia and the frequency of opioid-related side effects in observed patients. Not many similar studies have been published up to now. To the best of our knowledge, the published studies on the analgesic effects of tapentadol IR are mainly performed on orthopedic and dental patients ,21. We wHaving obtained the approval for the research of the Board of Ethics of the Oncology Institute of Vojvodina (4/20/2-3185/2-6), prospective research has been conducted in the Anesthesia and Critical Care Department of the Oncology Institute of Vojvodina, Serbia. All of the patients who consented to participate in this study have given their documented written consent. The study population was formed out of the patients who underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy because of the malignancy, and it included a total number of 100 patients. There were 6 patients excluded from this study for not meeting the inclusion criteria. This prospective observational study was conducted for five months (January–May 2021) until two cohorts with 50 patients in each were formed. The two cohorts had different types of postoperative analgesia, tapentadol IR or morphine hydrochloride, and the effects were observed for 24 h postoperatively. Inclusion criteria for this study were written consent to participate in this study, patients who are opioid naive, and patients who had a total abdominal hysterectomy with bilateral salpingo-oophorectomy.Patients were excluded if they did not consent to participate in this study; they had allergic reactions to analgesics that are part of standard analgesia protocol; they are patients with opioid dependency; they are patients who are under treatment for chronic pain; and they are patients in whom intraoperative findings suggested that the surgery cannot be performed . The following data were entered in the individual study protocol: age, sex, weight, preexisting comorbidities, and ASA (American Society of Anesthesiologists) physical status classification. BMI (body mass index) was calculated for both groups. Patients were operated on under general balanced anesthesia. All the women received transabdominal hysterectomy with bilateral salpingo-oophorectomy through a traditional abdominal incision in the lower abdomen, and the surgical procedure was similar in all patients.All patients were premedicated with midazolam (0.05 mg/kg intravenously). The anesthesia induction was achieved with propofol (1.5–2.5 mg/kg), fentanyl (1.5 μg/kg), and a non-depolarizing muscle relaxant rocuronium (0.6–1.0 mg/kg) for muscle relaxation for intubation, as well as during the surgery at a dose adequate to maintain the relaxation. Anesthesia was maintained with inhalational sevoflurane . The lung ventilation was ensured with the gas mixture O2:N2O 40:60 so that EtCO2 < 38 mmHg. Electrocardiogram, blood pressure, heart frequency, SpO2, EtCO2, and body temperature were monitored during the surgery. Intraoperative analgesia was provided with boluses of fentanyl (50–100 mcg) according to patient needs. Anesthetics were administered in such a way as to provide satisfactory anesthesia, blood pressure values, and heart frequency in the values ±30% as compared with the preoperative values. Drugs for the reversal of neuromuscular blockade (neostigmine 0.02 mg/kg and atropine 0.01 mg/kg) were given at the end of the surgery. A single dose of antiemetic medication ondansetron 4 mg intravenously (i.v.) was given at the end of the surgery to each patient.After the surgery, patients were admitted to the ICU ward, where they were provided with multimodal analgesia. Upon admission to the ICU, the patients from both groups were given 5 mg of morphine hydrochloride i.v. and, after an hour, 1 g of acetaminophen i.v. for immediate pain control, which is part of a standard analgesia protocol at our institution. Our institution has an analgesia protocol for total abdominal hysterectomy, where analgesia can be achieved with intravenously given opioid analgesic morphine hydrochloride or with oral opioid analgesic tapentadol immediate release (tapentadol IR) in the form of a tablet. The type of analgesia (tapentadol IR or morphine hydrochloride) that the patient obtained in the postoperative period was decided by a board-certified anesthesiologist who was assigned to the specific case, and no randomization into one of the following groups was carried out for the study purpose since both medications are equally used in our institution.Two hours after the surgery, patients in the tapentadol group were given the first oral dose of 50 mg of tapentadol IR. If the pain intensity was still high one hour after the first dose, they were given the second (rescue) dose of 50 mg. After that, they were given 50–100 mg every 6–8 h, alongside intravenous acetaminophen 1 g q8h (max 3 g/24 h) and ketorolac 30 mg q8h (max 90 mg/24 h) or metamizole 2.5 g q12h (max 5 g/24 h). The morphine group received 5 mg of morphine hydrochloride intravenously every 6–8 h, with intravenous acetaminophen 1 g q8h (max 3 g/24 h) and ketorolac 30 mg q8h (max 90 mg/24 h) or metamizole 2.5 g q12h (max 5 g/24 h). Patients’ vital functions were monitored in the ICU for the first 24 h after surgery, and the pain intensity was assessed 6, 12, 18, and 24 h postoperatively at rest and on exertion (while coughing) by using an 11-point Numerical Pain Rating Scale . Pain scores were taken at specific times by one of the medical doctors who were a part of the research team. The contentment with the quality of analgesia was also assessed 24 h after the surgery on a scale from 1 to 4 . Opioid-related side effects were noted in the study protocol: PONV—postoperative nausea and vomiting , sedation, respiratory depression (hypoventilation with a drop in SpO2 <95%), bradycardia, hypotension, and vertigo.t-test and χ2 test. Statistical significance was assumed at p < 0.05.The data were analyzed and processed by IBM SPSS statistics 10.0 software  and given in tables and figures created in Word and Excel Microsoft Office 2016 packs. The results were presented using standard statistical methods: frequency (f), arithmetic means (x), standard deviation (SD), value intervals (maximum and minimum), and percentages (%). Pearson correlation analysis was used. The patients’ characteristics were compared with the Student’s Both the tapentadol group and the morphine group had 50 patients in each. There were no statistically significant differences in age, BMI, smoking habits, kinetosis, ASA classification, and the duration of surgery between the groups .p = 0.07) was found between the groups only at 24 h after the surgery, where the mean pain score at rest was greater in the tapentadol IR group than in the morphine group. A marginal statistical difference (p < 0.01) than patients in the morphine group. A marginal statistical difference (p = 0.06) was found when assessing pain 18 h after surgery on exertion when patients from the tapentadol IR group had higher mean pain scores than those from the morphine group. Statistical significance was also found (p < 0.01) in assessing pain grade on exertion, where patients from the tapentadol IR group had higher mean pain grades than patients from the morphine group . About 96% of patients in the tapentadol group and 86% in the morphine group assessed their analgesia as “3—good” and “4—very good”. No statistical significance was found regarding mean scores of contentment with analgesia between the two groups . Correlation coefficients showed a stronger negative correlation in the morphine group.Pearson correlation analysis was carried out to assess the relationship between pain control level (NRS) and patients’ contentment with analgesia for both groups, at rest, as well as on exertion. Pearson correlation analysis  showed tn = 17) of patients from the tapentadol group and in 46% (n = 23) of patients from the morphine group. 2 = 8.7, df = 1, p = 0.003). There were no significant differences between the groups for postoperative nausea and vomiting, sedation, respiratory depression, bradycardia, and hypotension.One or more opioid-related side effects were noticed in 34% (n = 6) patients in the tapentadol group and 16% (n = 8) patients in the morphine group. A mild level of nausea was not experienced in any group. A moderate level of nausea was experienced by 6% (n= 3) from the tapentadol group and 8% (n = 4) from the morphine group. Intense nausea with vomiting was experienced by 6% (n = 3) of patients in the tapentadol group and 8% (n = 4) in the morphine group. Severe nausea and vomiting were not noticed in any of the groups. PONV was experienced in 12% (n = 43) received more than 4 tablets (200 mg) in 24 h, and they did not have significantly more opioid-related side effects experienced than those who had 4 tablets .The average number of tapentadol tablets received in 24 h was 5.22 ± 0.68 (261 ± 33.94 in mg) . About 8n = 20) had more than 20 mg of morphine hydrochloride in 24 h . There was no correlation found between experiencing opioid-related side effects and having a smoking habit, suffering from kinetosis, or belonging to a specific age group.The average morphine hydrochloride dose that patients received in 24 h was 20.20 ± 4.60 mg. About 40% , which is less than that in the published literature, where the incidence of opioid side effects in the tapentadol 50 mg group was as high as 70% . In our A limitation of our study might be a small sample of patients and the fact that it was conducted in one center for only a few months. It is difficult to observe rare side effects in a small study sample without doing the sample size calculation. A similar study with a higher number of subjects would contribute to the strength of our conclusions. Another limitation is that the study population was composed of only female patients, as we evaluated the efficacy of tapentadol IR in gynecologic patients. Moreover, our study findings may be limited by dosing the medication every 6–8 h and constant monitoring during treatment, as these patients spent the first 24 h in the ICU, which does not mirror the actual pain treatment in clinical practice. Pain scores were self-reported by patients, as well. We did not separately assess the patients who were given the rescue dose of tapentadol IR after their pain control was low after the initial dose of 50 mg. Additional limitations include the lack of evaluation of the long-term effects of analgesia up to 48 or 72 h.According to our study, it can be concluded that tapentadol IR and morphine hydrochloride are both effective analgesics used in the first 24 h after transabdominal hysterectomy with bilateral salpingo-oophorectomy. Pain control on exertion was significantly better in the morphine group only at one time point, which is 24 h after surgery. Overall satisfaction of patients with analgesia was good. Patients in the tapentadol IR group were significantly more content with analgesia quality. Tapentadol IR resulted in less dizziness than morphine, but there were no significant differences found for PONV, sedation, respiratory depression, bradycardia, and hypotension.


