Tapentadol is a dual-acting mu-opioid receptor agonist and noradrenaline reuptake inhibitor with non-inferior analgesic efficacy to oxycodone and better gastrointestinal tolerability than full mu-opioid receptor agonists. Tapentadol is approved for cancer pain in Japan; however, real-world evidence on tapentadol’s effectiveness and safety for cancer-related pain in Japan is limited.This retrospective study evaluated the effectiveness, safety, and tolerability of tapentadol (by patient type—opioid-naïve and opioid-tolerant) in 84 patients with moderate-to-severe cancer pain at Ichikawa General Hospital between September 2014 and August 2016.Almost 93% of patients achieved clinically relevant pain relief within 4 days (median). Over 90% of patients with neuropathic pain or mixed pain and all patients with nociceptive pain were responders. Pain intensity significantly decreased from baseline through to the end of maintenance period in opioid-naïve and opioid-tolerant patients. No patients discontinued tapentadol due to serious adverse events. No opioid-naïve patients experienced nausea or vomiting during tapentadol treatment. Only three opioid-tolerant patients experienced nausea which was considered to be related to tapentadol.Tapentadol is effective and well tolerated in opioid-naïve and opioid-tolerant patients with cancer pain of varying pathophysiology, including those with nociceptive and/or neuropathic components. Tapentadol may be considered for first-line use in moderate-to-severe cancer-related pain. Pain affects up to 70% of patients with cancer, especially those in the advanced stages of the disease . Even afNeuropathic pain is defined by the International Association for the Study of Pain as “pain that arises directly from a lesion or diseases affecting the somatosensory system” . NeuropaOpioids are the cornerstone in the treatment of moderate-to-severe cancer-related pain . OpioidsTapentadol is a centrally acting mu-opioid receptor agonist and noradrenaline reuptake inhibitor ; both meThe present study aimed to evaluate the effectiveness, safety, and tolerability of tapentadol by patient type (opioid-naïve and opioid-tolerant) in Japanese patients with moderate-to-severe cancer pain.We retrospectively evaluated 92 patients with cancer pain treated with tapentadol at Ichikawa General Hospital in Japan between September 2014 and August 2016. The study included opioid-naïve or opioid-tolerant patients who fulfilled the following criteria: diagnosed with moderate-to-severe cancer pain ; required opioids for cancer pain control; did not require adjuvant analgesics; and dissatisfied with the cancer pain relief from current analgesic treatment.Opioid-naïve patients were those not receiving opioid analgesic on a daily basis and, therefore, have not developed tolerance to opioids. Opioid-tolerant patients were those already treated with other opioid analgesics—i.e., at least 25 mcg/h fentanyl patch, at least 30 mg of morphine daily, at least 20 mg of oral oxycodone daily, or an equianalgesic dose of another opioid for a week or longer. Neuropathic pain was diagnosed based on a history of relevant neurological lesion, clinical evaluation of pain distribution that was anatomically consistent with the suspected location of the lesion and the existence of allodynia or hypoesthesia, and objective diagnostic tests (such as computed tomography and/or magnetic resonance imaging) confirming the presence of nerve lesion [Opioid-naïve patients were prescribed an initial tapentadol dose of 25 or 50 mg twice daily (50–100 mg/day). Opioid-tolerant patients were prescribed an initial tapentadol dose of 50–400 mg/day. Tapentadol doses were calculated based on previous opioid consumption, and at a conversion ratio of 5:1 (tapentadol:oxycodone). Patients discontinued previous opioid analgesic treatment prior to receiving their first dose of tapentadol.Oral immediate release oxycodone (5 or 10 mg) was available as rescue medication for breakthrough pain without limit on the number and timing of doses per day. Following stable dosing of tapentadol for at least 3 days, tapentadol doses were titrated at physician’s discretion. Tapentadol doses could be increased in increments of either 50 or 100 mg, up to a maximum of 400 mg/day for opioid-naïve patients or 600 mg/day for opioid-tolerant patients.Pain intensity was assessed by physicians or nurses at the following time-points: baseline, initial pain relief, and maintenance period. Patients rated their pain intensity using the NRS from 0 (no pain) to 10 (worst pain imaginable). Patients entered the maintenance period after achieving satisfactory pain relief and once tapentadol titration was completed. Satisfactory pain relief was defined as not having taken any rescue medications for breakthrough pain more than twice daily during a 3-day treatment period with stable doses of tapentadol. Following