A growing proportion of veterans treated at the Veterans Health Administration (VA) have a history of post-traumatic-stress-disorder (PTSD), and there exists a higher rate of PTSD amongst veterans than the general population. The purpose of this study is to determine the correlation between PTSD and intra-operative analgesia, intra-operative time, and anesthesia type for cataract surgery in a veteran population. Secondary objectives are to determine if patient age, and first or second eye surgery affect intra-operative pain control or are correlated with type of anesthesia modality.A retrospective study of 330 cataract surgeries performed by resident physicians between January and September 2012 at the Veterans Affairs Medical Center Tennessee Valley Healthcare System, Nashville and Murfreesboro Campuses was completed. Three hundred and thirty veteran patients were selected if their cataract surgery was performed between January and September 2012. Combined cases were excluded. The primary outcome evaluated was intra-operative analgesia. Secondary outcomes included history of post-traumatic-stress-disorder, anesthesia type, first or second eye, pain control, intra-operative heart rate and blood pressure, age, and case complexity. Data was analyzed using an unpaired two-sample Welch’s t-test assuming unequal variance and Z test of comparison of proportions.P < 0.05 was used consistently.Patients with post-traumatic-stress-disorder reported higher pain scores, had longer operative times, and were more likely to have received a retrobulbar block. Operative time was not associated with an increased pain score, irrespective of anesthesia type, when controlled for PTSD. Complex cases had longer operative times, more sedation, and higher pain scores. Post-traumatic stress disorder and anxiety are more prevalent in the veteran population. Our data suggests that a history of post-traumatic-stress-disorder was correlated with higher pain scores, longer operative times, and with having received a retrobulbar block. Patients without a history of PTSD were more likely to have received topical anesthesia with or without sedation. The veteran population requires more sedation to allay anxiety and perceptions of discomfort, which may account for longer surgical times. The veteran population is a special population and it is important to investigate how PTSD in the veteran population affects intra-operative analgesia. The rates of post-traumatic-stress-disorder (PTSD) are higher amongst the veteran population than the general United States population. Amongst all American men, estimated lifetime prevalence of PTSD is 3.6% according to the National Comorbidity Survey Replication (NCS-R) , while tCataract surgery is one of the most common surgeries performed in the Veterans Health Administration (VA) . In a giThere are many types of anesthesia that are currently utilized during cataract surgery in the VA. These include general anesthesia, retrobulbar block (RBB), peribulbar block (PBB), sub-Tenon’s injection, and topical anesthesia with or without perioperative intravenous sedatives . In studThere have been no studies examining which type of anesthetic choice is best suited for the veteran population or for patients with PTSD. Given the higher rates of PTSD, the veteran population should be studied as a separate special population that has unique characteristics and needs. The goal of the study was to determine the correlation of post-traumatic-stress-disorder (PTSD) with intra-operative analgesia, intra-operative time, and selection of different anesthesia modalities for cataract surgery in a veteran population. Secondary objectives were to determine if patient age, and first or second cataract surgery affect intra-operative pain control or are correlated with type of anesthesia modality. The data was subsequently analyzed to determine whether intra-operative time was correlated with different anesthesia modalities, patient age, and previous cataract surgery, and this was controlled for a history of PTSD.To the best of our knowledge, this is the first study to evaluate the effect of history of anxiety and PTSD on intra-operative analgesia and operative time.After local Institutional Review Board approval was obtained, we conducted a retrospective chart review of 330 cataract surgeries performed by second year resident physicians in the Veterans Affairs Medical Center Tennessee Valley Healthcare System, Nashville and Murfreesboro Campuses, between January and September 2012. Cases were collected in chronological order in that calendar year until 330 cases were obtained. There were no exclusion criteria. Data collected included history of anxiety disorder, post-traumatic stress disorder, or depression, operative time in minutes, anesthesia type , level of pain control obtained from anesthesia’s intra-operative assessment on a scale from 0 to 10, intra-operative average heart rate (HR) and blood pressure (BP), age, and complicated cases . Topical anesthesia was defined as one to two drops of tetracaine pre-operatively and intracameral lidocaine intra-operatively. Retrobulbar block consisted of a 3.5 mL mixture of 1.4 mL of 2% lidocaine (40% of injection), 0.75% bupivicaine (40% of the injection), and 10% of the injection hyaluronidase. Sedation consisted of midazolam, fentanyl, and/or propofol. The resident performing the surgery, under the supervision of the attending ophthalmologist, performed the RBB. Sedation was administered by the anesthesiologist or certified nurse anesthetist. As this was a retrospective study, patients were not randomized to a specific anesthesia type. All data is presented as mean and standard deviation. An unpaired two-sample Welch’s t-t test assuming unequal variance between groups was used to test the difference between group means. Welch’s t-test was used since it is insensitive to equality of the variances regardless of whether the sample sizes are similar. Z test of comparison of proportions was used to compare the percentages (proportion) of population receiving a specific anesthesia modality. A significance level of 95% was utilized. The data was independently sampled.Of the 330 cases reviewed, 54 of patients had PTSD, anxiety, or depression, and 276 did not have PTSD. Fifteen received general anesthesia, 146 received RBB, and 169 received topical anesthesia. Amongst patients receiving topical anesthetic drops, 116 received adjunct intravenous sedation, and 53 did not receive any sedation. All 330 cases were male patients, ages 53-82. Two hundred and one of the cases were the patient’s first eye cataract surgery; 129 cases were the second eye surgery. Seventy-eight patients reported some level of pain, and 252 did not report any pain. Operative times ranged from 18 to 120 min. One hundred thirty-five cases were <45 min, and 195 cases were >45 min, 216 cases were <60 min, and 114 cases were >60 min. Seventy-two cases were complicated, and 258 were uncomplicated.In the first part of the study, post-traumatic-stress-disorder (PTSD) was correlated with intra-operative analgesia, intra-operative time, and selection of different anesthesia modalities for cataract surgery. In the second part of the study, the cases were divided by time . Pain control, age, amount of sedation received, history of anxiety/ PTSD, and 1st or 2nd eye surgery were analyzed between the time groups. Pain scores between anesthesia modalities were analyzed between the time groups. The data was then controlled for complex cases with the same markers analyzed. Welch’s t-test was used for each comparison and Z test of comparison was used for proportions, and a significance level of 95% was utilized.p < 0.01  of our veteran population had PTSD, correlating with prevalence of PTSD found in the veteran studies cited above) –4. Patie6.3% of o.05 Fig. . Those pp < 0.01. Similarly, systolic blood pressure was higher in patients with pain (141.24 +/− 21.42) than those without (134.38 +/− 22.41), mean difference 6.86, p < 0.05; diastolic blood pressure was similarly found to be higher in patients with pain (84.28 +/− 9.20) than those without (71.89 +/− 10.19), mean difference 12.39, p < 0.0001  was higher in patients who reported any pain (75.12 +/− 10.52), than those who reported no pain (70.90 +/− 11.28), mean difference 4.22, p < 0.10 .Complex cases had longer operative times (62.52 +/− 21.66) than non-complex cases (46.30 +/− 15.51), mean difference 21.22, 001 Fig. , and had.01 Fig. . Complex.01 Fig. .Fig. 8There was no difference in age or 1st or 2nd eye surgery between those with and without PTSD, between anesthesia types and between the time groups.Our study found that there was a significant correlation between a history of anxiety/PTSD and higher pain scores, longer operative times, and having had received a retrobulbar block. This population requires more sedation to allay anxiety and perceptions of discomfort, and this may account for longer surgical times. Patients with anxiety and PTSD having higher correlations with RBB may suggest that RBB may simply reflect anesthetic choice for specific patients. Patient comfort and expected operative difficulty were factors that influenced the selection of anesthesia at the time. In addition to anxiety/ PTSD, there are numerous other patient factors, both ocular and systemic, that could have contributed to anesthetic selection that were not directly measured in this study . Such poThe correlation between intra-operative pain assessment and rise of intra-operative HR and BP could indicate pain, thus validating the pain assessment rubric. However, the rise in HR and BP is not specific and could represent increased sympathetic tone, which could be due to other reasons such as anxiety. Our data further showed that operative time was not associated with increased pain score, irrespective of anesthesia type, and irrespective of a history of PTSD. This may at least in part be due to longer operations receiving more sedation. This could suggest that the operative team prevents and responds well to patient pain.In our study, there was no difference in pain scores between first or second eye surgeries, but in previous studies second eye surgeries were found to be more painful . This isIt is unclear whether results from this study can be extrapolated to a non-VA hospital because of demographic differences. The veteran population is unique in that it consists mostly of males of older age; studies have shown that both older patients and males have higher pain thresholds during cataract surgery . In addiOur study was the first to evaluate the effect of PTSD on intra-operative pain control, intra-operative time and anesthetic choice. The validity of this study is limited by its retrospective nature, sample size and other potential confounding variables not analyzed. Like all retrospective chart reviews, this study was limited by a lack of randomization and a lack of matched groups. There were no women included and thus there is a gender bias. However, by limiting the patient population, the recommendations are more pertinent to this specific group.Several recommendations can be derived from this study. First, PTSD and anxiety are more prevalent in the veteran population. Next, PTSD is associated with longer operative times and is also associated with higher levels of intra-operative discomfort, which can include both pain and anxiety. Finally, RBB may be the preferred anesthetic technique for cataract surgery in this population because it completely obtunds sensory input. By investigating associations between post-traumatic-stress-disorder and pain, we can better anticipate the needs of our veteran patients. Anesthesia providers need to be cognizant of increased intra-operative sedation for patients with PTSD who have longer operative times and may subsequently require more sedation.