Peripheral neuropathy is not only the most prevalent consequence of diabetes but also the main reason for foot ulceration, disability, and amputation. Therefore, the current study aims to determine the effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients.This 12-week, randomized, and parallel-group trial was conducted to compare the efficacy of oral clonidine and gabapentin with gabapentin alone in diabetic patients in southwest Iran during the first half of 2021. Thirty patients with type 2 diabetes with peripheral neuropathy as assessed by a visual analog scale (VAS) and divided into two groups of 15 patients, treated for up to three months. The data were analyzed using SPSS-21 software. In order to report the results, descriptive indices, independent t-test, one-way analysis of covariance (ANCOVA) and analysis of variance with repeated measures were used.The mean and standard deviation of the age of the participants in the clonidine + gabapentin group was equal to 50.20 ± 7.44, and in the gabapentin group was equal to 50.47 ± 7.57 . This research showed a significant difference between the clonidine + gabapentin group and with gabapentin group in terms of neuropathic pain and the severity of neuropathic pain (P < 0.001).According to this research results, clonidine + gabapentin can reduce neuropathic pain and the severity of neuropathic pain in diabetic patients. Therefore, it is recommended that healthcare professionals with diabetes expertise prescribe these medications to reduce neuropathic pain and its severity.This study was registered in the Iranian Clinical Trials System with the ID (IRCT20211106052983N1) on 14/01/2022. Diabetes Mellitus (DM) is a metabolic disorder caused by low insulin production or function, resulting in chronic hyperglycemia . This ilAs a significant cause of foot ulceration, disability, and amputation, Diabetic Peripheral Neuropathy (DPN) is the most prevalent complication resulting from diabetes. More than 50% of diabetic patients undergo Diabetic Neuropathy (DN), which affects their nervous system . Further12 [Currently, there are few treatments for DN, most of which include many side effects. In previous investigations, the results of melatonin , 15, caf12 , alpha-l12 , vitamin12 , acupunc12 , gabapen12 , 23, pre12 , gabapen12 , 26, the12 , and clo12 . Anticon12 . Gabapen12 . On the 12 . Therefo12 . Accordi12 , 34. Clo12 . Alpha-212 . The sou12 , and neiThe current research is a randomized clinical trial on two groups with a pre-intervention phase and three post-intervention assessments . The population consisted of all diabetic patients with peripheral neuropathy who sought medication in the diabetes clinic of Yasuj during the first half of 2021. The inclusion criteria were: (1) Informed consent of all participants, (2) being diagnosed with diabetes and having symptoms of peripheral neuropathy, (3) being aged between 30 and 60, (4) being able to participate in the study, (5) not suffering from chronic , neurological, and severe psychiatric illnesses, (6) not being pregnant or involved in breast-feeding, (7) no simultaneous use of medicines  which can affect neuropathic pain, and (8) not having hypotension (having + 11 blood pressure). Also, our exclusion criteria were (1) being highly allergic to clonidine, (2) being diagnosed with neuropathy for causes other than diabetes, (3) experiencing worsened symptoms due to taking the medicines, and (4) having a severe drop in blood pressure or drug interaction.In the present study, 49 diabetic patients were included using a purposeful sampling method. Thirty-four people entered the research process based on the entry criteria. Still, in operation, in each of the research groups, according to the exit criteria, two people left the research process. Finally, analyzed the information from 30 participants. They were then assigned to the clonidine + gabapentin and gabapentin groups randomly . 15 participants were assigned to each group. In the present study, the researcher and the participants did not have any information about the drugs received. The researcher had only assigned the participants to the groups and evaluated them in the evaluation stages, but he had no information about the drugs that the participants were taking. In addition, the participants had no knowledge about which group they were in. The participants had no information about the number and type of medication prescribed for the opposite group. However, the attending physician was aware of the type of prescription drugs for each group based on the inclusion criteria and control of their side effects (drugs). Therefore, since the researcher and the participants did not know about the treatment process, the current research was double-blind (for the researcher and the participants). The participants in the experimental group received a daily clonidine dosage of 0.10 milligrams (Clonidine tablets were used at night) and a gabapentin capsule (100 milligrams) for eight weeks. However, the individuals in the control group took only gabapentin capsules (100 milligrams) daily for eight weeks. The participants in both groups completed the demographic—background information forms and the study measurements at all stages of the investigation.DNS combines scores from a neurological examination and standard nerve conduction stimulation. A 128-hertz diapason generates vibration to calculate this variable, and pain is induced on the back of the examinee’s toe using a sharp tool. During this procedure, the examinee is asked yes/no questions and is expected to answer. Responses with seven or more correct answers and one to seven or no correct answers are interpreted as average, weak, or lack of sensation, respectively. In addition, muscular strength is also examined in the distal muscles and rated on ranges of 0-normal, 1-weak-medium, and 2-very weak. Score 3 is given when examinee’s are unable to contract their muscles deliberately. The current tendon reflexes requiring facilitation and having no reflexes are scored by 0, 1, and 2, providing a maximum total score of 46. Higher scores than six are associated with neuropathic pain .In the current investigation, the patients were asked to rate their pain on the visual analog scale (VAS). This measurement consists of a scoring system varying between 0 (no pain) to 10 (unbearable pain), being known as the pain ruler .In the current research, frequency, percentage, mean and standard deviation indicators were used to examine descriptive results. Also, to check the homogeneity of demographic and background variables, the Chi-square test, Fisher’s exact test, and independent t-test were used. In addition, an independent t-test was used to investigate the differences between groups of neuropathic pain variables and neuropathic pain severity in different stages of the research. Finally, in order to check the results of research hypotheses, univariate analysis of covariance (ANCOVA) and variance test with repeated measurements were used.Table As can be seen in Table As shown in Table As shown in Table Table It is demonstrated in Table the pain visual analog scale scores).As shown in Table According to Table According to the results of the Bonferroni posthoc test, in the experimental group (clonidine + gabapentin), there are significant differences in terms of neuropathic pain severity between the first assessment and the other three assessment stages P < 0.001). Also, the second assessment stages significantly differ from the third and fourth stages in neuropathic pain severity (P < 0.005). However, stages three and four are not significantly different (P > 0.05). Also, based on the results of the Bonferroni test in the control group (gabapentin), a significant difference was shown between the first assessment and the rest of the assessment stages (P < 0.05) and between the second assessment and the third and fourth assessment (P < 0.05). Despite these findings, no significant difference was discovered between stages three and four (P > 0.05). Figure . Also, tIn addition, based on the results of multivariate effects between groups, there is a significant difference between the research groups regarding the severity of neuropathic pain . In addition, eta squared demonstrates that compared to gabapentin, prescribing clonidine combined with gabapentin can explain 0.44 of the between-group variances of the severity of neuropathic pain.The current research aimed to determine the effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients. The results indicated that combining clonidine and gabapentin significantly affected peripheral neuropathy more than a single gabapentin consumption. To the best of our knowledge, to date, no previous investigation has examined the effectiveness of a combined treatment of gabapentin and clonidine  on peripheral neuropathy among individuals who have diabetes. Below is information from other studies with similar results. Fulas et al.  describeClonidine is a high blood pressure medication that can affect the alpha-adrenergic receptors and imidazoline as an agonist . A critiThere were limitations in the present study, which include: not having a group that was prescribed only clonidine. In this regard, it is suggested to consider a group for clonidine alone in future research. Another limitation of the research was the use of a purposeful sampling method, which led to a reduction in the generalizability of the results. In this regard, it is suggested to use a random sampling method to select participants in future research.The current research determines the effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients. Therefore, according to the results, it has been concluded that a combination of oral clonidine and gabapentin can effectively reduce peripheral neuropathy symptoms in diabetic patients. Consequently, it is suggested that diabetes clinics, hospitals, and specialists prescribe a combination of these drugs for reducing peripheral neuropathy pain in diabetic patients if needed.