tapentadol titration, clinically relevant pain relief was defined as having at least 50% reduction in NRS score from baseline; patients who had clinically relevant pain relief were considered “responders”.Safety assessments included recorded nausea and vomiting and serious adverse events. We specifically assessed nausea and vomiting, because these are common adverse effects of opioid treatment. Data on constipation were not collected in this study, because prophylactic laxatives had been already prescribed or were prescribed at the time of tapentadol initiation in most patients. Reasons for discontinuation of tapentadol were also assessed.P value of less than 0.05 was considered to be statistically significant.Demographics, patient characteristics, and effectiveness and safety endpoints were summarized using descriptive statistics. The effectiveness and safety endpoints were also evaluated by patient type . Pain intensity scores between time-points  were compared using the two-way analysis of variance test. Discrete variables were compared using the Friedman test and post hoc Bonferroni correction. Statistical analyses were performed using Microsoft Office Excel 2013 . A n = 55; 65.5%); patients were previously treated with oxycodone , tramadol , fentanyl , or morphine . Among the opioid-tolerant patients, only four patients received more than 120 mg/day of morphine equivalent dose of opioid prior to switching to tapentadol: two patients received 100 mg/day of oxycodone and two patients received 120 mg/day of oxycodone. Approximately 41, 37, and 23% of patients were assessed as having mixed pain, neuropathic pain, and nociceptive pain, respectively.A total of 92 patients entered the study. Eight patients had oral intake difficulty due to general physical health deterioration and were excluded from the analysis, leaving 84 patients for analysis. Patient demographics and characteristics are summarized in Table P < 0.0001; Fig. P < 0.0001; Fig. Following tapentadol administration, 92.9% (78 of 84) of all patients achieved clinically relevant pain relief  within a median (range) of 4 1–13) days. The proportion of responders in patients with mixed, nociceptive, and neuropathic pain were 91.1% (31/34), 100% (19/19), and 90.3% (28/31), respectively. The median (range) NRS score decreased significantly from 7 (4–10) at baseline to 2 (0–6) at initial pain relief  daily dose of 75 (50–200) mg and increased to daily dose of up to 100–400 mg. In these six patients, the median (range) NRS score was 6 and remained unchanged from baseline to the end of the maintenance period; they were considered non-responders and were subsequently switched to other opioid analgesics such as oxycodone or transdermal fentanyl.Of 55 opioid-tolerant patients, 52 patients (94.5%) achieved clinically relevant pain relief within a median of 3 days and were responders. The median (range) NRS score decreased from 7 (4–10) at baseline to 3 (0–6) at initial pain relief. The median (range) NRS scores decreased from 3 (0–6) at initial pain relief to 1 (0–5) at the end of the maintenance period.P < 0.0001; Fig. P < 0.05).Of 29 opioid-naïve patients, 26 patients (89.7%) achieved clinically relevant pain relief within a median (range) of 3 (1–11) days and were responders. The median (range) NRS scores decreased from 8 (4–10) at baseline to 2 (0–4) at initial pain relief  patients, of whom 19 were opioid-tolerant and three were opioid-naïve. Nausea disappeared in nine of 19 (47.3%) patients who had exhibited nausea caused by previous strong opioids. No opioid-naïve patients experienced nausea or vomiting during tapentadol treatment. Only three opioid-tolerant patients experienced nausea which was assessed to be related to tapentadol by the physician. During the maintenance period, three patients discontinued tapentadol due to general health deterioration caused by disease progression. No patients discontinued tapentadol or had dose reduction due to serious adverse events, and none exhibited withdrawal symptoms. There were no somnolence or delirium which required treatment discontinuation or dose reduction.This study aimed to evaluate the effectiveness, safety, and tolerability of tapentadol in Japanese patients with moderate-to-severe cancer pain. The findings revealed that tapentadol was effective at relieving cancer pain and well tolerated in both opioid-tolerant and opioid-naïve patients during the study period. More than 90% of patients with neuropathic pain or mixed pain, and all patients with nociceptive pain were responders.Previous exposure to opioids, among others such as pain type , and progressive disease, can influence a patient’s response to analgesic treatment , 26 and,Both ascending and descending pathways are implicated in pain and are common sites of actions of analgesics , 27. TapIn the present study, 41, 37, and 23% of patients were assessed as having