To assess the presence of Dengue, Chikungunya, and Zika in serum samples of patients with acute febrile illness in Piura, Peru and describe the most common clinical features.Dengue was the most common arbovirus detected in 170/496 (34.3%), followed by Zika in 39/496 (7.9%) and Chikungunya in 23/496 (4.6%). Among the 170 samples positive for Dengue, serotype 2 was the most predominant type present in 97/170 (57.1%) of samples, followed by the serotype 3 in 9/170 (5.3%). Headaches, muscle pain, and joint pain were the most common symptoms associated with fever in patients with Dengue and Zika. No symptoms predominance was observed in patients with Chikungunya.Dengue is considered the most frequent arbovirus in Peru and the number of cases has increased dramatically in the last 5 years. However, it is not the only arbovirus that circulates along the northern coast of Peru. It has also been determined the presence of Zika and Chikungunya in our population, which may suggest the circulation of other arboviruses that have not been detected. In the last years, the incidence of emerging and reemerging arboviral diseases has increased producing a serious social and economic impact in Latin America –4. DenguDengue which is considered the predominant arboviral disease in Peru has experienced a rapid prevalence increase in the last 5 years. In 2017, the number of cases has tripled compared to the previous year being the Peruvian coasts the most affected areas , 9. HoweIn 2013, the first native case of Chikungunya was reported on the Caribbean Island of San Martin . FurtherZika was detected in Peru for the first time in 2016, and until now more than 865 confirmed cases have been registered , 16. ZIKThe acute febrile illness which can be associated with nausea, vomiting, muscle pain, joint pain, rash, abdominal pain among others , 5, 6. TIn Peru, arboviral infections represent a major health concern . Additio“Dirección Regional de Salud de Piura – Red de Salud Morropón -Chulucanas”. Piura is a coastal region in Northwestern Peru which has been extensively recognized as an endemic area for dengue [We conducted a descriptive Cross-sectional study using convenience sampling. Data collection was performed by experienced personnel trained in the health establishments who were responsible for filling out epidemiological data sheets. The study was conducted in Piura in coordination with the r dengue , 9, 19.In this study, 496 patients with an acute febrile illness were evaluated, who met our inclusion criteria were studied from May to August 2016.Inclusion criteria: Patients who presented to the to health establishment with acute febrile illness  along with one or more of the following symptoms: chills, headache, dizziness, cough, sore throat, nausea and/or vomits, loss of appetite, back pain, dysuria, myalgias, arthralgias, retro-ocular pain, rash, melena, nasal bleeding, gums bleeding, petechiae, ecchymosis, blood tinged sputum, abdominal pain, chest pain, fatigue and altered mental status.Patients with samples inadequately conserved, or with an incomplete data sheet.Hospital Regional de Cajamarca, Peru. A written informed consent was signed before enrollment; for participants under 18 years old the informed consent was signed by parents or children caregivers before enrollment.This study was approved by the Research Ethics Board of the ® TUBE Serum Separator Clot Activator ; all the samples were stored at − 80 °C.One serum sample per patient was collected by using VacuetteThe Centers for Disease Control and Prevention  provided positive controls for DENV, CHIKV, and ZIKV.From 200 μL of serum samples, RNA was extracted with the High Pure RNA Isolation Kit , according to the manufacturer’s instructions.® 2.0 Instrument and data was analyzed with the LightCycler® Software 4.1 . The primers and the probe used for DENV, CHIKV, and ZIKV described by Leparc-Goffart et al. [A one-step RT-PCR was performed using TaqMan with BHQ quencher probe at 125 nM and 250 nM of primers in a final volume of 20 μL. Five microliters of the extracted RNA was combined with 15 µL of the master mix and the reverse transcription step was performed 95 °C for 15 min, 60 cycles of 15 s at 95 °C and 45 s at 60 °C. All the procedure was performed in Light Cyclert et al.  and Fayet et al. , respectQualitative variables were reported as frequencies and percentages. All analyses were processed with the IBM Statistical Package for the Social Sciences (SPSS) software version 21.0 . and between 5 and 19 years old (27.8%) with no gender predominance. DENV was the most common arbovirus detected in 170/496 (34.3%), followed by ZIKV in 39/496 (7.9%) and CHIKV in 23/496 (4.6%) .3% and bFurthermore, DENV positive samples were classified by serotypes 1–4 based on their amplified primers. Among the 170 samples positive for DENV, serotype 2 was clearly the most predominant type as it was present in 97/170 (57.1%) of samples, followed by the serotype 3 in 9/170 (5.3%). No serotypes 1 or 4 were detected , myalgia 86.5% (147/170) and arthralgia 84.1% 143/170) were the most common symptoms accompanying fever. In addition, sore throat and back pain were more common in patients with DENV. In the group of patients with positive samples for ZIKV the most frequent symptoms upon presentation were myalgias 89.7% (35/39), headaches 87.2% (34/39) and arthralgias 82.1% (32/39). For the patients with CHIKV, no symptoms predominance was observed; the most common symptoms were headaches, joint pain, loss of appetite, back pain, retro-ocular pain and muscle pain in 74–87%  even though we used molecular characterization via real-time RT-PCR. We believe this might be explained due to possible mutations in the DENV circulating in Peru. The presence of mutant variants of DENV can occur as intra-epidemic events sometimes enhancing the replication of specific serotypes , 26. ThiCHIKV cases have also been increasing in 2017 after the outbreaks in Tumbes, Piura, and Ancash [Suspected autochthonous Zika cases have been reported in 10 departments of Peru and in 2017 a total of 5760 cases of ZIKV have been registered with only an 8.5% of laboratory-confirmed cases. In Piura, only 27 cases have been reported and no autochthonous cases have been confirmed , 28. HowWe also reported preliminary information about clinical features in patients with acute febrile illness upon presentation in our population. Among the patients with DENV positive samples, headaches 89.4% (152/170), muscle pain 86.5% (147/170) and joint pain 84.1% (143/170) were the most common symptoms accompanying fever. Similarly, for patients with ZIKV the most frequent symptoms were muscle pain 89.7% (35/39), headaches 87.2% (34/39) and joint pain 82.1% (32/39). This information demonstrates once more the similar presentation these both pathogens can have and highlights the importance of laboratory confirmation. Interestingly, for CHIKV no predominant symptom was observed being headaches, joint pain, loss of appetite, back pain, retro-ocular pain and muscle pain in 74–87% of patients. Although we observed that a sore throats and back pain were more common in patients with DENV compared to the other arboviruses, due to our limited sample we cannot conclude that these clinical features can categorically aid for a DENV diagnosis.In conclusion, DENV is the most common arboviral cause of acute febrile illness in our study population from Piura, Peru. However, the presence of CHIKV and ZIKV should not be underestimated in the northern coast of Peru. Clinical presentations among these arboviruses can be very similar highlighting the importance of laboratory confirmation to achieve an etiological diagnosis and improve patients management. Further investigations are encouraged to improve prevalence estimates for these arboviruses and understand the causes of their resurgence. In addition, retrospective studies in stored samples should be considered to assess if Zika virus was present in Peru before 2016.This study has two main limitations. First, since we only included patients from primary care facilities in an outpatient setting, it is likely that we might have neglected more severe cases. Second, since the study was designed for DENV, CHIK and ZIKV detection via real-time PCR, it is possible that other arboviral etiologies might be present in the negative samples of patients with acute febrile illness.