Locoregional transarterial therapies such as transarterial embolization are essential in the treatment of neuroendocrine tumors. However, side effects of embolization, such as nausea, pain, and fever (collectively termed post-embolization syndrome), are significant and can adversely affect patient recovery and post-procedural quality of life. This study aimed to determine if administration of a periprocedural hepatic hilar nerve block as an analgesic would be significant in affecting post-procedural pain and quality of life metrics. Management of post-embolization syndrome is necessary for optimal patient comfort and recovery, and this research fills a critical gap in this area of study.n = 153; TAE + HHNB, n = 12). For HHNBs, ≤10 mL bupivacaine HCl 0.25% ± 2 mg methylprednisolone were injected under ultrasound guidance. The aims were to assess safety of HHNB and reduction in pain. Groups were compared with Pearson’s chi-squared and Wilcoxon rank sum tests. Logistic regression assessed independent risk factors for pain. Results: No immediate complications from HHNBs were reported. No difference in incidence of major complications between TAE and TAE + HHNB one month post-embolization was observed . No differences in mean length of hospital stay after treatment were observed . Post-procedure pain was reported in 88.2% of TAE and 75.0% of TAE + HHNB patients (p = 0.185). HHNB recipients were more likely to use analgesic patches . No other differences in analgesic use were observed. Conclusions: HHNBs can safely be performed in patients with NETs. No difference in hospital stays or analgesic drug use was observed. Managing pain after TAE is an important goal; further study is warranted.Purpose: This study investigates whether hepatic hilar nerve blocks (HHNB) provide safe, effective analgesia in patients with neuroendocrine tumors (NET) treated with transarterial embolization (TAE). Methods: The retrospective study included all NETs treated with TAE or TAE + HHNB from 1/2020 to 8/2022. Eighty-five patients (45 men), mean age 62 years, were treated in 165 sessions (TAE,  Neuroendocrine tumors (NETs) represent a heterogeneous family of neoplasms, arising primarily from the gastrointestinal tract, pancreas, and lung. Approximately 175,000 people in the United States are living with NETs ,3. Over A major obstacle in managing PES in patients with NETs is that there is no standardization in the literature or clinical practice. Current practice is heavily reliant on the use of opioid medications for post-procedural pain management, which are associated with numerous complications and side effects, including cardiopulmonary depression, addiction/reliance, nausea/vomiting, altered mental status and gastrointestinal complications . AlthougThis retrospective study was approved by the Institutional Review Board and is compliant with the Health Insurance Portability and Accountability Act. Written informed consent was waived.n = 153; TAE + HHNB, n = 12). A variety of preprocedural and postprocedural variables were collected and assessed from the electronic medical record and picture archiving and communication system. Preprocedural variables included age, prior liver interventions, presence of extrahepatic disease, liver treatment data  and use of pre-existing pain medication(s) (opioid vs. non-opioid). Postoperative variables included length of hospital stay, development of nausea and use of antiemetics, development of pain and use of pain relievers and/or opioids, and unplanned rehospitalizations within thirty days. Of note, the length of hospital stay was determined for those patients who were admitted to the hospital at the time of the procedure. Nine patients treated over 12 sessions were admitted prior to treatment for symptoms secondary to neuroendocrine tumors, including hypoglycemia, heart failure, dehydration, and liver dysfunction. These encounters were not included in calculations of the overall length of stay. Complications were graded according to the SIR Adverse Events Classification [This study included all NET patients treated with TAE alone or TAE + HHNB at a single specialized tertiary care institution between January 2020 and August 2022. A total of 85 patients (45 men), with a mean age of 62 years (range 36–87) were treated in 165 sessions  department by medical oncologists in the gastrointestinal oncology division and were evaluated in IR clinic prior to treatment. All patients were required to have updated cross-sectional imaging, including computed tomographic (CT) imaging and/or magnetic resonance imaging, and updated laboratory values, specifically complete metabolic panel, complete blood count, and coagulation factors. Inclusion criteria included a platelet count ≥ 50, an international normalized ratio ≤ 1.5, and total bilirubin levels ≤ 2. One hour prior to treatment, all patients received 250 mcg of subcutaneous octreotide and 1 g of IV cefazolin for prophylaxis; those patients with a documented penicillin allergy received clindamycin 900 mg IV and gentamicin 1.5 mg/kg IV. All procedures, including HHNBs, were performed under moderate sedation, monitored anesthesia care, or general anesthesia.Prior to the embolization, those patients undergoing a HHNB were positioned supine and had a 21- or 22-gauge spinal needle directed towards the periportal fat at the portal bifurcation with ultrasound guidance. Aspiration was used to confirm the absence of intravascular communication, and contrast was injected under fluoroscopic guidance to confirm extravascular location. A solution containing up to 10 mL of 0.25% bupivacaine with or without 2 mg of methylprednisolone was injected into the hepatic nerve plexus and the needle was subsequently removed. Appropriate localization of the solution in the hepatic hilum was confirmed under CT imaging .Transarterial embolization procedures were performed by a board-certified interventional radiologist, as previously described in the literature . EmbolizPost-procedure, patients were admitted for pain control and monitoring. Patients were treated with oral and/or intravenous pain medications, including, ketorolac, acetaminophen, opioids, analgesic patches, and/or hydromorphone patient-controlled anesthesia (PCA) pump, as needed and as determined by the treating provider. Antiemetics were administered if patients reported nausea or had episodes of emesis. Discharge timing was determined based on patients’ ability to tolerate a diet and control pain with oral analgesics. For those patients admitted with severe symptoms secondary to hormone secretion of their NETs, discharge was based on resolution of their presenting symptom(s).Outcomes assessed to evaluate the safety and efficacy of HHNB included rates of adverse events and complications associated with HHNB use, the association between HHNB use and post-procedural quality of life (QoL) measures, including pain reduction and hospital stay length, and the effect of HHNBs on post-procedural analgesic use.p-value were obtained. Variables with a p-value less than or equal to 0.05 were considered statistically significant. Statistical analysis was accomplished with the use of Stata, version17 .Groups were compared using Pearson’s chi-squared and Wilcoxon rank sum tests. Univariate logistic regression was used to assess a variety of independent risk factors  for pain. For each regression, an odds ratio, 95% confidence interval, and Demographic information and pre-procedural variables, including prior liver interventions, extrahepatic metastases, and pre-procedural pain medications are summarized in p = 0.014).Post-procedural QoL metrics related to post-embolization syndrome, including the presence of nausea , subjective reports of pain, and post-procedural use of oral and intravenous pain medications  are presented in Data regarding post-procedural hospital length , rehospitalization within 30 days, and complication data are shown in Logistic regressions for independent factors for post-procedural pain are presented in This study aimed to determine if HHNBs provided safe, effective analgesia in patients with neuroendocrine tumors treated with TAE. Logistic regression demonstrated no significant association between HHNB treatment and post-procedure pain. Additionally, the use of HHNBs did not correlate with shorter hospital length of stay or reduced rehospitalization rate in this small, retrospective study. There were no immediate complications of HHNBs reported, and after one-month post-embolization, there were no significant differences in the incidence of major adverse events as classified by the Society of Interventional Radiology Adverse Events Criteria.p = 0.014). Of note, there was a larger percentage of patients in the HHNB group with tumor volume ≥ 50% of the liver volume, which may have resulted in worse post-procedure pain due to the larger volume of tumor treated and larger subsequent tissue ischemia. This may have resulted in the similar use of post procedure analgesics between both study groups, despite the additional analgesic effect offered by the nerve