mixed pain, neuropathic pain, and nociceptive pain, respectively. All patients with nociceptive pain and more than 90% of patients with neuropathic pain or mixed pain were responders. These findings highlight tapentadol’s effectiveness not only for cancer-related nociceptive pain, but also neuropathic pain and the results are mirrored in other studies , 30–32.Tapentadol’s additional mechanism of action   means thGastrointestinal side effects are commonly associated with opioid therapy . In the This study also presents some inherent limitations. For example, the retrospective study design limited our scope of analysis and interpretations as pertinent information  were lacking due to the use of data originally recorded for other purposes. Additionally, having an active comparator would have provided a more balanced representation of tapentadol’s clinical effectiveness. Our study would also benefit from evaluating the reduction in pain intensity across subgroups of patients with different pain types. Furthermore, this was a single-center study where the size of the study population was small and all patients were treated at the same center; the results should, therefore, be interpreted with caution. However, it is notable that our results are consistent with those of other studies. Although these limitations are important, our study adds on to the evidence of the real-world use of tapentadol in Japanese patients with cancer pain, and provides valuable insights into the use of tapentadol in a different ethnic patient population compared with those from previously conducted studies.In conclusion, our study showed that tapentadol is effective and well tolerated in opioid-naïve and opioid-tolerant Japanese patients with cancer pain of varying pathophysiology, including those with a nociceptive and/or neuropathic components. Tapentadol is a valuable option for opioid-naïve or opioid-tolerant patients with inadequate pain relief or intolerable adverse effects with other opioids.


Pediatric craniofacial reconstruction surgery is associated with significant perioperative analgesic requirements. As dexmedetomidine mediates central nervous system sympathetic activity and pain modulation, its intraoperative use could be beneficial in craniofacial surgery. We hypothesized that intraoperative administration of dexmedetomidine in children undergoing craniofacial reconstructive surgery would result in reduced opioid requirements, pain, sedation scores, and opioid-induced side effects compared to patients who did not receive dexmedetomidine. All patients who underwent craniofacial reconstructive surgery at our institution from July 2013 to June 2017 were retrospectively evaluated. The primary outcome measure was mean postoperative morphine equivalent requirements. Secondary outcome measures included incidence of opioid-related side effects, pain scores, and hospital length of stay. Thirty-nine patients received dexmedetomidine intraoperatively while 41 patients did not. There was no difference in postoperative opioid requirements or pain scores between the two cohorts. However, patients who received higher doses of dexmedetomidine (4.7 mcg/kg) intraoperatively exhibited significantly lower rescue medication requirements for nausea and vomiting postoperatively. Contrary to the hypothesis, dexmedetomidine was not associated with reduced postoperative opioid requirements or pain scores in children undergoing craniofacial reconstructive surgery. However, our findings do suggest that dexmedetomidine may be beneficial in reducing side effects such as postoperative nausea and vomiting. A randomized controlled trial would be necessary to verify these findings. Postoperative pain is a common challenge in the daily practice of anesthesia, and in many cases, continues to be inadequately managed. This is particularly true of pain in children due to difficulties with pain assessment and concerns related to side effects of opioids . While oDexmedetomidine is a highly selective alpha-2 receptor agonist that mediates central nervous system sympathetic activity and pain modulation, particularly in the spinal cord dorsal root ganglia . DexmedeComplex cranial vault reconstruction (CCVR) is extensive, often requiring wide scalp dissections and multiple osteotomies, and is associated with significant postoperative pain and analgesic requirements. The aim of this pilot study was to determine if dexmedetomidine is associated with reduced postoperative opioid requirements in infants and children undergoing CCVR. We hypothesized that children with craniosynostosis undergoing CCVR who received intraoperative dexmedetomidine as an adjunct to multimodal pain management would have decreased postoperative opioid requirements and opioid-related side effects compared to children who did not receive dexmedetomidine.This retrospective study was conducted after approval from