Dexmedetomidine (DEX) has sedative, sympatholytic and analgesic effects and might be beneficial if used as an adjuvant to: improve analgesia; modulate haemodynamic responses to intubation and pneumoperitoneum and; reduce the number of opioid-associated adverse events. The aim of this study was to evaluate the efficacy and safety of DEX infusion during elective laparoscopic cholecystectomy (LC).n = 30) or normal saline infusion . The primary efficacy outcomes were postoperative morphine consumption. Secondary efficacy outcomes included: time to first use of rescue analgesia; postoperative morphine consumption; intraoperative fentanyl consumption; time from end of surgery to extubation; lengths of intensive care unit (ICU) and general ward stay; degree of postoperative pain 3, 6, 12 and 24 h after surgery; incidence of persistent post-surgical pain.A randomized, single-centre, parallel-group, placebo-controlled study was carried out between May 2016 and June 2017. Adult patients (18–79 years) with American Society of Anesthesiology (ASA) physical status I–II were randomly assigned to 0.5 μg/kg/h DEX infusion from induction of anaesthesia to extubation , lower incidence of severe postoperative pain  and significantly longer time to first use of rescue analgesia (p = 0.001). Group D also had significantly lower fentanyl consumption both intraoperatively (p = 0.001) and in the time from end of surgery to extubation (p = 0.001) plus decreased incidence of persistent post-surgical pain . The incidence of postoperative nausea and vomiting was lower in Group D than Group C . Median pain intensity did not differ between the groups 3, 6, 12 or 24 h after surgery and there were no inter-group differences in the lengths of ICU stay or overall hospital stay between groups. The incidence of hypertension was significantly higher in Group C ; there were no inter-group differences in incidences of hypotension and bradycardia.DEX infusion was associated with a decrease in postoperative morphine consumption (Intraoperative DEX infusion is safe and effective for improving analgesia during and after elective LC. DEX appears to significantly reduce the number of patients with severe postoperative pain, postoperative morphine consumption and prolong time to first use of rescue analgesia.NCT03211871.ClinicalTrials.gov: Retrospectively registered on July 7, 2017,  Laparoscopic cholecystectomy (LC) is usually associated with less pain compared with an open approach. Postoperative pain is nevertheless still the main complaint after LC and one which often prolongs hospital stay . ModeratOpioids remain one of the main options for postoperative pain relief after LC and are widely used , 4. HoweDexmedetomidine (DEX) is a centrally-acting alpha-2-adrenoceptor agonist that has sedative, sympatholytic and analgesic effects. This pharmacodynamic profile identifies DEX as a potential non-opioid adjuvant to improve analgesia and haemodynamic responses to intubation and pneumoperitoneum and to decrease the number of opioid-associated adverse events. The aim of this study was to evaluate the efficacy and safety of DEX infusion during elective LC. The primary efficacy outcome was: number of patients with severe pain. Secondary efficacy outcomes included: time to first use of rescue analgesia; postoperative morphine consumption; intraoperative fentanyl consumption; time from end of surgery to extubation; lengths of intensive care unit (ICU) and general ward stay; degree of postoperative pain 3, 6, 12 and 24 h after surgery; incidence of persistent post-surgical pain.A randomized, single-centre, controlled study was carried out between May 2016 and June 2017 at the Department of Surgery, Anesthesiology and Intensive Care of the Postgraduate Institute of Bogomolets National Medical University, Kiev, Ukraine. The study design was approved by the Ethical Committee at Bogomolets National Medical University.Sixty patients who elected to undergo LC were included in the study. Inclusion criteria comprised age 18–79 years and American Society of Anesthesiology (ASA) physical status I–II. Exclusion criteria were pregnancy or lactation, severe systemic disease  and use of beta-blockers or calcium-channel blockers.After the primary patient assessment, eligible participants were assigned in a 1:1 ratio to either the intervention (Group D) or control (Group C) groups using random assignment in blocks of four. The randomization sequence was generated using a computer algorithm. Randomization and data analysis were conducted by an independent blinded member of the research team, so the PROBE design was used .Group D received a 0.5 μg/kg/h DEX infusion from induction of anaesthesia to extubation and Group C received a normal saline infusion. To prepare the infusion, 2 ml of DEX containing 100 μg of the drug was diluted to 50 ml with normal saline, resulting in a final concentration of 4 μg/kg. DEX or normal saline infusion was given via a BBraun Space infusion pump.After transferring the patient to the operation room, a Philips vital signs monitor and bispectral index (BIS) and analgesia nociception index (ANI) monitors were attached to determine pulse, heart rate, electrocardiogram (ECG), arterial pressure (AP) and oxygen saturation. A peripheral intravenous cannula was inserted for intravenous (i.v.) fluids and an infusion pump (separate line). Patients did not receive premedication. Before induction they received 50 mg of i.v. dexketoprofen and 40 mg of omeprazole.2 level of 35–45 mmHg. The BIS monitor target was 40–60 and the ANI monitor target was 50–70. Anaesthetics and drug infusions were stopped at the end of surgery.Pre-oxygenation was performed for 2 min before induction of anaesthesia with 2 mg/kg i.v. propofol and 1.5 mg/kg i.v. succinylcholine. After intubation, anaesthesia was maintained with sevoflurane and atracurium bromide. Patients were ventilated using a circle system with a target COThe primary efficacy outcome was: postoperative morphine consumption during first 24 h and cumulative during hospital stay. Subcutaneous injection of 5 mg morphine hydrochloride was used as a rescue analgesic, patient control analgesia (PCA) was not used in this study.time to first use of rescue analgesianumber of patients with severe painintraoperative fentanyl consumptiontime from end of surgery to extubationlengths of intensive care unit (ICU) and general ward staydegree of postoperative pain 3, 6, 12 and 24 h after surgeryincidence of persistent post-surgical pain (6 month after surgery).Secondary efficacy outcomes included:Time to first use of rescue analgesia was estimated as the time from the end of anaesthesia to the time postoperatively when the patient requested analgesia or had a VRS score of ≥4. Severe pain was estimated using a verbal rating scale (VRS)  and defiDuring the first 48 h after surgery, patients in both groups were evaluated by the nursing staff using the Richmond Agitation-Sedation Scale (RASS) for sedation (every 2 h) and the VRS .Safety was assessed by monitoring vital signs and recording adverse events. During anaesthesia, all patients underwent continuous ECG, BIS, pulse oximetry and capnographic monitoring. AP was measured every 3–5 min. An adverse event was recorded if systolic blood pressure was < 90 or > 160 mmHg or if heart rate was < 50 or > 110 beats/min. Interventions for bradycardia, tachycardia, hypertension and hypotension comprised titration or interruption of study agent or additional drug therapy. Postoperative sedation was recorded if the patient had a RASS score of ≤ − 3 during the 24-h period after surgery.Persistent post-surgical pain was evaluated 6 month after surgery using the following criteria : the paip-value of < 0.05 was considered significant.Sample size was calculated using MedCalc Software version 16.8.4 . Based on minimum mean difference of 25% in morphine consumption  with α =A total of 60 patients were randomized (30 in each group). There were no significant differences between the study groups regarding demographic characteristics, comorbidities or ASA physical status Table .Table 1Dp = 0.04), a significantly longer time to first use of rescue analgesia (p = 0.001) and a marked decrease in postoperative morphine consumption . There were also no differences in the lengths of ICU stay or hospital stay between Groups D and C: 14 h (IQR 12–21 h) and 13 h (IQR 12–20 h), p = 0.9 and 72 h (IQR 70–80 h) and 74 h (IQR 72–82 h), p = 0.8, respectively. Also patients in Group D also had significantly lower intraoperative fentanyl consumption (p = 0.001), a shorter time from end of surgery to extubation (p = 0.001) and a decreased incidence of persistent post-surgical pain .The main outcomes of the study are presented in Tables Patients randomized to DEX were significantly less likely to experience post-operative nausea or vomiting or to develop hypertension or tachycardia Table . Few patUncontrolled postoperative pain is associated with increased morbidity and complications, prolonged hospital stays, and the risk of chronic postsurgical pain . OpioidsIntraoperative opioids could induce hyperalgesia, wich increase pain intensity and opioid consumption. While intraoperative DEX infusion may be a new and effective treatment option for preventing opioid-induced hyperalgesia .Study of Volkov et al.  reportedIn this randomized controlled study we have similar results, in patients undergoing elective LC, − DEX infusion was associated with a marked decrease in postoperative morphine consumption, lower incidence of severe postoperative pain, and significantly longer time to first use of rescue analgesia. However, the median pain intensity measured with a VRS did not differ between the groups 3, 6, 12 or 24 h after surgery. Other studies also shoved synergic action of intraoperative dexmedetomidine with local anesthetics on postoperative acute pain after craniotomy , morphinp = 0.7). Other studies showed a higher incidence of sedation in the DEX group, with a mean difference on the Ramsay Sedation Scale of 1.60 units (95% CI 1.49–1.71 units) [p = 0.005), which is similar with what was observed in another study [p < 0.0001). Similar results were reported by other authors [Regarding adverse events in this study, there was no inter-group difference in the incidence of postoperative sedation (1 units) , 19. Incer study . In our er study . Concern authors , 9, with authors . Other a authors .n = 70).The limitations of this study include the partially blinded design and the small sample size (Our trial supports the use of i.v. DEX as an analgesic adjuvant for LC and provides efficacy and safety data. In the authors’ opinion, we have enough data to consider DEX as a valid adjuvant to intraoperative opioids during elective LC.Intraoperative DEX infusion is a safe and effective method for improving analgesia during elective LC. DEX appears to significantly reduce the number of patients with severe postoperative pain, postoperative morphine consumption and prolong time to first use of rescue analgesia, while the incidence of postoperative nausea/vomiting or cardiovascular events is similar to or less than with saline control.