block, albeit this is largely speculative.There was no significant decrease in post-procedure opioid analgesic use, but analgesic patches were more frequently utilized by patients after an HHNB  therapy for hepatocellular carcinoma (HCC) also found no significant differences in post-procedure hospital stay length or adverse event incidence, but groups did observe improvements in pain ratings and opioid consumption . An earlThe evaluation of QoL following interventional radiology/interventional oncology procedures is an important undertaking that results in a greater understanding of pain palliation and allows for a longitudinal focus on patients’ post-procedure pain and well-being. Measurement and analysis of health related QoL measures is an integral element of disease management. Unfortunately, very little research and attention has been focused on quality-of-life measures after liver directed therapies. Salem and colleagues conducted a multicenter observational cohort pilot study in patients with HCC who underwent transarterial radioembolization and collected serial patient-reported outcomes to assess health-related QoL . The stup = 0.011) [Several research studies have been performed in the past examining the efficacy, safety, and long-term outcomes of TAE; while these studies have been critical to establishing TAE as an effective treatment modality for neuroendocrine tumors, there has been limited literature on the definitive mitigation and management of PES even though it is the most frequently reported complication of TAE . In addi= 0.011) . It is i= 0.011) . HoweverThe safety results of HHNBs in this study, particularly the lack of serious immediate adverse events or increase in hospitalization time/readmission rates, remain promising for the implementation of HHNB as an adjunct analgesic for TAE. HHNBs have reported advantages over celiac and paravertebral nerve blocks, including greater liver specificity and separation from critical structures such as the lungs and spine . Addition = 12) and the non-HHNB embolization group (n = 153). The small number of patients who received nerve blocks likely provided insufficient power to properly assess the impact of HHNBs on post-procedure pain and QoL measures. While other studies in the literature have shown added benefits to incorporating nerve blocks to liver-directed therapies, the lack of significant findings in the current study may be attributable to the study being underpowered. The retrospective nature and the variation in the treatment of post-procedure pain across patients, namely the lack of standardization in analgesics offered and/or dose escalation, is an inherent flaw. Additionally, there were variations in the medications delivered in the HHNB, with one patient receiving steroids. Of note, utilization of steroids in nerve blocks allows for longer-term mitigation of inflammation and pain, as bupivacaine has a short half-life of 1.5 to 5.5 h. Validation of the utility of nerve blocks in combination with embolization would require a prospective study, where patients receive a standardized post-procedure pain regimen. While there were no significant differences in post-embolization opioid use in this study, the nearly five-fold increase in HHNB patients using analgesic patches remains an unexplained result, but the small sample size of the HHNB group could be one contributing factor. Future studies with larger study groups and performed in a prospective nature would provide a more robust analysis.The design of this study had multiple limitations. Perhaps the greatest limitation to this study was the sample size discrepancy between the HHNB + embolization group (HHNBs are a promising periprocedural intervention for mitigating PES following NET embolization. While this small, retrospective study did not identify an association between HHNB use and decreased post-procedural pain, hospital length of stay, readmission rates, or opioid use relative to the standard of care, this study did highlight that HHNBs are a safe and well-tolerated modality of pain control for NET embolization. Measurement of patient QoL is a complex yet important aspect of interventional radiology procedures, and future studies should continue to identify strategies to mitigate patient discomfort.


Background: Lower back and radicular pain are leading causes of disability and loss of quality of life, especially due to its high prevalence in the general population. Cooled radiofrequency treatment (CRT) has emerged as a novel non-invasive technique for the management of discogenic pain with safe and effective results. The aim of this study was to evaluate the effectiveness of CRT in the treatment of radicular pain secondary to a lumbar hernia in patients with chronic neuropathic pain after receiving conservative treatment that did not achieve adequate pain management.Methods: A prospective study of patients undergoing CRT for the management of discogenic low back pain was carried out. When attending the first evaluation and corroborating the lumbar hernias by magnetic resonance imaging (MRI), treatment was offered one month of physiotherapy before CRT. To assess the evolution of the patients, measurements were taken before and after the intervention with the visual analog scale (VAS) and the Oswestry low back pain disability scale (OLBPDS) scores.Results: A total of 74 patients  were included, who were undergoing a total of 134 herniated intervertebral lumbar discs. When comparing the initial perception of low back pain and after finding a non-significant partial improvement with one month of physiotherapy treatment, it was observed that the patients who were offered CRT showed an average improvement in discogenic pain of 79.92%  in 98.64% of cases. This was accompanied by an increase in their functionality of daily living activities, as measured by OLBPDS. No patients presented significant adverse events, and in the only case where the desired pain management was not obtained, the patient's discomfort did not worsen.Conclusions: Intradiscal biacuplasty by CRT is a considerable treatment for lumbar radiculopathy. Postoperative results demonstrated its effectiveness and safety in the management of radicular pain without the presence of significant adverse effects. Low back pain is a leading cause of disability and productivity loss, associated with high costs and some of the most frequent reasons for visiting a general practitioner ,2, so adLumbar post-traumatic herniated disc is one of the main causes of discogenic back pain as it causes compression of the nerve root. As there is a compromise of the nervous system, it generates more complex clinical presentations that are difficult to explain by simple mechanical compromise. Within the processes that occur in pain due to a herniated disc are the inflammatory cascades  and the With technological progress, less invasive therapeutic strategies have been sought that offer better clinical results. Intradiscal electrothermal therapy has gained great relevance in the last decade since it is a procedure that may eliminate or delay the need for surgical intervention for an extended period in properly selected patients, whereas only a few adverse effects have been reported . IntradiStudy designA crossover clinical trial was carried out, where the patients with chronic radicular pain secondary to lumbar disc herniation, who had received previous conservative treatment and a month of physiotherapy without achieving adequate pain control, underwent CRT in the discs that presented hernias. It evaluated the VAS and the OLBPDS pre- and postintervention. After the initial clinical evaluation by a physician specializing in interventional pain medicine, physical therapy treatment with a certified therapist was offered for one month. Patients who did not show significant clinical improvement were offered CRT intervention. Subsequently, the patients were summoned to monitor the evolution of the pain and functionality by applying the aforementioned scales again. In accordance with the Declaration of Helsinki and Good Clinical Practices, each patient was informed about the procedure after being selected followed by a specialized medical evaluation by a certified algologist, who explained the risks and benefits, which were accepted by the patients through a signed and dated informed consent.PatientsAdult subjects with a history of discogenic lumbar back pain for at least three months were included. The patients to be selected had to present back pain of intensity ≥ 7/10 points on the visual analog scale (VAS) and moderate or severe score on the Oswestry low back pain disability scale (OLBPDS), express their desire to receive the intervention, have previously subjected to conventional treatments such as analgesics or physical therapy without success, and have documented the presence of disc herniations by means of magnetic resonance imaging (MRI).Initial physiotherapy approachTreatment was started with objectives to control pain and promote muscle relaxation, relieve pressure on pain-sensitive