the Children’s National Hospital Institutional Review Board on 24 October 2018, and need for patient or parental consent was waived. All patients with craniosynostosis who underwent CCVR between July 2013 and June 2017 were identified and included in the study. Demographic and perioperative data collected included age, weight, gender, race, ethnicity, American Society of Anesthesiologists (ASA) classification, craniofacial syndromic status, number of cranial sutures, operative time, pediatric intensive care unit (PICU) days, total hospital days, and mechanical ventilator days.Postoperative outcomes of interest included pain scores and administration of opioids , acetaminophen, ketorolac, benzodiazepines and dexmedetomidine in the first 24 h postoperatively. Need for rescue medications for opioid-related side effects as evidenced by administration of ondansetron, promethazine, diphenhydramine and/or naloxone was also noted. Mean pain scores and highest pain scores in the first 24 postoperative hours were recorded using the Faces Legs Activity Cry Consolability Revised (FLACC-R) Scale.t-test, morphine and acetaminophen were compared using a Wilcoxon rank sum test, whether or not ketorolac was administered was compared using a Fisher’s exact test, and lastly, the relationship between dexmedetomidine and need for rescue medications was determined using Poisson regression models with a goodness of fit test performed . The statistically significant level was set a priori at 0.05 and all analyses were performed with STATA V15 .Demographic characteristics of sex, race, ethnicity, ASA classification, number of sutures, and syndromic status were compared between those receiving dexmedetomidine and those who did not using a Fisher’s exact test. Age and weight, neither of which was normally distributed, were compared using a Wilcoxon rank sum test. Pain scores were compared using a Student’s Eighty patients with craniosynostosis underwent CCVR, with 39 patients receiving dexmedetomidine intraoperatively and 41 patients who did not receive any intraoperative dexmedetomidine. There was a significant difference in terms of sex between the two cohorts in that those receiving dexmedetomidine were more predominantly female than those that did not receive dexmedetomidine . There wp = 0.9). There was no significant difference in operative times between the two groups or the number of cranial sutures involved in the surgical repair  between children who received intraoperative dexmedetomidine and those who did not  and when limited to only patients receiving intraoperative dexmedetomidine (p = 0.017). In each case, as the amount of dexmedetomidine administered increased , the number of ondansetron doses decreased. This model tells us that, in all patients, with each increase in dexmedetomidine of one unit, we can predict the number of ondansetron doses given postoperatively to decrease by 0.342. In only those receiving dexmedetomidine intraoperatively (range = 0.2–4.7 mcg/kg), with each increase in dexmedetomidine by one unit, we can predict the number of ondansetron doses administered to decrease by 0.789 (There was no difference in postoperative opioid requirements or pain scores when comparing the two cohorts . Additioby 0.789 .This preliminary study suggests that intraoperative dexmedetomidine use during craniofacial reconstructive surgery is not associated with improved postoperative pain scores or reduced perioperative opioid requirements. This is contrary to our hypothesis and other studies, which have highlighted dexmedetomidine as an opioid-sparing agent. Despite the lack of difference in opioid requirement between the groups, the need for ondansetron appeared to be inversely related to dexmedetomidine use. There is also evidence to suggest that dexmedetomidine has antiemetic efficacy in other types of surgery ,14,15.This retrospective observational study has some important limitations, including small sample size and a demographic difference between the two groups studied. Those receiving dexmedetomidine were more likely to be female than those that did not receive dexmedetomidine. While it is a well-known concept that female gender is a reliable predictor of postoperative nausea and vomiting in adults , there iDexmedetomidine was not associated with reduced postoperative opioid requirements or pain scores in children undergoing CCVR. These preliminary results highlight that opioid-sparing multimodal approaches to pain management, though preferable, are not always a panacea. Furthermore, as dexmedetomidine is a relatively expensive analgesic medication with potential added financial burden for patients, the lack of significant benefit may not warrant the additional cost. While dexmedetomidine may not be a beneficial adjunct for pain control in this setting, its relationship with a lower use of antiemetics needs to be further explored.