High post-operative pain scores after “minor” orthopedic/trauma surgery are in part attributed to inadequate prescription of opioid analgesics. Novel concepts aiming to achieve sufficient analgesia while minimizing opioid-related side effects by avoiding fluctuating plasma levels are based on perioperative oral administration of extended-release opioids beginning with the first dose pre-operatively. This is the first study to evaluate analgesic efficacy and side effect rates of extended-release tapentadol compared to oxycodone/naloxone following orthopedic/trauma surgery.This randomized, observer-blinded, active-controlled prospective clinical trial had 2 co-primary endpoints: (1) Analgesic efficacy: Mean pain level on a numeric rating scale (NRS) from 0 to 10 during exercise over 5 days. (2) Safety: Side effect sum score of the following events: Nausea, vomiting, constipation, sedation, vertigo, somnolence. The study was powered to detect superiority of tapentadol for at least one endpoint pending statistical proof of non-inferiority for both endpoints in a first step.n = 133) or oxycodone/naloxone (n = 133). Analgesic efficacy: Mean (±SD) daily pain levels in the first five post-operative days were 2.8 ± 1.3 in both groups. Mean maximum pain intensity during exercise in the first 24 h after surgery was 3.8 ± 1.9 (tapentadol) and 3.8 ± 2.1 . Statistically tapentadol was non-inferior but not superior to oxycodone/naloxone. Safety: Vomiting on day 1 occurred in 11%, constipation in 35% of the tapentadol patients and in 16% and 30% of the oxycodone/naloxone patients (p = 0.60 and 0.33), respectively. The incidence of sedation/ vertigo was <10%, that of somnolence <2% in both groups . The sum score of side effect events was 51% in the tapentadol vs. 49% in the oxycodone/naloxone group; risk difference 3% ; p = 0.6). Non-inferiority of tapentadol could not be concluded as the pre-defined non-inferiority margin was exceeded.Two hundred sixty-six trauma patients were randomized to receive either tapentadol ; October 24th, 2012.https://eudract.ema.europa.eu (EudraCT- Nr.  A large prospective cohort study comparing the painfulness of 179 surgical procedures revealed that even ‘minor’ operative procedures may be associated with considerable pain  to 10) [Previous studies have shown that preemptive analgesia regimens based on oral extended-release opioids  -starting with the first dose as premedication- provided improved pain control with a lower rate of side effects compared to conventional i.v. morphine PCA in spine and orthopedic surgery –6. HowevThe study design was based on equianalgesic starting doses – either 10 mg oxycodone or 50 mg tapentadol , 15–17.https://eudract.ema.europa.eu (EudraCT number 2011–003238-15) by Gertrud Haeseler October 2012. Principal investigator was Dirk Schaefers. The study was conducted at two hospital sites  operated by one trust  in cooperation with scientists affiliated at Hannover Medical School. Adult (≥ 18 years) trauma surgery patients ASA I-III were enrolled after written informed consent. Exclusion criteria were: inability to give informed consent, pregnancy or breast-feeding, pre-existing chronic pain treated with opiates, severe renal or hepatic impairment, and treatment with MAO- inhibitors.This randomized controlled observer-blind prospective clinical trial was approved by the German Competent Authority  and the Ethics Committee of Hannover Medical School (Nr 5897 M), and was registered at Patients were randomized to receive either the test intervention tapentadol ER  or the control intervention oxycodone/naloxone ER (Targin®) by the Institute for Biostatistics, Hannover Medical School. Randomization was stratified for sex and study site.The first dose of tapentadol (50 mg) or oxycodone/naloxone (10/5 mg) was given as premedication. The analgesic regimen then continued according to the initial allocation. Anesthesia was induced and maintained with propofol 4 mg/kg/h and remifentanil 0.15–0.25 μg/kg/min as total intravenous anesthesia (TIVA) adjusted to obtain stable cardiovascular parameters with no fluctuations in response to surgical stimuli. Adjunctive long-acting intravenous opioids and PONV prophylaxis were at the discretion of the anesthetist and subject to secondary analysis. Risk factors for post-operative nausea and vomiting (PONV) like female sex, no smoking habit, anticipated post-operative opioid analgesia and history of PONV were documented.Post-operative pain in the recovery room was treated with intravenous piritramide and the second oral dose of study medication. The patient was observed for an hour following the second dose of study medication and discharged when he was comfortable without further opioid requirement. The cumulative dose of oral study medication  established as effective  was continued 2× daily on the surgical ward. Analgesia was supplemented with non-opioids dipyrone or acetaminophen, and/or a coxib, respectively, to achieve a residual pain score up to 3–4. In case that this level of analgesia was not obtainable, a trauma surgery consultant was involved to address surgical reasons. If there were none, opioid doses were increased. The doses of coxibes were not standardized in this study as we included ASA I-III patients and had no restrictions with respect to higher age, cardio-vascular disease and /or moderately comprised renal function- which may represent contra-indications for the use of coxibes. Thus, coxibes were prescribed after individual risk/benefit-analysis.Nausea and vomiting: metoclopramide, ondansetron, dimenhydrinate and/or droperidolConstipation: As gastro-intestinal tolerability with respect to constipation is reported to be higher in both tapentadol and oxycodone/naloxone compared to oxycodone without naloxone, routine prophylactic laxatives are not generally recommended and we used the following rescue medication when constipation was observed: oral PEG 3350 (macrogol); oral sodium picosulfate, oral or rectal bisacodyl, oral lactuloseCentral-nervous side effects : Reduction of study medicationWhen pain intensities decreased, the study medication was stepwise reduced. The treatment algorithm is depicted in Fig. The maximum pain levels quantified by patients on a numeric rating scale (NRS) from 0 (no pain) to 10 (maximum conceivable pain) during exercise and at rest as well as opioid side effects incidence and severity were obtained once a day by a blinded investigator and 3-times daily by non-blinded staff. Constipation was noted when the patient had no daily defecation. Sedation included only mild levels of drowsiness with the patient easy to awake as opposed to somnolence where the patient was difficult to awake. All therapeutic interventions including dosing of the study medication, of additional non-opioid analgesics and rescue medication were documented by non-blinded investigators. Dosing of long-acting intravenous opioids during anesthesia and in the recovery room and PONV risk factors and prophylaxis were obtained from the anesthesia protocols. The primary endpoints were derived from blinded observations only.Analgesic efficacy defined as the mean NRS level during exercise over the 5 days observation period.Safety measured by the incidence and severity (score 1–2) of side-effects. Score 1 is side effect observed but no requirement for intervention, 2 is side effect requiring intervention. The sum scores for each side effect over the five days observation period were calculated (maximum: 10) as well as the overall sum score across all side effects (maximum: 60). We defined, that a patient had a relevant side effect event at a sum score over the 5-days observation period ofconstipation ≥1nausea ≥3vomiting ≥3somnolence ≥1sedation ≥3vertigo ≥3, and/oroverall sum score ≥ 5.There were 2 co-primary endpoints:The primary endpoint was occurrence/non-occurrence of relevant side effect events. The differential weighted ranking of the severity of the side effects took into account that constipation and somnolence are potentially dangerous, resulting in either bowel paralysis or respiratory depression. Nausea, vomiting, sedation and vertigo were considered clinically relevant only if they persisted at least during two days of opiate therapy with intervention, or during three days without intervention. The decision to intervene in case of side effects was individualized according to the patient’s need.tapentadol is non-inferior to oxycodone/naloxone regarding pain during exercise with a non-inferiority margin of 1, andtapentadol is non-inferior to oxycodone/naloxone regarding occurrence of relevant side effects with a non-inferiority margin of 5%, andeithertapentadol is superior to oxycodone/naloxone regarding pain during exerciseortapentadol is superior to oxycodone/naloxone regarding occurrence of relevant side effects (or both (3) and (4)).Superiority of the tapentadol-based regimen would only be concluded when tapentadol was superior in at least one of the co-primary endpoints (pain or side effects) and not inferior in any of the two co-primary endpoints. Thus, the study formally had four primary objectivesMean NRS-level at restSeparate analysis of patients with high pain scores at the end of the observation period (NRS ≥ 5)Required daily doses of study medication, concomitant non-opioid medication and intra-operative long-acting intravenous opioidsType and dosing of rescue medicationAnalysis of expected and unexpected adverse eventsTotal duration of post-operative opioid requirementPatient satisfaction at the end of the 5 days observation periodn = 123 patients per group as calculated for hypothesis (4). A low drop-out rate (<5–10%) was expected due to the inpatient setting and the short duration of observation. The final sample size to be recruited was increased to n = 133 patients per treatment arm.Sample size estimation was performed in nQuery Advisor 7.0. It was predefined that the tapentadol-based regimen was superior if three of the four hypotheses were proven. The one-sided type-I-error was α = 2.5% for the non-inferiority hypotheses (1) and (2) and α = 1.25% for the superiority hypotheses (3) and (4) with a Bonferroni-correction. In order to reach an overall power of 80%, the power for each objective was set to 93%. A two-group t-test, and a two-group t-test for equivalence, respectively, were used for sample size calculation for the objectives related to pain. For the objectives related to the occurrence of side effects, a chi-square test with continuity correction and an equivalence test for the comparison of two proportions were used. Data were available from a phase III clinical study showing a more than 5% higher incidence of gastro-intestinal side effects with oxycodone compared to tapentadol , and froIn the analysis of the non-inferiority hypotheses, the per-protocol (PP) population was used. Superiority hypotheses were evaluated in the intention-to-treat (ITT) population. For the analysis of pain during exercise, a linear regression model was applied with the mean pain level of the first 5 post-operative days as dependent variable, and