or neurological structures, strengthen muscle, reduce paresthesias in the lower limb, and improve postural hygiene. We worked with physical agents such as thermotherapy, electrotherapy, and manual therapy to control pain, with patients who had a posterior or posterolateral protrusion. The therapist worked with passive extension exercise, correction of lateral deviation, and stretching of the soft tissues anterior to the lumbar spine (to increase trunk extension). If the protrusion was anterior, it was worked with passive flexion exercises and stretching of the lumbar erector spinae muscles and the posterior soft tissues of the spine (increased trunk flexion). Reeducation and strengthening of the lumbar extensors as trunk stabilizers and increased muscular resistance to control the spine, as well as stretching of the shortened muscles of the lower extremities that affect posture, were carried out. All patients were re-educated in postural hygiene for their activities of daily living, and active break techniques were implemented in patients who had work activities.Intradiscal biacuplastyA COOLIEF®  radiofrequency electrode is used for the procedure, which is connected to the generator and peristaltic pump unit for energy supply and internal cooling. The radiofrequency ablation process is carried out with the tip of the probe at 60°C, while the temperature of the target tissues reaches 80°C, ensuring no damage to other surrounding structures through the cooling system of the probe. A radiopaque marker is located at the proximal end of the active tip; this marker defines the location of the lesion under fluoroscopy, confirming the position and improving visualization. After signing the informed consent, in the operating room with C-arm, the patients were positioned in the prone position with sterile technique through the asepsis and antisepsis protocol to initiate intradiscal biacuplasty Figure .Skin and deep tissues are infiltrated with 1% lidocaine at the level of the affected disc. The interdiscal spaces of the area of interest are identified in oblique projection at 30º by fluoroscopy, as well as facet joints. With tunnel vision, a supra-pedicular approach was performed through the herniated disc, placing a working channel in the posterior third of the intervertebral disc. Diagnostic evoked discography is performed, which is considered positive if the patient reports pain at the time, corroborating disc herniations. Lumbar decompression is performed, in response to the evoked discography and neurotomy of the gray branches of the corresponding disc with intradiscal bipolar energy bilaterally at 80°C for 15 minutes, after a motor and sensory safety protocol. The event ends by corroborating with the patient's sensitivity and perception of pain, intentionally interrogating incidents or immediate adverse effects. The procedure is performed under local anesthesia and partial sedation, thus keeping the patient conscious for feedback on their somatic perception at all times. The patient remained hospitalized for 24 hours after the intervention for observation and was discharged with oral analgesics and follow-up appointments for interventional pain management and physiotherapy to facilitate timely physical rehabilitation.Statistical analysisContinuous demographic data were summarized using descriptive statistics, and the subject was compared with its own control by two-way ANOVA, comparing the initial VAS score, the one after physiotherapy treatment for one month and the subsequent one after undergoing CRT. Categorical demographic data were summarized and expressed as percentages. To determine the homogeneity of the age of the patients, the one-sample t-test and Wilcoxon test were performed. Data comparisons were performed at a 5% level of significance (p ≤ 0.05). In some cases, not every eligible subject provided observations at each follow-up point. GraphPad Prism 9  for macOS software was used for the analysis.A total of 106 patients were recruited; however, 74 of them met all inclusion criteria, received physiotherapy treatment for one month without significant improvement, and underwent intradiscal biacuplasty by CRT; the rest were excluded from this study. It should be noted that several patients received CRT at two or three lumbar spinal levels per intervention, resulting in a total of 134 herniated intervertebral discs that were treated. As shown in Table Table In the evaluation of the VAS, 74 subjects were considered for intervention after reporting a VAS score equal to or greater than 7 points in their initial evaluation by pain medicine. After physical therapy treatment, a vast majority of patients mentioned having a partial improvement in their pain and functionality; however, it was not significant . On the other hand, in the initial evaluation, 54 (72.88%) subjects reported a moderate OLBPDS, and 20 (27.11%) reported a severe one. Regarding the laterality of neuropathic pain, 29 (38.98%) subjects reported that it was unilateral, and 45 (61.02%) reported that it was bilateral. All the patients who underwent surgery presented a post-traumatic etiology of their pain, which had an evolution time between three months and five years, with an average of 11.83 ± 12.1 months between the triggering event and the intradiscal biacuplasty. Regarding previous treatment, 72.88% of subjects were receiving non-opioid analgesics, 10.16% were receiving opioid treatment, and 16.94% received physical therapy on all occasions without obtaining significant pain improvement; none of them had seen a pain specialist.After intradiscal biacuplasty, the patients were followed up between one and six months, obtaining a mean follow-up of 2.42 ± 1.29 months. From the new measurement of the VAS at follow-up, a global improvement of 79.92% of the pain was found , obtaining adequate pain management in the 98.64% of the cases (Figure Although there was only one case in which the patient did not report any improvement in radicular pain, during his clinical follow-up, a moderate reduction in lumbar discogenic pain was found; it is important to highlight that there was no worsening of the original painful condition. Relating to the OLBPDS, 98.64% of the patients reported having reached the minimum score, while the patient who did not present improvement in his pain did not increase his functionality significantly either. No patient reported adverse effects other than transient pain in the postoperative period or after their discharge from the hospital. Perhaps, as physiotherapy did not obtain the expected results before CRT, all patients received personalized physical rehabilitation early to accelerate recovery after the intervention under an exercise scheme similar to the previous one, thereby strengthening the clinical outcome.Back pain is one of the most frequent causes of consultation with primary health providers as it is highly prevalent in the general population and is associated with a worsening of quality of life and mental health throughout life ,12. Its Candan et al.  reportedConsidering this, CRT emerges as a therapeutic option with greater effectiveness and a lower risk of severe adverse effects. This technique has been shown to offer statistically superior improvements across the spectrum of patients with chronic sacroiliac joint pain , intercoThe main limitation of this study has been the number of patients and the possibility of comparing the subjects against controls. As it is the first single-center approach in a private hospital in Mexico, the possibility of offering both procedures is complicated; therefore, the selection of patients was made at convenience from the population that voluntarily and autonomously came to this Pain Management Center. Additionally, it is necessary to follow these patients over time and observe how their clinical outcomes have evolved.Intradiscal CRT biacuplasty is a safe and effective minimally invasive method for treating chronic neuropathic pain secondary to root compression due to a lumbar hernia and discogenic pain. The subjective perception of pain as measured by the VAS score has decreased significantly after the intervention, improving the quality of life in patients with chronic pain, especially in those who have considered different types of orthopedic spinal interventions or who suffer from pain due to failed back surgery syndrome, after undergoing laminectomies or lumbar instrumentation that failed to provide adequate pain management. On the other hand, the improvement in functionality measured by OLBPDS also demonstrated the superiority of this technique over invasive options. In the case where pain improvement was not achieved, the patient did not show worsening symptoms, not limiting the ability to perform other surgical interventions after conservative and minimally invasive treatment has been refractory, as suggested by the guidelines. More research is needed in the field of algology and pain medicine to offer techniques that are increasingly less invasive, more effective, and have the fewest possible long-term effects.