It is important to analyze the types of etiologies and provider demographics that drive opioid prescription in our emergency departments. Our study aimed to determine which patients in the ED are receiving opioid prescriptions, as well as their strength and quantity. Secondary outcomes included identifying difference in prescribing between provider classes.  We conducted a retrospective study at a tertiary care university-based, level-one trauma ED from November 2017 to October 2018. We identified and analyzed data from 2,259 patients who were sent home with an opioid prescription. We retrieved patient and provider demographics, diagnosis, etiologies, and prescription information.  The mean age of a patient receiving an opioid prescription was 45, and 72.7% of patients were white. The most common diagnosis groups associated with an opioid prescription were abdominal pain (18.5%), nonfracture extremity pain (18.4%), and back/neck pain (12.5%). Hydrocodone-acetaminophen 5–325 mg was the most commonly prescribed (67.4%). The median total prescribed milligram morphine equivalent (MME) was highest for extremity fracture . The median total prescribed amount of pills was highest for patients with extremity fractures .  Our study elucidates the prescribing patterns of an academic level 1 trauma center and should pave the way for future studies looking to maximize effectiveness at ways to curb ED opioid prescription. In 2008, prescription opioid deaths surpassed those caused by heroin . This riA recent observational study showed that for every 48 patients prescribed a new opioid in the ED, one patient will become a long-term opioid user , 10. ForRecently, there has been a push to curtail physician opioid prescribing patterns. These efforts, for the most part, have largely been based on limiting the number of opioids prescribed from the ED to short courses, identifying patients at risk for abuse, and identifying physicians that prescribe the most. One multicenter study was conducted in 2012 over a week-long period that analyzed the various diagnoses in the ED that were prescribed opioids. The results indicate a variety of diagnoses prescribed opioids, with musculoskeletal back pain and abdominal pain being the largest proportion of patients discharged with an opioid prescription . HoweverFor context, in California, providers must consult the Controlled Substance Utilization Review and Evaluation System (CURES), which is the state's prescription drug monitoring program, prior to prescribing Schedules II-IV controlled substances for the first time and at least once every four months thereafter if the patient continues to use controlled substances. However, if these medications are prescribed within the emergency department, providers do not have to consult CURES if the quantity of controlled substance does not exceed a nonrefillable seven day supply . The genThere is an immediate need for the development of targeted, nonopioid pain therapy for common diagnoses in the ED. In this study, we aim to further analyze which diagnoses (ICD-10) are receiving opioids as well as characterize both the patients who are receiving these opioids and the providers who are prescribing. With this information, we hope to add to the existing data to create directed pain protocols for a fixed diagnosis more confidently.We conducted a retrospective chart review study at a tertiary, academic level-one trauma center, university-based ED between November 2017 to October 2018.Patients aged 18 or older that presented to the ED and were discharged with an opioid medication between the study period were analyzed. We excluded patients who were admitted to the hospital, transferred to another hospital, or not discharged with a new opioid prescription. The study was reviewed and approved by the university's Institutional Review Board as an exempt category. Patient informed consent was not applicable to this study.Our data were obtained from the hospital medical record database. We extracted the following information for each patient from this database: age, sex, ethnicity, insurance payor, provider , diagnosis (ICD-10), prescription medication (name and dose), and quantity (number of tablets). For each patient, a total prescribed milligram morphine equivalent (MME) was calculated by multiplying the prescribed amount (in mg) by potency of prescribed medication. In this study, the total MME, prescribed amount, and number of pills prescribed refer only to medications prescribed to patients upon discharge and does not include any medications administered within the ED visit. We grouped each patient diagnosis into one of the following etiological categories: abdominal pain, nonfracture extremity pain, extremity fracture, headache, chest pain, genitourinary, back/neck pain, unspecified trauma, dental/facial pain, and others/missing/unspecified. The primary outcome of this study was to identify chief complaints associated with the highest opioid prescriptions upon discharge in terms of total MME and total amount (number of pills). Secondary outcomes included differences in the total MME and total number of pills prescribed upon discharge amongst different provider classes  along with identifying the most commonly prescribed opioid formulations .N (%) and continuous variables as mean (SD) or median (IQR), according to their distribution. The KolmogorovSmirnov test was used to examine the distribution of continuous variables. The independent-sample median test was used to compare total prescribed MME and also number of pills prescribed between EM vs. non-EM providers. A P value <0.05 was considered statistically significant. IBM SPSS Statistics 26 for windows was used for data analysis.Frequencies are presented as N = 1648) of patients were white, 