treatment, center and sex as independent factors. The treatment difference in pain and the corresponding 95% confidence interval (CI) were derived from the regression analysis and compared to the predefined non-inferiority margin of 1. Evaluation of treatment differences in the occurrence (yes/no) of relevant side effects was done using a Mantel-Haenszel-estimator for the risk difference, stratified by center and sex. The corresponding 95% confidence interval was calculated and compared to the predefined non-inferiority margin of 5%.Demographic and baseline characteristics, dosing of concomitant analgesic and rescue medication were compared by a two-sample t-test for numeric variables. Dichotomous secondary outcome data like incidence of side effect events yes/no were compared using a chi-square test. Associations between treatment group and secondary continuous outcome variables  were analysed by linear regression with study medication as independent factor adjusted for study site and sex. Effect sizes are presented as differences in means with corresponding 95% CIs. The primary analysis was adjusted for sex and study site. The influence of further risk factors, e.g. BMI as continuous variable or PONV prophylaxis, was analysed by extended regression models . Again, linear regression was used for continuous outcomes. Logistic regression was used for categorical outcomes, especially occurrence of side effects. Odds ratios with corresponding 95% CIs are presented.n = 133) and oxycodone/naloxone (n = 133) within a time frame of two years. Only two patients were lost to follow-up , see Fig. A total of 831 patients were assessed for eligibility. Of these, 266 patients were randomized to tapentadol . Mean maximum pain intensity during exercise in the first 24 h after surgery was 3.8 ± 1.9 (tapentadol) and 3.8 ± 2.1 . Pain intensities during exercise decreased with time to a mean level of 2.0 ± 1.7 (tapentadol) versus 2.0 ± 1.5  on day 5. Maximum pain levels during exercise over five post-operative days beginning with the day of the operation (day 1) are depicted in Fig. Mean adjusted daily pain levels during exercise in the first five post-operative days were 2.8 ± 1.3  and 2.8 ± 1.3 . In the tapentadol group patients had received lower doses of long-acting opioids intra-operatively ). There was no difference between the groups with respect to post-operative piritramide requirement and concomitant non-opioid analgesic medication (see There was a weak association between the cumulative dose (mg ME) of intra-operative i.v. opioids other than the short-acting remifentanil  and pain reduction during exercise on day 1 . The incidence of constipation was 35% in the tapentadol vs. 30% in the oxycodone/naloxone group (p = 0.33). The incidence of a sedation/ vertigo event was <10%, somnolence <2% in both groups . The incidence of side effect events in the two groups is depicted in Table p = 0.6), non-inferiority of tapentadol could not be concluded because the upper bound of the 95% confidence interval for the risk difference  was 14% and thus exceeding the predefined non-inferiority margin of 5%.Vomiting on day 1 occurred in 11% of the tapentadol and in 16% of the oxycodone/naloxone patients (The unadjusted risk for nausea and vomiting was lower in the tapentadol group (Odds Ratios of 0.6 and 0.4), while the risk of constipation was higher (Odds Ratio 1.3). However, a multivariate regression analysis including PONV prophylaxis and risk factors to the logistic regression model revealed that the differences in the incidence of PONV between the treatment groups could be explained by confounding effects of PONV risk factors and PONV prophylaxis, now only leading to a treatment Odds Ratio of 0.98. Type and dose of rescue medication against nausea, vomiting and constipation is depicted in Incidence and severity of central-nervous side effects was low in both treatment arms. Somnolence was noted in three patients allocated to tapentadol and in one patient allocated to oxycodone/naloxone. In one patient (tapentadol) the finding of somnolence in the blinded observation was not consistent with the unblinded observation. In the three other cases, passing somnolence was noted in the immediate post-operative period in the intermediate-care unit in higher aged patients not requiring discontinuation of study medication.p = 0.3. Mean maximum pain at rest in the first 24 h after surgery was 2.6 ± 2.0 (tapentadol) and 2.8 ± 2.0  and decreased to 0.8 ± 1.0 (tapentadol) and 1.0 ± 1.4  on day 5. Maximum pain levels at rest over five post-operative days beginning with the day of the operation (day 1) are depicted in Fig. Mean pain at rest in the first five post-operative days was 1.5 ± 1.1  versus 1.7 ± 1.2 . Daily doses of post-operative study medication during the 5-days observation period are depicted in Fig. Mean equianalgesic daily dose of study medication over the 5-days observation period did not differ between the groups. The mean daily oxycodone equivalent dose was 19.0 ± 9.4 mg (tapentadol) versus 18.5 ± 9.4 mg . Analyses additionally adjusted for BMI gave the same results like the primary analysis. Female sex was an independent risk factor for the occurrence of side effects . BMI had no significant influence on the incidence of side effects .The effect of female sex on pain during exercise was not significant  and only 60% of patients received intra-operative sufentanil or fentanyl at study site 1 (compared to 90% at study site 2). Mean daily pain intensities were significantly higher at study site 1 compared to study site 2: Mean pain during exercise was 3.1 ± 1.4  vs. 2.5 ± 1.2 . Patients at study site 1 received higher mean daily doses of study medication for the first three days. Mean daily oxycodone equivalent dose over 5 days was 20.3 ± 9.1 mg (study site 1) vs. 17.3 ± 9.5 mg . As a consequence, the incidence of relevant AEs was 62% at study site 1 compared to 38% at study site 2 (p < 0.001). Study site 1 was associated with a higher risk for side effects in the multivariate logistic regression model, probably as a result of higher doses of study medication .Subgroup analysis of the primary hypotheses at the two study sites yielded the same results as the primary analysis. However, there were differences between the study sites which, apparently, did not affect the primary results: Mean (±SD) duration of the operation was 88 ± 44 min. at study site 1 and 68 ± 38 min. at study site 2  had developed anxiety disorder with high pain scores unresponsive to opioid medication, in one patient (tapentadol) high pain scores were resulting from pre-existing spinal stenosis, not from pain at the operation site which was well controlled with low doses of study medication.p = 0.95). Most patients were satisfied with their treatment. On a scale of 0 (very satisfied) to 10  the mean score was 2.3 in the tapentadol group and 2.1 in the oxycodone/naloxone group . Patient satisfaction scores are depicted in Fig. There were no differences regarding mean treatment duration with study medication  were <4 in our study in both groups- compared to 6–7 for trauma/orthopedic surgery in the large prospective cohort study presented by Gerbershagen et al. [ were <4 Our main hypothesis -non-inferiority of tapentadol compared to oxycodone/naloxone regarding pain during exercise- was confirmed, but neither non-inferiority of tapentadol with respect to side effect incidence nor superiority for analgesic efficacy and/ or side effect incidence could be established.Still, the remarkably low median level of pain at rest on day 1 in the tapentadol group seen in our study merits further attention as it has been suggested that adrenergic descending inhibitory systems might be of potential relevance in (1) attenuating remifentanil-induced post-infusion hyperalgesia and anti-analgesia , and (2)The lower incidence of nausea and vomiting seen in tapentadol-treated patients could in part be explained by confounding factors of PONV (patients in the tapentadol group received more frequently a prophylaxis). Due to the differing use of PONV prophylaxis we could not show superiority of tapentadol with respect to PONV in this study. It has previously been established that the prevalence of nausea and vomiting in patients requiring opioids for post-operative analgesia (i.e. that have at least one risk factor) ranges between 21 and 79% . The comBoth oxycodone/naloxone and tapentadol were associated with a lower risk of constipation in trauma surgery patients compared to oxycodone without naloxone where the risk of constipation was 46% in trauma surgery patients .However, despite higher gastro-intestinal tolerability of oxycodone/naloxone and tapentadol compared to i.v. opioids or oxycodone without naloxone, the problem of opioid-induced gastro-intestinal side effects in trauma surgery patients is not yet solved. Thus, based on our results, we recommend that established principles for the prophylaxis against PONV and opioid-induced constipation are pre-emptively applied in trauma surgery patients receiving opioids. Severe central nervous side effects like somnolence and/or confusion were rare (< 2%) and probably unrelated to study medications as neurologic function recovered spontaneously while study medication was continued. Only in one patient receiving 20/10 mg daily dose of oxycodone/naloxone study medication had to be discontinued due to delirium. No patient had opioid induced respiratory depression that required reversal with iv naloxone. Anxiety, sleeplessness and agitation was only seen in patients allocated to oxycodone/naloxone- in one patient anxiety resolved when oxycodone/naloxone was discontinued, in four cases agitation and sleeplessness occurred when oxycodone/naloxone had been withdrawn. These results indicate that psychomimetic effects of oxycodone and oxycodone withdrawal might constitute a problem even during short-term use.The primary results on the effects of study medication were reproduced at two different study sites- despite the differences between the study sites with respect to duration of the operations and intra-operative opioid analgesic management. The fact that there was no association between sex, BMI and post-operative pain during exercise in trauma/orthopedic surgery is in accordance with a recent study showing no sex difference in post-operative pain in the joint surgery group .In six /264 patients no acceptable pain relief (NRS < 5) was provided by either treatment until day 4 or 5 of treatment duration. In three patients management has been inadequate (study medication discontinued at an early stage). In the three remaining patients, not responding to either tapentadol or oxycodone/naloxone was indicative of either a surgical problem or a wider, more complex medical issue  requiring particular attention by an experienced pain specialist. Thus, as previously suggested , it seemThe aim of our study was to evaluate and compare the efficacy and safety of both opioid-based analgesic regimens under the conditions of daily practice in our trauma surgery departments. As a