Echium amoenum is among the important therapeutic herbs in Iranian traditional medicine. Various studies have shown its pain control properties. This study aimed to evaluate this herb’s efficacy in controlling pain after periodontal surgeries.  Pain after periodontal surgeries is one of the most common complications. E. amoenum), 24 hours before surgery, E. amoenum was administered to the patient at home every 12 hours, and a dose of E. amoenum was administered one hour before the procedure. The postoperative pain was assessed using VAS 30 minutes, 1 hour, and 3 hours after the surgery and verbal rating scale (VRS) 24, 48, and 72 hours postoperatively. A chi-square test was used to compare the pain severity between the two groups.  In this randomized clinical trial, 50 patients referred to Tabriz Dental School for clinical crown lengthening surgery were divided into two equal groups: control and test. In the test group  (P<0.05). In both groups, pain severity increased significantly up to 3 hours postoperatively (P<0.05). In the first 24 hours, the VRS index of the E. amoenum group was significantly lower than that of the control group (P<0.05), with no significant differences between the two groups at 48 and 72 hours (P>0.05).  The VAS index was significantly lower in the E. amoenum herb reduced the pain severity after clinical crown lengthening surgeries. The  With the help of phospholipase, it will lead to cell membrane rupture and the release of membrane phospholipids, which in turn will be transformed into prostaglandins, thromboxane, and other metabolites by COX-1 and COX-2 enzymes, causing pain.4 However, many factors, such as the patient’s temperament, the duration, type, and extent of the surgery, psychological aspects such as stress and excitement, the extent of the tissue trauma, duration of the gingival disease, and type of the anesthetic agent used  may affect the pain severity, making the accurate comparison of the studies in this area difficult.2 Traditional medicine, as an inspiration for human health, has played a major role in replacing chemical medicines with various herbal medicines in some countries, such as Iran. Moreover, the tendency of the Iranian society to use traditional herbal treatments due to their harmlessness and cost-effectiveness has led to the widespread use of herbal medicines in traditional medicine.5 Pain after periodontal surgeries is among the most common unpleasant problems and complications for patients.Echium amoenum is one of the important therapeutic herbs in Iranian traditional medicine.6 This plant has been used as a demulcent, anti-inflammatory and analgesic, anxiolytic, and sedative in the folk medicine of Iran. Several studies have evaluated this herb in recent years, investigating its antibacterial effects,7 the essential oil components of petals,8 pyrrolizidine alkaloids,9 phenolic compounds,10 and anxiolytic,11 analgesic,12 and anticonvulsive effects.13 In addition, its antioxidant effects,14 mild-to-moderate anti-depressive effects,15 and its effect on mental disorders have been studied.16 All of these studies have been conducted by Iranian researchers on the herbal organ of the E. amoenum flowers. A study by Abed et al17 showed that E. amoenum significantly decreased pain and inflammation in acute pancreatitis patients. However, based on a literature search, no study has investigated the effect of this herb on pain control after gingival surgeries. Hence, this study was conducted to determine whether E. amoenum can control pain after periodontal surgeries and whether E. amoenum can replace or at least supplement conventional medications used after periodontal surgeries. In this randomized clinical trial with a placebo group and parallel, double-blind groups, random sampling was performed among the people referring to the Periodontics Department of the Faculty of Dentistry, Tabriz University of Medical Sciences, for clinical crown lengthening. The study was conducted according to the declaration of Helsinki.18 and considering the alpha value of 0.05 and a test power of 80%, the sample size was determined at n = 21 in each group. To increase the study’s validity, 20% was added to this number, and 25 samples were included in each group. Based on a study by Babaloo et alE. amoenum was harmful, patients who needed increased doses of analgesic drugs, patients with no need for bone surgery, and pregnant and lactating women. The necessary explanations were provided to the patients, and their written informed consent was obtained. The caregivers of the patients who could not read and sign the informed consent form  were asked to assist them in these steps. One periodontist performed the clinical crown lengthening surgery, who was blinded to the procedures. Fifty patients were selected after meeting the research inclusion criteria and randomly assigned to the control or examined group using the randomizer website at randomizer.org. The research inclusion criteria included informed consent of the patients, patients undergoing dental crown lengthening (in the posterior maxilla) surgery, an age range of 20‒65 years, and patients’ physical and mental health. The research exclusion criteria also included patients with a systemic or mental illness, consuming alcohol or any psychotropic drugs, known sensitivity to NSAIDs, caffeine, or acetaminophen, any bleeding disease, patients at risk of any infection after surgery, patients with hepatic problems, patients with heart problems and hypertension, patients who did not have the necessary cooperation during the study, patients with mental and physical disabilities , patients in which the use of  Before the surgical phase, the patient was motivated and given oral hygiene instructions for the nonsurgical removal of calculus. The surgery site in all the patients was in the posterior maxilla, and the bone removal site was about 3‒4 mm between the bone margin and the healthy edge of the tooth. The surgery duration was the same for all the patients (approximately 20 minutes). Topical infiltration technique and 2% lidocaine with 1:800 000 epinephrine were used for anesthesia (one cartridge was used in each area). A full-thickness flap was elevated using sulcular incisions of one tooth beyond the surgical site without a releasing flap. After surgery, the area was closed with a vertical mattress suture. After surgery, the patients were advised not to spit, not to drink through a straw, to avoid chewing in the areas of surgery, to avoid hard food, to drink plenty of liquids, not to use alcohol, and not to smoke.Echium amoenum was used in the first group. E. amoenum was monitored and consulted with the Faculty of Pharmacy of Tabriz University of Medical Sciences. Each pack was prepared with a demo bag from the Golestan brand in 250 mL of water in a covered container. Twenty-four hours before the surgery and every 12 hours, a dose of E. amoenum was used by the patients at home. The second group used the placebo . Due to ethical considerations, after the surgery, the patients in both groups were given an analgesic drug (Novafen) according to the surgeon’s guidance. The first dose of the medicine was administered immediately after the end of the surgery, and the subsequent doses were used at 6-hour intervals after the first dose for three days. The level of pain after the surgery was assessed 30 minutes, 1 hour, and 3 hours after the surgery using the visual analog scale (VAS), completed by the patients at home. The pain level was assessed 24 hours, 48 hours, and 72 hours after the surgery using the verbal rating scale (VRS), completed and evaluated through phone contact with the patients. In this measurement scale, the rating system used was as follows: 0: (pain-free), 1: mild pain (tolerable), 2: moderate pain , 3: severe pain , and 4: very severe pain. No antibiotic was administrated to the patients.P< 0.05 was considered significant. Friedman test was used to assess the pain severity in two groups 30 minutes, 1 hour, and 3 hours after the surgery using the VAS index, and the pain severity in the two groups 1, 2, and 3 days after the surgery was assessed using the VRS index. A chi-square test was used to compare the pain severity between the two groups. Statistical analysis was performed using SPSS 17, and  The results showed the highest pain in the control group 3 hours after the surgery (6.44 ± 1.38), with the lowest pain in the test group 30 minutes (0.72 ± 0.54) and 24 hours (0.72 ± 0.52) after the surgery. According to the results, there were significant differences between the control and test groups regarding pain severity. To examine the significance of this difference, inferential statistics were used. In addition, since the data were of ranked type data, Friedman and Wilcoxon’s tests were used for data analysis. The Wilcoxon test was used to compare pain in the control and experimental groups at the study intervals. The results revealed that the statistical value of the test used to assess the pain severity in the control and experimental groups was significant at all three intervals  (P = 0.00). Therefore, the patients’ pain in the control and test groups differed significantly at all the three intervals. In addition, the Wilcoxon test showed that the pain severity in the test group was significantly lower than that of the control group at 30 minutes, 1 hour, and 3 hours postoperatively.P= 0.00). The Wilcoxon test showed that pain was significantly different at all three intervals (P= 0.05). According to the results of the Wilcoxon test, pain severity in the control group increased significantly up to 3 hours after the surgery (P= 0.00). The test group patients at the study intervals exhibited the same results as the control group (P< 0.05). Friedman test was used to compare patients’ pain in the control group. There was a significant difference in patients’ pain in the control group at study intervals (P= 00.00). However, 48 hours (P= 00.26) and 72 hours (P= 00.674) after the surgery, no significant difference was found between the patients of the control and test groups. Therefore, pain severity in the control group increased significantly 24 hours after the surgery, with no significant differences between the pain scores of the control and test groups 48 hours and 72 hours postoperatively. The Wilcoxon test was used to compare pain severity in the control and test groups at the study intervals. There was a significant difference between the test statistic values related to the patients’ pain in the control and test groups 24 hours postoperatively (P= 0.00). According to the Wilcoxon test, there was a statistically significant difference in pain scores between the three intervals in the control group (P< 0.05). Therefore, pain severity in the control group decreased significantly from 24 hours after surgery to 72 hours after surgery (P< 0.05). The Friedman test was used to compare pain in the control group at the study intervals. There was a significant difference in pain severity in the control group patients between the three intervals (P= 0.794). The Friedman test was used to compare pain in the control group at the study intervals. There were no significant differences in the pain scores in the test group at 24, 48, and 72 hours postoperatively , the type of periodontal surgery, the patient’s mental condition, gender, duration of surgery, level of the trauma, duration of the gingival disease, etc.E. amoenum group compared to the other group. At the same time, there were no significant differences between the two groups at 30-minute and one-hour postoperative intervals due to the anesthetic effect. However, the pain severity increased significantly up to 3 hours after the surgery in both groups. Heidari et al12 examined the analgesic effects of E. amoenum on mice. The results showed that E. amoenum extract had good analgesic effects. In the present study, the VRS index indicated the pain severity 1, 2, and 3 days after the surgery, with a significant difference between the two groups on the first day. The anti-inflammatory properties of E. amoenum were responsible for pain relief,12 consistent with the current study. Based on the present study, the pain severity was significantly lower in the E. amoenum that improves memory and reduces anxiety.20 Given the anxiolytic property of E. amoenum, the group receiving E. amoenum experienced less pain even in the early hours of the day due to reduced anxiety and higher mental relaxation. Sayyah et al21 found that E. amoenum had an analgesic effect on patients with generalized anxiety disorder. Faryadyan et al22 showed that the hydroalcoholic extract of E. amoenum could have anxiolytic effects by increasing dopamine levels. By modulating the function of serotonergic nervous systems that play a key role in reducing anxiety, depression, and neurological disorders, it reduces the level of anxiety. In addition, no significant difference was found between the two groups two and three days after the study. Due to reduced pain severity two and three days after the study, the pain severity was similar in the two groups. Saponin is among the ingredients of E. amoenum was another cause of lower pain in the patients using the E. amoenum. A study by Abed et al17 also showed that E. amoenum significantly reduced pain and inflammation in acute pancreatitis patient. Moreover, the sedative effect of E. amoenum reduced the pain severity after clinical crown lengthening procedures. The pain severity decreased two days after the clinical crown lengthening surgery in normal conditions; therefore, the effect of this herb decreased. Based on the results of the present study,  Not applicable. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. All authors declare that they have no conflicts of interest. The protocol of the study was approved by the Ethics Committee of Tabriz University of Medical Sciences under the code IR.TBZMED.REC.1398.373. In addition, the study was registered at the Clinical Trials Website of the Ministry of Medical Education (IRCT) under the code IRCT20180630040290N3. Not applicable.