9.3% (N = 209) asian, and 4.4% (N = 99) black. Furthermore, 49.2% (N = 1111) of these patients had Medicaid insurance, 25.8% (N = 583) had a commercial insurance, and 14.5% (N = 328) had Medicare , and 73.0% (Medicare .N = 373), nonfracture extremity pain , back/neck pain , genitourinary , and extremity fracture   patients were admitted to the hospital, and 40,013 (73.8%) patients were discharged from the emergency department. Given there were 2,259 patients included in this study, only 4.2% of patients who were discharged from the emergency department received a prescription for an opioid. Of these patients, the most common diagnosis groups associated with an opioid prescription were abdominal pain  .The median total prescribed milligram morphine equivalent (MME) was highest for extremity fracture , and for the category of “others/missing/unspecified” , all other body system categories had a median of 60.00 with varying IQR . The medN = 1523), followed by hydrocodone-acetaminophen 10–325 , tramadol 50 mg , acetaminophen-codeine #3 300–30 mg Tabs , oxycodone-acetaminophen 5–325 mg tabs , oxycodone 5 mg tabs, oxycodone-acetaminophen 10–325 mg tabs , and morphine sulfate 15 mg tabs . All other opioid prescriptions were prescribed at less than 1% frequency and are not listed. Of note, all of the above listed medications were immediate release formulations. Extended release formulations of opioids were all prescribed at less than 1% frequency and thus not listed above.Hydrocodone-acetaminophen 5–325 mg was the most commonly prescribed  of the prescriptions were made by attending physicians, 32.6% (N = 737) by nurse practitioners, and 20.2% (N = 457) by resident physicians. A subgroup analysis revealed no statistically significant difference in the provider classes prescribing habits, for both total MME (P=0.211) and for total number of pills prescribed (P=0.456) , 47.1% (P < 0.001) and median number of pills prescribed (100.0 vs. 20.0) (P < 0.001)  (< 0.001) . AdditioThis table represents an analysis in which emergency medicine (EM) providers were compared to non-emergency medicine (Non-EM) providers in terms of total MME and total number of pills, represented in medians.n = 214) of opioids were prescribed in the presence of an already existing opioid prescription. Of these 214 cases, 30.4% of the total MME was increased, 39.4% of the time, it was decreased, and 30.2% of the time, it was kept equal. For 41.1% of the time, the provider discontinued the prior opioid prescription, whereas 58.9% of the time prior prescriptions were unchanged and an opioid was added.Also found was the frequency of instances in which providers prescribed opioids in the presence of an already existing opioid prescription as seen in Given our study was conducted at a single, level-one trauma center, university-based ED, our data may not be generalizable to other populations or other emergency departments. Higher acuity patients inherent to a level-one trauma center, social and medical complexity of the patient population, and timely access to primary care are all factors that may limit the external validity of this study.Another limitation to this study is that diagnosis codes were not available for each patient. Of the 2259 patients included in the study, 240 (10.6%) had missing diagnosis codes and 113 (4.8%) had diagnosis codes that could not be classified into a body system given the ambiguity of certain ICD codes. Furthermore, the diagnoses were assigned during or shortly after an ED encounter . Thus, diagnosis may lack specificity or may not reflect the true diagnosis of the patient.Furthermore, our study had a few outliers. A common scenario that explained our upper limit outliers were physicians from the palliative care service prescribing large quantities and higher MMEs to opioid tolerant patients. Although these prescriptions were not made by ED trained physicians or NPs, they were still made upon discharge from the ED by the consulting service and were thus included within the analysis. In order to limit the effects of these outliers, medians were used instead of means for the majority of our analyses. Although only 5% of opioids prescribed were from non-EM providers, our study found that non-EM-trained providers prescribed a statistically significant greater amount of opioids in terms of both total MME and total number of pills. Therefore, this study can only claim to depict prescription habits from the emergency department as a whole not solely from EM-trained faculty.Our subgroup analysis may have been limited, given NPs in this particular ED are assigned lower acuity patients and are seen in the ED's “Fast-Track,” whereas ED attendants and residents may see both low- and high-acuity patients. A difference in patient population and severity of illness therefore may have confounded the results of the subgroup analysis. Additional retrospective observational studies looking into attending, residents, and nurse practitioner prescribing habits for low-acuity patients (Emergency Severity Index: 4–5) may be required to correct for confounding variables present in this study.Lastly, given analysis was based mainly off of diagnosis codes, we are unable to ascertain how the severity of each condition might be related to the prescription of opioids. At this particular institute, pain scores are not consistently recorded by physician or nursing staff, and therefore given the retrospective nature of this study, we are unable to ascertain the level of severity of each injury. Although some diagnoses can be inferred to appropriately warrant opioid pain prescriptions , there are challenges to determining the appropriateness of opioid pain medications for many other diagnoses  without factors such as severity or duration of