consequence, there was a considerable heterogeneity in the types of surgeries performed, even within one category  which might constitute a confounding factor. The postoperative exercise protocols differed with regard to the degree of mobilization and pain intensity. Still, it is interesting to note that while joint procedures are usually predicted to have the greater post-procedural pain, the amount of morphine equivalents consumed within that surgical category was similar to all other categories. Reconstructions of ligaments and muscle like rotator cuff repair or anterior cruciate ligament reconstruction were associated with the highest doses of study medication. However, the relatively small subgroup sizes limit the generalizability of these results. Another shortcoming of our study was the lack of patient blinding which might have biased the results.Both the tapentadol- as well as the oxycodone/naloxone-based perioperative multimodal oral analgesia concept provided reliable post-operative pain relief with mean pain scores over five days below 2 at rest and below 3 during exercise. The most common side effects were gastro-intestinal implying that trauma surgery patients receiving opioids might benefit from a routine prophylaxis against PONV and constipation. Analgesic failure with high pain levels at the end of the observation period despite continuing opioid medication was low (<2%) – and indicative of either a surgical problem or a complex pain condition independent from surgery. Severe anxiety and signs of withdrawl even after short-term use was only seen in oxycodone/naloxone- treated patients.This study supports the existing clinical evidence in favor of the peri-operative use of oral extended-release opioids. Severe opioid-induced side effects like respiratory depression resulting in hypoxemic brain damage or death have been shown to be almost entirely associated with parenteral routes of opioid administration or combinations of different opioids . For saf


Fibromyalgia is a chronic pain state that includes widespread musculoskeletal pain, fatigue, psychiatric symptoms, cognitive and sleep disturbances, and multiple somatic symptoms. Current therapies are often insufficient or come with significant risks, and while there is an increasing demand for non-pharmacologic and especially non-opioid pain management such as that offered through complementary and alternative medicine therapies, there is currently insufficient evidence to recommend these therapies. Percutaneous electrical neural stimulation (PENS) is an evidence-based treatment option for pain conditions that involves electrical current stimulation through needles inserted into the skin. Percutaneous electrical neural field stimulation (PENFS) of the auricle is similar to PENS, but instead of targeting a single neurovascular bundle, PENFS stimulates the entire ear, covering all auricular branches of the cranial nerves, including the vagus nerve. The neural mechanisms of PENFS for fibromyalgia symptom relief are unknown.We hypothesize that PENFS treatment will decrease functional brain connectivity between the default mode network (DMN) and right posterior insula in fibromyalgia patients. We expect that the decrease in functional connectivity between the DMN and insula will correlate with patient-reported analgesic improvements as indicated by the Defense and Veterans Pain Rating Scale (DVPRS) and will be anti-correlated with patient-reported analgesic medication consumption. Exploratory analyses will be performed for further hypothesis generation.A total of 20 adults from the Atlanta Veterans Affairs Medical Center diagnosed with fibromyalgia will be randomized into 2 groups: 10 subjects to a control (standard therapy) group and 10 subjects to a PENFS treatment group. The pragmatic, standard therapy group will include pharmacologic treatments such as anticonvulsants, non-steroidal anti-inflammatory drugs, topical agents and physical therapy individualized to patient comorbidities and preferences, prescribed by a pain management practitioner. The PENFS group will include the above therapies in addition to the PENFS treatments. The PENFS subject group will have the Neuro-Stim System placed on the ear for 5 days then removed and replaced once per week for 4 weeks. The primary outcome will be resting functional magnetic resonance imaging connectivity between DMN and insula, which will also be correlated with pain relief and functional improvements. This connectivity will be analyzed utilizing functional connectivity magnetic resonance imaging (fcMRI) and will be compared with patient-reported analgesic improvements as indicated by the DVPRS and patient-reported analgesic medication consumption. Pain and function will be further evaluated using Patient-Reported Outcomes Measurement Information System measures and measures describing a person’s functional status from Activity and Participation section of the International Classification of Functioning Disability and Health.This trial has been funded by the Veterans Health Administration Program Office. This study attained approval by the Emory University/Veterans Affairs (VA) institutional review board and VA Research & Development committee. Institutional review board expedited approval was granted on 2/7/17 (IRB00092224). The study start date is 6/1/17 and estimated completion date is 5/31/20. The recruitment started in June 2017.This is a feasibility study that is meant to demonstrate the practicality of using fcMRI to study the neural correlates of PENFS outcomes and provide information regarding power calculations in order to design and execute a larger randomized controlled clinical trial to determine the efficacy of PENFS for improving pain and function.ClinicalTrials.gov NCT03008837; https://clinicaltrials.gov/ct2/show/NCT03008837 (Archived by WebCite at http://www.webcitation.org/6wrY3NmaQ). Fibromyalgia is a chronic pain syndrome that affects multiple body systems and is characterized by widespread pain, decreased physical function, fatigue, psycho-emotional and sleep disturbances and various somatic complaints ,2. It afFibromyalgia remains a poorly understood condition with regards to pathophysiology of the disease process, though maladaptive plasticity in the central  nervous system has been strongly implicated . CurrentAlthough the precise pathophysiology of fibromyalgia is not fully understood, there is a large consensus that it is a sympathetically or centrally mediated pain syndrome ,10,11,12Percutaneous electrical neural stimulation (PENS) involves the placement of needles near neurovascular bundles within a sclerodermal, myodermal or dermatomal distribution and delivering current to these structures . The MilPENFS of the auricle is similar to PENS, but instead of stimulating a certain neurovascular bundle it stimulates the entire ear and all the auricular branches of the cranial nerves, including the vagus nerve. The vagus nerve mediates sensation of the auricular tissue that makes up the ear; therefore, auricular stimulation has been used to modulate its activity and treat pain . NapadowAlthough vagal nerve stimulation for pain relief has been studied, the mechanisms supporting PENFS stimulation to the auricle has not yet been studied with functional magnetic resonance imaging (fMRI) . The basThis study attained approval by the Emory University/Veterans Affairs (VA) institutional review board and VA Research & Development committee. The study protocol will be conducted in accordance with ethical principles from the Declaration of Helsinki.The specific aims of the study are (1) to evaluate the feasibility of using fcMRI as a biomarker for functionally correlated neural substrates of pain in patients undergoing PENFS and (2) to evaluate whether PENFS leads to analgesia and functional improvements as compared to standard treatment in veterans with fibromyalgia. Our primary hypothesis is that PENFS will result in decreased functional connectivity between the insula and default mode network as evaluated by fMRI ,25,26,27This is a feasibility trial comparing PENFS to standard therapy in veterans with fibromyalgia. Enrollment according to the stated inclusion and exclusion criteria will be conducted and subjects who meet study criteria will undergo baseline assessments. These include a collection of bio-behavioral data such as cognitive and psychological assessments, eating, sleeping and drinking habits, and Patient-Reported Outcomes Measurement Information System (PROMIS) measures including physical function, anxiety, depression, fatigue, sleep disturbance, social function, pain interference, and global health. In addition, included are measures from the realms “Activity and Participation” from the International Classification of Functioning, Disability, and Health including arm curls, 30 second chair stands, and handgrip strength tests. Information from the Defense and Veterans Pain Rating Scale (DVPRS), and documented baseline analgesic consumption will also be included. Stratification based on age and sex will be performed to account for differential pain perception and neurological responses to pain based on age and gender. fMRI studies will then be conducted within 2 weeks prior to initiation of treatment and will be repeated within 2 weeks after the final treatment. Participants are advised to avoid caffeine and smoking the day of the neuroimaging analysis. The bio-behavioral assessments will be repeated at 4, 8, and 12 weeks after the final treatment.The PENFS subject group will have the NSS placed on the ear for 5 days then removed and replaced at weekly intervals. The PENFS group will receive treatments once per week for a total of 4 weeks. Participants will be randomized to one of the two treatment groups. See The fMRIs will occur at an Emory Imaging Center. All other visits will be conducted at the VA pain clinic in Atlanta, GA.Male and female Veterans age 20-60 with a diagnosis of fibromyalgia as diagnosed by a clinician, by chart review, and by the most recent American College of Rheumatology 2010 criteria for the diagnosis of fibromyalgia. The inclusion and exclusion criteria are listed in Subjects will be randomized to one of two groups; the control group will be standard therapy and the treatment group will be the PENFS treatment for this feasibility study. Simple randomization stratified by age and sex with equal allocation to treatment and control groups will be used. An age of 60 years old is set as a limit to minimize brain structural changes due to aging . SubjectThe primary outcome measure is connectivity between the insula and DMN. Areas of the DMN found to be relevant in prior studies regarding fibromyalgia are the inferior parietal lobule (IPL), medial prefrontal cortex (MPFC), and posterior cingulate cortex (PCC) . Based oInclusion Criteria:Subjects must be male and female Veterans age 20-60 with a diagnosis of fibromyalgia as diagnosed by a clinician, by chart review, and by the most recent American College of Rheumatology 2010 criteria for the diagnosis of fibromyalgia ,29.Subjects must