Choosing the optimal treatment approach for patients with painful bone metastases during the COVID‐19 pandemic became challenging. A simple technique, single fraction radiotherapy was recommended for these patients usually referring to bone metastases as a single entity, although it is a very heterogeneous group of patients.This study aimed to analyze the response to palliative single fraction radiotherapy in relation to age, performance status, primary tumor, histopathology, and bone localization in the group of patients with painful bone metastases.A clinical, prospective, non‐randomized study was conducted at the Institute for Oncology and Radiology of Serbia, which included 64 patients with noncomplicated, painful bone metastases who underwent palliative, pain‐relieving radiation therapy with a single tumor dose of 8Gy in a single hospital visit. Response to treatment was patient reported via telephone interview using visual analog scale. The response assessment was based on the international consensus panel of radiation oncologists.In the entire group of patients, 83% responded to radiotherapy. No statistically significant difference was observed in response to therapy, time to reach the maximum response, degree of pain reduction, nor in response duration depending on the patient's age, performance status, the primary origin of the tumor, histopathology, or location of the metastasis (bone) that was irradiated.Regardless of clinical parameters, palliative radiotherapy with a single dose of 8Gy can be considered very effective in quick pain relief in patients with noncomplicated painful bone metastases. Single fraction radiotherapy in a single hospital visit, as well as patient‐reported outcome for these patients may be considered favorable beyond Covid pandemics. The complexity of choosing the optimal treatment approach for these patients in the context of efficiency, cost‐effectiveness, and quality of life is rising.For decades, radiotherapy has been considered the most effective therapeutic method for painful bone metastases. Based on the results of numerous studies and meta‐analyses, the American Society of Therapeutic Radiology and Oncology (ASTRO) provided a guideline in 2017. with the conclusion that the radiotherapy technique of high radiation dose delivered in one fraction  is equally effective in controlling pain in bone metastases as fractionated radiation regimens. However, duration of pain response, bone stability, and remineralization happen to be inferior after single fraction than after multifraction radiotherapy, leading to significantly higher re‐irradiation rate in the single‐fraction group of patients.With the COVID‐19 outbreak, oncology departments throughout the world were challenged, especially when it comes to patients needing palliative radiotherapy. At that point, some authors suggested that palliative radiotherapy should be limited only to emergencies,Following guidelines during COVID‐19 pandemics, patients with painful bone metastases are recommended to undergo a simple technique, 8Gy single‐fraction radiotherapy in only one hospital visit, with telephone follow‐up whenever possible.Therefore, we set the goal to analyze the response to treatment concerning age, performance status (PS) of the patient, primary tumor, histopathology, and localization of metastases in the group of patients with painful bone metastases who underwent palliative, pain‐relieving, 8Gy “single shoot” radiotherapy. The analysis of these clinical parameters might give another perspective in selection of patients with painful bone metastases for an optimal palliative approach.2In the period from October 2019 to June 2020, a clinical, prospective, non‐randomized study was conducted at the Institute for Oncology and Radiology of Serbia, which included 64 patients with painful bone metastases. All patients were treated based on the current protocols for the diagnosis and treatment of malignant diseases, and the treatment was proposed by a multidisciplinary tumor board. Also, all patients were informed about the treatment protocol and gave written informed consent for participation in the study.2.1The study enrolled patients older than 18 years, with histopathologically verified any malignant disease, with radiographically and/or histopathologically confirmed bone metastases (one or more), previously treated or not treated with specific oncological therapy, and whose expected survival time was longer than 1 month. Patients with complicated bone metastases , patients previously irradiated for the same bone metastases, and those with an expected survival time of <1 month were excluded from the study.2.2All patients were clinically examined with an assessment of their performance status according to the ECOG performance scale.2.3All patients underwent palliative, pain‐relieving radiation therapy using the “single shoot” technique with a tumor dose of 8Gy in one fraction, with high‐energy photons  on a linear accelerator. Radiation fields were determined individually for each patient based on reference bone X‐ray, CT, or MR images, and according to ICRU 62 recommendations.Radiotherapy was delivered in a “single hospital visit” manner, that is, in the single hospital visit, patient was presented to the tumor board, delineated, planned for radiotherapy, and irradiated.2.4Complete response: the complete absence of pain after radiotherapy without additional analgesics.Partial response: pain reduction of ≥2 on the ordinal pain scale without increasing the analgesic dose.Absence of response to radiation therapy: pain intensity remained the same or worsened within 4 weeks of radiation.Duration of therapeutic response was recorded from the date of maximal response to the date of pain relapse or until study closure or death.Pain relapse: worsening of pain by ≥2 on the ordinal pain scale after initially achieving response.For each patient in our study, follow‐up lasted 3 months from the date of irradiation or until the date of death.Pain intensity, performance status, as well as correction of analgesic use were evaluated first after 48 h following radiation, then once a week during the first 4 weeks, and then once a month until the third month after the radiation, using the same scales as before radiation. These assessments were carried out through telephone interviews or regular check‐ups, based on the standards of the international consensus panel of radiation oncologists2.5To examine the agreement of sample distributions with the normal distribution, graphs were used: normal QQ plot and histogram, as well as tests: Kolmogorov–Smirnov and Shapiro–Wilk.To describe important parameters, and depending on their nature, measures of descriptive statistics were used: frequencies, percentages, mean value (average), median, standard deviation (SD), and range (range).α = 0.05 was adopted for the level of statistical significance. In case of multiple testing on the same data set, Bonferroni correction of α‐value was used.The value To test the differences between treatment groups, and depending on the nature of the examined parameters, the following were used: Fisher's exact test; Kruskal–Wallis test, Wilcoxon rank sum test.The Kaplan–Meier product‐limit method was used to display the time to maximum response, time to progression, and overall survival, and survival analysis medians and corresponding 95% confidence intervals (95% CI) were used to describe them. The log‐rank test was used to test differences in time to maximum response and time to progression.www.r‐project.org; Retrieved: 2017‐01‐21) were used in data processing and analysis.Standard tests in the statistical program R version 3.3.2 (2016‐10‐31) — “Sincere Pumpkin Patch”; Copyright (C) 2016 The R Foundation for Statistical Computing; Platform: x86_64‐w64‐mingw32/x64 (64‐bit)  and 26 were women (41%), with an average age of 66 years (range 43–87 years). Even a third of the patients (34%) were ECOG performance status 3 (PS3). Based on the primary location of the tumor and histological type, the group was very heterogeneous with almost 35% of patients having confirmed primary lung cancer. The largest number of cases (33%) was adenocarcinoma. More than half of the patients in our group (58%) had metastases in the spinal column, and 25% of the patients had metastases in the pelvis. Very strong pain (VAS 8–10) had the largest number of patients, 23 of them (36%), of which 6 (10%) had a severity of 10 on the VAS. Almost 40% of patients used strong opioids to control the pain.3.2In the entire group of 64 patients, 53 of them (83%) responded to radiotherapy, while 11 patients (17%) did not.Of the 53 radiation responders, 19 (36%) achieved a complete response, that is, the complete absence of pain. In the other 34 patients (64%), a maximum partial response was noted with a median difference in pain reduction of 4 points on the VAS (rank 3–6). The median time to maximal response was 25 days (range 2–93 days), or an average of 3 weeks (0–13 weeks).3.3p = 0.39), performance status (Fisher's exact test p = 1), the primary origin of the tumor, that is, histological type of tumor (Fisher's exact test p = 0.17), nor depending on the location of the metastasis (bone) that was irradiated (Fisher's exact test p = 0.999)  Table .p = 0.138), performance status , the primary origin of the tumor, that is, histological type of tumor , as well as depending on the location of the metastasis (bone) that was irradiated . , performance status , primary tumor origin , and metastasis localization .  