illness.th out of 58 counties in California for rates of prescription opioid deaths and unintentional injuries, drug overdose being the largest contributor, which was the number 1 cause of death in patients between the ages of 15 and 44 [This medical center is located in Orange County, California, which is a densely populated setting in Southern California. Orange county is ranked 175 and 44 .Rising trends in ED opioid prescriptions is a public health concern, given studies have demonstrated the potential for these medications to be misused, diverted, or lead to opioid related deaths , 20. TheSimilar to the prior cross-sectional study, this study demonstrates that the most common diagnoses associated with opioid pain prescriptions were extremity pain, abdominal pain, and back/neck pain . IdentifIn order to maximize the effect of the implementation of such guidelines, targeting patients with extremity pain, abdominal pain, and back/neck pain may be the best initial steps to reducing opioid prescriptions as a whole given these diagnoses are more frequently associated with opioid pain medications. Combining extremity pain, extremity fracture, and back/neck pain under a single “Musculoskeletal” category would account for 42.7% of the opioid prescriptions. Thus, exploring specific approach to musculoskeletal pain may account for nearly half of the patients in this particular center. In order to implement more targeted prescribing guidelines, additional analysis can be performed in order to divide the broad diagnosis groups  presented in this study into more specific diagnoses .In our study, extremity fracture pain was associated with the highest median number of pills dispensed at 15.0 pills, with most other diagnosis groups receiving less than 12 pills total. This is consistent with available guidelines which suggest no more than three days worth of opioids for acute pain assuming six times daily dosing regimens , 25. AlsA total of 1.3% of ED opioid prescriptions are written for extended release or long acting (ER/LA) formulations which include methadone (0.5%), morphine ER (0.5%), and oxycodone ER (0.3%). These habits are consistent with CDC guidelines suggesting immediate-release opioid formulations given ER/LA opioids have been associated with greater risk for overdose , 27. OneHydrocodone-containing products (77.4%), oxycodone-containing products (8.9%), and morphine (1.6%) were found to be prescribed in decreasing frequency as listed above. A systematic review of nine studies comparing abuse potential of these three products found that oral oxycodone had an elevated abuse liability profile when compared to morphine and hydrocodone . Furthernd and 3rd year resident physicians obtain licenses to prescribe opioids. In general, the decision to prescribe opioids, both type and quantity of pills, is left up to the discretion of the resident prescribing with minimal attending physician input after the first year of training. The same is true for nurse practitioners, who work fairly independently at this particular institution and use their own license to prescribe opioids. Despite the lack of statistical significance, there are several notable trends. Residents tended to have more variability in their prescribing habits across different organ systems, whereas attending physicians and nurse practitioners tended to have more consistency when prescribing across different organ systems. For unspecified trauma, genitourinary, and extremity fractures, resident physicians tended to prescribe the most number of pills and overall higher amounts of MME. However, for headaches, resident physicians seemed to have prescribed less than any other provider class for both MME and number of pills. Although the reasoning cannot be ascertained from the data alone, one possible explanation could be that the resident physicians have not had enough time to develop their particular practice patterns.The fact that no significant difference was found for prescribing habits between the three provider classes  seems to corroborate the findings of a previous study that showed that patient encounters involving physician trainees reflected similar trends in attending practice.  At this Furthermore, the fact that residents seemed to prescribe opioids for headache notably less than any other chief complaint may be attributable to resident physician training, which includes preparation for EM in training examinations and eventually EM board certification upon graduating from residency. Common resources used in studying for these examinations are Adam's Emergency Medicine, Rosen's Emergency Medicine, and Tintinalli's Emergency Medicine textbooks. In all three of these resources, it is stressed that opioids are only to be used for headaches as a second line therapy, and even then, they should be used sparingly and to be considered only if there is a lack of response and/or intolerance of all first line therapies which include but are not limited to acetaminophen, ibuprofen, prochlorperazine, metoclopramide, sumatriptan, or ketorolac. –33 It isOur study found that opioid-prescribing habits  were in accordance with national opioid prescribing guidelines that recommend no more than three days of opioids assuming six times daily dosing with a preference towards immediate release formulations. Given abdominal pain (18.5%), extremity pain (18.4%), and back/neck pain (12.5%) were the most common chief complaints that received opioids, any future guidelines for curbing opioid prescriptions upon discharge should have a strong emphasis on these chief complaints. Although there was no difference in prescribing habits between different provider classes , future studies accounting for patient complaint severity could help to elucidate any true differences.