self-report consistent, daily pain (greater than 5 on a 0-10 VAS) >90 days.Subjects must have intact skin free of infection at the site of implantation.Subjects must be willing to participate and understand the consent.Subjects must be right-handed in order to provide consistency in brain structure and function.Exclusion Criteria:Subjects must not be currently pregnant, since effects of fMRI and electrical current on the developing fetus are not well-known.Subjects must not have an implanted electrical device such as a vagal stimulator, pacemaker, or spinal pain pump, which are not compatible with MRI.Subjects must not have a history of seizures or neurologic condition that may alter the structure of the brain.Subjects must not have a history of drug abuse or severe, uncontrolled psychiatric illness such as schizophrenia or major depressive disorder with suicidal ideation.Subjects must not have psoriasis vulgaris or other skin conditions that may increase the risk of infection at the implantation site.Subjects must not have severe anxiety, claustrophobia, or other conditions that may prevent their ability to lie at rest in an MRI scanner. This will be determined after discussion with the patient regarding their own perceived ability to lie at rest in an MRI scanner without the use of additional sedating medications.Subjects must not introduce new medications or treatments for fibromyalgia symptoms during the course of the study, expect for those prescribed by the pain practitioners involved in the study, to prevent confounding results.Subjects must not have a concurrent autoimmune or inflammatory disease that causes pain such as systemic lupus erythematosus, inflammatory bowel disease or rheumatoid arthritis, since this could decrease the effect of treatment.Subjects must not experience trauma, injury or severe disease during the course of the study.The secondary outcome is whether functional improvements occur with the application of PENFS, as the ultimate goal of reducing pain is to improve function. Secondary dependent variables for the evaluation of functional improvements with PENFS include PROMIS and International Classification of Functioning, Disability, and Health measures, the arm curl, 30 second chair stand and handgrip strength tests. These tests will be performed before treatment initiation and again at 4, 8 and 12 weeks follow-up after the completion of the 4-week treatment period for comparison.There will be a total of 20 subjects divided into 2 groups, 10 subjects in the control (standard therapy) group and 10 subjects in the PENFS treatment group. Age, gender, and comorbid conditions may confound effects on neurological response to pain, therefore subjects will be block randomized, stratified by age and sex. This will result in an adequate sample size while minimizing confounding variables between groups. Roberts and Brown demonstrated a decrease in VAS for pain using a series of 4 PENFS treatments in a cohort of 20 chronic pain patients . Based oOur study is a feasibility study being conducted with the purpose of providing better estimates of effect size and power calculations for sample size in future studies. The data gathered from this study will be used to inform power analyses for a future pilot study or randomized control trial. Therefore, we will have a power analysis after completing the study. Recruitment will be performed through direct contact with patients at the pain clinic, and by letter invitation to veterans in the Atlanta VAMC system identified as carrying a diagnosis of fibromyalgia. Patients not already established in the pain clinic will only be contacted by study personnel with permission from the primary care physician.There are sufficient numbers of patients at the Atlanta VAMC from which to recruit fibromyalgia patients, and due to the principal investigator’s role as a pain management physician, she has sufficient exposure to fibromyalgia patients within her own clinical practice. In order to demonstrate the feasibility of recruitment, we performed a data query for the Atlanta VA medical center, excluding satellite clinics, and found that over the course of a 1-year period , a total of 1,451 unique veterans were seen who carried a diagnosis of fibromyalgia. In age groups < 50 years old, there is a preponderance of females who carry the diagnosis, while in age groups > 50 years old, there is a preponderance of males. This is likely due to a gender difference in military enrollment in these age groups. The ratio of female to male veterans with fibromyalgia is more reflective of the general population in the <50-year-old age groups. On average, 2 patients are seen in the VA pain clinic with fibromyalgia per day, with 10 fibromyalgia patients a week. Of these, 60% would qualify for the present investigation. This is a conservative estimate. The prevalence of patients with fibromyalgia seen at the Atlanta VAMC and the pain clinic supports the feasibility of the study, given the planned recruitment of 20 study subjects from a population of at least 1,451 local veterans who carry the diagnosis of fibromyalgia, many of whom have been referred to and are followed in the pain clinic. We have allotted 6-9 months to recruit all patients. Given that 5 patients have already been recruited within 3 weeks of beginning the study, we don’t expect recruitment to be an issue.In previous studies, the IPL, MPFC, and PCC are DMN regions that have been found to be relevant regarding fibromyalgia ,27,28,29P<.010, and cluster size of 20 for the two correlations for each group. Patient-reported changes in pain will be evaluated using (1) DVPRS severity scores and (2) analgesic consumption before and after treatment (4 weeks) and at long-term follow-up  following the 4th week of treatment for each group. We will use 2 groups (PENFS versus control) 4 times  for repeated measures analysis of variance to compare outcome for the groups over time. We will employ a generalized linear mixed model (GLMM) framework to fit the ANOVA model to the data. GLMM approach is more robust than traditional ANOVA methods as it better handles the possibility for imbalance in the effects due to dropout and other losses to follow-up and provides a stronger estimate of the fixed group effect while controlling for time as a random effect in the model. After the completion of the above analyses, we will use Spearman Rank correlation coefficients to investigate the predictive ability of pre-PENFS (baseline) resting insula connectivity to predict post-PENFS changes in pain levels. Baseline connectivity will be extracted as z-scores from imaging data. Categorical variables such as gender and bio-behavioral data will be assessed using Fisher’s exact test, but continuous variables such as age will be assessed using two-tailed t-tests. All reported P values will be 2-tailed and considered significant at the .05 level, FWE corrected.The primary outcome measure is connectivity between the insula and DMN as a biomarker for pain. Based on previous research, we hypothesize that the addition of PENFS will decrease connectivity between the insula and DMN structures relative to standard treatment ,25,26,27We will also perform a linear regression with z-scores from fcMRI correlations and baseline pain levels using the DVPRS in order to evaluate links between baseline resting insula connectivity and baseline individual differences in pain sensitivity. In addition, we will also use a linear regression model to assess any association between treatment-modulated clinical pain and changes in the posterior insula resting brain connectivity.P<.050. Similar analyses will be conducted at 6 and 12 weeks follow-up. Data from each time point can be considered its own family of comparisons for this purpose. Further, analysis of sample characteristics for the groups, PENFS versus control, will be conducted to assess comparability of the samples. Categorical variables such as gender and bio-behavioral data will be assessed using Fisher’s exact test, but continuous variables such as age will be assessed using two-tailed t-tests. All reported P values will be 2-tailed and considered significant at the .05 level, FWE corrected. Data collected and analyzed regarding functional changes related to PENFS treatment will be assessed for new hypothesis generation.The secondary outcome is whether functional improvements occur with the application of PENFS, as the ultimate goal of reducing pain is to improve function. Secondary dependent variables for the evaluation of functional improvements with PENFS include PROMIS and International Classification of Functioning, Disability, and Health measures, the arm curl, 30 second chair stand and handgrip strength tests at 4, 8, and 12 weeks follow-up after the completion of the 4-week treatment period. Pairwise repeated measures comparisons between pretreatment and posttreatment DVPRS, analgesic consumption and functional assessments will be performed within each group, FWE corrected to This trial has been funded by the Veterans Health Administration Program Office. This study attained approval by the Emory University/VA institutional review board and VA Research & Development committee. Institutional review board expedited approval was granted on 2/7/17 (IRB00092224). The study start date is 6/1/17 and estimated completion date is 5/31/20. The recruitment started in June 2017.Fibromyalgia is a syndrome that, despite affecting millions of Americans, remains a difficult condition to treat. The current therapies continue to fall short and many times leave these patients with intolerable side effects. PENFS is a Food and Drug Administration approved, non-pharmacologic therapy that is currently utilized within the military and VA system, but sufficient evidence regarding its outcomes and neural mechanisms have not been adequately investigated. Auricular PENFS has not been studied with fMRI. Stimulation of the auricle may produce neural changes that differ from traditional therapies. Understanding the underlying neural mechanisms of auricular PENFS could assist in developing targeted treatments for fibromyalgia and chronic pain. An understanding of its neural underpinnings and analgesic effects could lead to improvements in pain management and quality of life, cost-savings, and development of new techniques to address pain.The present investigation is a feasibility study being conducted with the purpose of providing better estimates of effect size and power calculations for sample size in future studies. The data gathered from this study will be used to inform power analyses for a future pilot study or randomized control trial. This study will not only serve to elucidate neural changes with PENFS, but could provide evidence regarding the relative effectiveness of this already clinically employed non-pharmacologic treatment. This in turn can result in evidence-based implementation that be utilized to treat not only veterans suffering from fibromyalgia but also all fibromyalgia patients. Informed consent will be obtained from all trial participants.