according to all the mentioned parameters: age of the patient , that is, the duration of the response was an average of 1 month after reaching the maximum response.p = 0.39), performance status (log‐rank test p = 0.64), and the primary origin of the tumor, that is, histological type of tumor (log‐rank test p = 0.98), as well as depending on the location of the metastasis (bone) that was irradiated (log‐rank test p = 0.70). . By the end of the study, 26 patients had died (41%), while almost two‐thirds (38 of them) were still alive (61%).4Based on multiple clinical trials, meta‐analysis and guidelines, “simple”, high dose, single fraction radiotherapy is considered an effective, short‐term regimen that enables quick and long‐lasting pain relief. It can significantly improve a patient's performance status and quality of life, with no delay in other oncological treatment and reduce the use of analgesics. It does, however result in higher re‐irradiation rate than with multi‐fractionation regimen and it is generally suitable for patients with uncomplicated bone metastases. With the use of modern techniques such as IMRT, Rapid Arc, SBRT, etc. the additional confusion was made in the treatment of patients with painful bone metastases regarding both optimal technique selection and the optimal tumor dose. Ultimately, with the COVID‐19 outbreak, radiation oncologists were challenged to quickly adjust the approach to these patients reintroducing fast regimen. But did we rush?In the clinical practice as well as in most of the studies, palliative radiotherapy of painful bone metastases is usually seen as a single entity, although it is a very heterogeneous group of patients, the primary site of disease and histopathological diagnoses, as well as localization of metastases on the skeleton.In our study, the VAS scale was used to assess pain, and the response to radiotherapy was defined according to the recommendations of the radiotherapy consensus panel. Regardless of the applied pain assessment scale, in response to therapy, the definition of a complete response is the same everywhere—the complete absence of pain. The definition of a partial response, however, varies between studies but is defined as a reduction in pain by 1 category on a 4‐ or 5‐category scale, or by 2 points on the VAS. In this way, the studies are methodologically consistent, and our study fully corresponds to this system for assessing pain intensity. Also, in most studies, pain intensity was recorded 1, 2, 3, 4, 8, 12, and 24 weeks after irradiation, with which our study is in full agreement. Another important finding was that patient's compliance to telephone interview and patient reported outcome was 100% and we found it non‐challenging whatsoever. True, we did not have electronic patient‐reported outcome measures developed for that particular scenario.The assessment of the patient's performance was based on the ECOG performance scale. In most previous studies, the inclusion criterion was Karnofsky performance scale (KPS) ˃40 (PS3), while in the study by Foro Arnalot et al., out of the 160 patients included, as many as 131 patients had KPS ≥70 (PS2).In the entire group of 64 patients, 53 of them (83%) responded to radiotherapy. Of those 53 patients, 19 (36%) achieved a complete response, that is, complete absence of pain, of which 13 maintained a complete response without pain progression until the end of follow‐up. In 34 patients of our group (64%), a partial response to radiotherapy was recorded with a median difference in pain intensity of 4 points on the VAS (rank 3–6), which correlates with other series (average pain reduction—3.5 points on VAS).In the meta‐analysis by Wu et al., which included eight clinical trials, the total response to a single shoot was 62%, while complete remission was recorded in 33% of patients.In the group of patients who responded to radiotherapy, the average time to reach the maximum response was 25 days (range 2–93 days), that is, an average of 3 eeks (0–13 weeks). The average time until pain progression was 34 days (1–69 days), that is, the response duration was an average of 1 month. In the Foro Arnalot study,Gaze et al. recorded a duration of response of 13.5 weeks, and Linden et al. of 18 weeks,In the available literature, there are very few comments regarding the patients who did not respond to radiation. In 11 patients of our study (17%), no reduction of pain was recorded, although six patients achieved stabilization of pain by the end of the study, which did not increase further. In these patients, there was no increase in the use of analgesics. These patients were women, predominantly elderly (median 72 years) and all had radioresistant malignancy . In five patients of this group, a rapid progression of pain after irradiation was noted.Therefore, it is of great clinical importance to distinguish the group of patients who would benefit from radiotherapy compared to those who will not respond to it. Based on our results, no statistically significant difference was observed in the response to therapy depending on the age of the patient, performance status, primary origin of the tumor, histological type of the tumor, as well as depending on the location of the metastasis (bone) that was irradiated. There was no statistically significant difference in the time to pain progression, nor in the level of response to radiotherapy by any of the mentioned parameters. Even by separating the group of patients who had a response to radiotherapy (53 of them), no statistically significant difference was observed in the time to reach the maximum response according to any parameter. Several large‐world studies have analyzed the potential influence of pre‐therapeutic prognostic and predictive factors such as the patient's age, sex, and histology of the primary tumor and localization of metastases. None of these studies showed that any of these factors influenced response to therapy or survival.Overall survival in our entire group of patients was an average of 12 weeks (range 1–18 weeks), that is, 3 months. By the end of the study, 26 patients had died (41%), while almost two‐thirds (38 of them) were still alive (61%). In a retrospective study by Liu et al., 537 patients previously irradiated for painful bone metastases were examined. Median survival from irradiation was 6 months, which is longer than in our series. However, in this study, a significantly larger number of patients were in good performance status, in contrast to our study. Among other things, this study also concluded that patients with KPS below 80% have significantly worse survival. The worst survival was recorded in the gastrointestinal cohort, as well as in the lungs (4 months), which is correlated with our results, considering that in our study, patients with lung cancer were the most represented.The whole paradigm in the palliative approach was challenged during COVID‐19 pandemic, favoring quick, but non‐inferior radiotherapy regimens.5Palliative radiotherapy using the technique of radiation in one session with a dose of 8 Gy can be considered very effective in quickly relieving the pain syndrome in patients with painful bone metastases. It has not been proven that any of the mentioned predictive factors have an influence on the response to therapy, the level of response (degree of pain reduction), the time to reach the maximum response, as well as the time to the progression of pain. Single‐fraction radiotherapy in a single‐hospital visit, as well as patient‐reported outcome for these patients may be considered favorable beyond COVID pandemics.Tatjana Arsenijević: Conceptualization ; data curation (lead); investigation (lead); methodology ; writing – original draft (lead). Aleksandar Stepanović: Data curation ; writing – review and editing . Brankica Milošević‐Maračić: Data curation . Bojana Poparić‐Bandjur: Data curation . Ivana Mišković: Methodology . Dušica Gavrilović: Software (lead). Marina Nikitović: Conceptualization ; methodology ; writing – review and editing .This research received no external funding or any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.All authors declare no conflict of interest.The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical review and approval were waived in this study, as in this study no experiments or novel treatments were conducted on humans (patients). The methodology represents a standard treatment modality that does not need ethical approval. The decision to treat the patients in the manner described in the study was made by the multidisciplinary tumor board of the Institute for oncology and radiology of Serbia.The manuscript is a part of the academic sub‐specialist thesis of T.A. approved by the Faculty of Medicine, University of Belgrade, Serbia, 2019 (Protocol number: 04 BR: 18‐UON‐15).Written informed consent was obtained for all subjects involved in the study. All subjects were fully aware that the data will be published. Written informed consent included that statement too. No personal identifiers are presented in this study.No other sources material was reproduced in this study.