Chronic face pain syndrome is a diagnostic and therapeutic problem for many specialists, and this proves the interdisciplinary and complex nature of this ailment. Physiotherapy is of particular importance in the treatment of pain syndrome in the course of temporomandibular joint functional disorders. In patients with long-term dysfunction of masticatory muscles, the palpation examination can localize trigger points, that is, thickening in the form of nodules in the size of rice grains or peas. Latent trigger points located in the muscles can interfere with muscular movement patterns, cause cramps, and reduce muscle strength. Because hidden trigger points can spontaneously activate, they should be found and released to prevent further escalation of the discomfort. Kinesiotaping (KT) is considered as an intervention that can be used to release latent myofascial trigger points. It is a method that involves applying specific tapes to the patient's skin in order to take advantage of the natural self-healing processes of the body. The aim of the study was to evaluate the effect of the kinesiotaping method and trigger points inactivation on the nonpharmacological elimination of pain in patients with temporomandibular disorders. The study was conducted in 60 patients (18 to 35 years old). The subjects were randomly divided into two subgroups of 30 people each. Group KT (15 women and 15 men) were subjected to active kinesiotaping application. Group TrP, composed of 16 women and 14 men, was subjected to physiotherapy with the release of trigger points by the ischemic compression method. The results show that the KT method and TrP inactivation brought significant therapeutic analgesic effects in the course of pain-related functional disorders of the muscles of mastication. The more beneficial outcomes of the therapy were observed after using the KT method, which increased the analgesic effect in dysfunctional patients. Chronic myofascial pain syndrome is a diagnostic and therapeutic problem for many specialists, such as dentists, laryngologists, neurologists, neurosurgeons, general surgeons, anesthetists, psychiatrists, and oncologists . This inThe role of occlusal and nonocclusal parafunctions is emphasized potential etiological factors, along with malocclusion, missing teeth in the lateral areas, macro- and microinjuries of the joint, stress leading to hyperactivity of the masticatory muscles, the activation of masticatory muscles by the route descending from the limbic system and reticular formation, the lack of effective contraction of both lateral pterygoid muscles, and rheumatic diseases .The multiple manifestations of the symptoms lead to a multitude of treatment methods and indicate that there is still no consensus in understanding the pathophysiology of the underlying TMD mechanisms. Because of the heterogeneity of the causes, the treatment of pain syndrome in the course of temporomandibular dysfunction should have a multiprofile character , 9.Temporary pain relief can be obtained by pharmacological treatment with nonsteroidal anti-inflammatory drugs. Drugs that reduce muscle tone, antidepressants, and intra-articular steroids are also used. Dental treatment includes the use of, among others, flexible or hard occlusal splints –12. PhysIn patients with long-term dysfunction of masticatory muscles, the palpation examination can localize trigger points, that is, thickening in the form of nodules in the size of rice grains or peas. These are muscle fibres with increased tension, felt as thickening in the course of the muscle fibres. Latent trigger points located in the muscles can interfere with muscular movement patterns, cause cramps, and reduce muscle strength. Because hidden trigger points can spontaneously activate, they should be found and released to prevent further escalation of the discomfort . PhysiotThe aim of the study was to evaluate the effect of the kinesiotaping method and trigger points inactivation on the nonpharmacological elimination of pain in patients with temporomandibular disorders.The study was conducted during the years 2015-2016 in 60 patients (18 to 35 years old). All qualified patients suffered from painful functional disorders within the masticatory muscles of myofascial characteristic. Patients were also tested by the research diagnostic criteria for temporomandibular disorders (RDC/TMD) introduced by Dworkin and LeResche in 1992 . This enThe exclusion criteria were as follows: regular drug therapy, mental illness, coagulopathy, diabetes, or chronic infections. The subjects were not addicted to nicotine, alcohol, or drugs. The participants with joint clicking and a clinical diagnosis of disc displacement were also excluded, and they were asked to refrain or not to use self-treatment during the therapy.The study was approved by the Bioethics Committee of the Pomeranian Medical University in Szczecin (KB–0012/36/15). It is in accordance with ethical standards; all participants signed written informed consent and were acquainted with the technique and the course of the research.The subjects were randomly divided into two subgroups of 30 people each. Group KT  were subjected to active kinesiotaping application  . SubjectGroup TrP, composed of 16 women and 14 men, was subjected to physiotherapy with the release of trigger points by the ischemic compression method, which was based on applying pressure to the active trigger point until it was switched off, that is, the pain disappeared . SubjectBefore performing the physiotherapeutic procedures in groups KT and TrP and after their application, all patients were subjected to diagnostic actions, including the measurement of pain intensity using the visual analogue scale (VAS). Two dentists were involved in the selection of participants. Only one physiotherapist performed KT applications and TrP therapies. The therapeutic effectiveness of the two methods was verified by comparing the mean values of pain intensity before and after performing the physiotherapeutic procedures. Changes in pain intensity were considered as dependent variable, while the therapy used and patients' gender and age were considered as independent variables.Prior to the examination, each patient gave written consent to participate in the therapy and was provided with information about the technique and the course of the tests. The protocol was developed in accordance with the latest version of the World Medical Declaration of the Helsinki Association . The patt-test. The linear regression models were also used to examine the influence of gender and age on treatment efficacy.The statistical analysis included determining the physiotherapeutic effects, examining the influence of gender and patient's age on the outcomes, and comparing the analgesic efficacy of the treatment methods. In order to check the efficacy of the therapy, mean pain values were compared before and after performing the procedures. The statistical significance of the change in mean values was verified using the paired sample Welch t-test is a generalization of Student's t-test for populations with different variances. Significant differences in the value of variance were observed in the measurements taken before and after the treatment, as well as in the comparison of changes after the use of both therapeutic methods.)The hypothesis about greater analgesic efficacy of KT compared to TrP was additionally tested. For this purpose, the mean values of absolute and relative pain intensity changes obtained from two groups of patients were compared using the unpaired sample Welch t-test.  in the group of male and female patients were compared by analyzing the mean values of changes using the t-statistic values less than 1).In the linear regression models, the absolute change in pain intensity was a dependent variable. For both therapy methods, the models with age, gender, and their cross-factor as independent variables were examined. There were no significant variables in any model  and TrP inactivation have brought significant analgesic effects to the treatment of painful forms of functional disorders of the masticatory muscles.The more beneficial results were observed after using the KT method, which increased the analgesic effect in dysfunctional patients.No influence of gender or patient's age on the treatment results was reported.There is also a need to develop algorithms for the diagnosis and treatment of oral and facial pain syndromes with a strict definition of the role of dentists and physiotherapists.


The management of painful end-neuromas of the superficial branch of the radial nerve (SBRN) remains challenging due to high levels of pain relapse. The novel technique of stromal vascular fraction (SVF)-enriched fat grafting showed continuous pain relief, although failed to prove statistically significant. Besides acting as a mechanical barrier, SVF-enriched fat grafting might also affect the cellular level. The aim of this study was to compare clinical outcomes of SVF to the widely popular intramuscular transposition technique.In this cohort study, 10 consecutive patients treated for painful end-neuromas of the SBRN between 2010 and 2013 were analyzed retrospectively. Microsurgical resection of end-neuromas was performed in all patients. Five patients were treated with subsequent intramuscular transposition into the brachioradialis muscle and five patients received SVF-enriched fat grafting. Five different pain modalities and various predictors were compared pre- and up to 36 months post-operatively.In the transposition group, sustained pain reduction was not observed after an initial significant reduction 2 months’ post-surgery, resulting in pain relapse at 36 months and comparable to the preoperative assessment. In the graft group, some degree of pain reduction was observed at 2 months after the surgery and proved to be constant in the long-term outcome, although not statistically significant compared to preoperative levels.Both SVF-enriched fat grafting and intramuscular transposition failed to prove statistical significant pain reduction in treating symptomatic neuromas of peripheral nerves. The management of painful end-neuromas of the superficial branch of the radial nerve (SBRN) remains difficult with multitude of existing proposed surgical treatments. Principally, neuroma excision and/or repositioning of the nerve stump into neighboring muscles , 2, boneRecently, our group reported the novel treatment for symptomatic neuromas of the SBRN by stromal vascular fraction (SVF)-enriched fat grafting . SVF is Our small collective of five patients was the largest ever published series reporting SVF-enriched fat grafting in a single nerve population, although failed to show statistically significant pain reduction. However, a trend in continuous pain reduction could be demonstrated .Indeed, none of described treatments resulted in superior outcome yet, and hence failed to establish a therapy consensus considering high rates of pain relapse . FurtherThis cohort study compares a long-term outcome of SVF-enriched fat grafting as a novel surgical option for symptomatic end-neuromata of SBRN to the still frequently assessed alternative of intramuscular transposition of the nerve stump.This study was carried out in accordance with the recommendations of the University of Zurich Ethics Committee with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the University of Zurich Ethics Committee (BASEC-Nr. Req-2016-00655).All patients operated on painful end-neuromata of the SBRN between 2010 and 2013 in our institution were analyzed retrospectively. From 2010 to 2012, five consecutive patients were treated with neuroma excision and intramuscular transposition into the brachioradialis muscle (the transposition group) and from 2012 to 2013 five consecutive patients received SVF-enriched fat grafting (the graft group). All the surgeries were performed by the same surgeon. Duration of pain, employment status, previously diagnosed CRPS II symptoms, and smoking habits of all patients were documented prior to the surgery. The data of both groups were statistically analyzed and compared. Symptoms of CRPS II were often primarily diagnosed in peripheral hospitals and not confirmed by specialists in our institution.In order to confirm the diagnosis, all relevant nerve blocks were performed proximally to the neuroma in the middle third of the forearm in order to exclude pain from overlapping nerves, such as the lateral antebrachial cutaneous nerve (LACN) , posteriUnder the microscope, the painful neuroma was resected and dissection of the proximal nerve stump was performed until the sufficient length was obtained for tension-free relocation into the brachioradialis muscle Figure . A recip® 800/CRS System and processed by one ampule of Celase® processing enzyme reagent   . Meanwhis Figure . FinallyU test was used to verify statistical significance between the respective pain scores of each group. Statistical significance was considered at p-value less than 0.05.The data were analyzed using the IBM Statistical Package for Social Sciences, version 22  and presented as mean ± SDs. The Kolmogorov–Smirnov test was employed to verify the nonparametric nature of the study population and confirmed a nonexistent empirical distribution. Based on the nonparametric nature of the study population, the Wilcoxon’s test for related samples was applied to compare preoperative and postoperative results. The Mann–Whitney The baseline characteristics of the study population are presented in Table The standard postoperative immobilization period amounted 4 weeks in the transposition group and 10 days in the SVF-enriched fat grafting group.The comparison of pre- and postoperative pain scores of the two groups are listed in Tables p = 0.157), hyperesthesia from 2.8 ± 0.45 to 2.2 ± 0.84 (p = 0.180), tap pain from 3 ± 0.0 to 2.8 ± 0.45 (p = 0.317), and motion pain from 2.8 ± 0.45 to 1.6 ± 1.52 (p = 0.194). Spikes were assessed 36 months after the surgery at the same level as before the surgery (p = 1.0) , spikes from 2.2 ± 1.3 to 1.4 ± 1.34 (p = 0.180), hyperesthesia from 1.6 ± 1.14 to 1.2 ± 1.64 (p = 0.713), tap pain from 2.8 ± 0.45 to 1.8 ± 1.3 (p = 0.197), and motion pain from 2.8 ± 0.45 to 1.4 ± 1.34 (p = 0.066) .All authors  are substantial contributors to the conception of the manuscript, took part in revising the content of the work critically, and gave their final approval of the current version to be published. Questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved by all authors .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.