Trials of intraoperative chemical splanchnicectomy during resection of pancreatic and gastric masses resulted in significant difference in a patient's postoperative pain. This study aims to determine if splanchnicectomy by alcohol neurolysis can relieve postoperative pain after gastrectomy and Whipple surgery. The study explores differences in outcomes at first four months after surgery.  Fifty-eight patients with gastric and 60 patients with pancreatic resectable masses were included (28 were lost to follow-up). Each randomized in control and intervention subgroups. Intervention subgroups underwent chemical blockage of celiac ganglions by ethanol injection at both sides of suprapancreatic aorta. Participants were asked to report their pain intensity according to the Visual Analogue Scale (VAS) at specific times. p < 0.001). The pain-modifying effect of the injection was not different between Whipple and gastrectomy groups (p=0.125)  The overall postoperative pain of injected Whipple and gastrectomy subgroups was lower than the noninjected Whipple and gastrectomy subgroups (Perspective. This article presents positive effect of intraoperative chemical splanchnicectomy during resection of pancreatic and gastric masses on postoperative pain. This is an easy, effective, safe, and inexpensive procedure recommended for all operable gastric or pancreatic masses to palliate the pain degree. Splanchnicectomy is recommended for pain reduction after abdominal operations.  Gastric and pancreatic cancers and their increasing prevalence are included in today's concerns of surgeons and palliative care workforce.Gastric and pancreatic cancers are two of the most common malignancies that are mostly diagnosed at an advanced stage notably in Eastern/Southeastern Asia. Five-year survival is expected in 25% and 22% of gastric and pancreatic masses, respectively, and can be only achieved by early onset diagnosis and providing critical therapies –3. PancrThe majority of patients in both groups will have pain requiring increasing doses of narcotic analgesics during the course of their illness.Cases of pancreatic cancers suffer from extreme loss of appetite and considerable weight loss; they mostly represent an excruciating pain as the most disturbing and incapacitating symptom , 6.The pain caused by the upper abdominal cancers may originate from visceral, somatic, or neuropathic. Sympathetic fibers responsible for visceral pain signals are located close to celiac trunk at level T12-L2, anterolateral to the aorta. Three pairs of celiac plexus ganglions are found less than 1 cm inferior to the origin of the celiac artery. Somatic and neuropathic pains may characterize involvement of adjacent organs including peritoneum or retroperitoneum .Several methods of splanchnicectomy or interruption of the main pancreatic sympathetic pathway has been applied to make this pain more tolerable , 9.At recent clinical trials, unilateral and bilateral splanchnicectomy were performed throughout open abdominal surgeries and thoracoscopy. Unpredictable complications and different efficacies have been reported; however, immediate pain relief and long-term improvement achieved in 80 and 50 percent of patients, respectively . Some otCeliac plexus block (CPB) was first performed in 1916. Later trials on patients with unresectable pancreatic cancer in 1969 demonstrated that this method can apply through bilateral injection of ethanol in a procedure called chemical splanchnicectomy or ethanol celiac plexus neurolysis (ECPN). CPB interrupts signal transfer rapidly, so that the result of CPN may remain for years .Despite the result of similar researches in the past two decades, neurolytic celiac plexus block (NCPB) significantly decreases chronic pancreatic cancer pain, by decreasing both reported pain scores and reducing postsurgical opioid intake .Different methods of NCPB including the retrocrural, transaortic, and bilateral chemical splanchnicectomy which were performed intraoperatively or through thoracoscopy have been compared in a few studies, but they all showed considerably efficient outcome , 12, 13.Although NCPB has been found as the preferred method due to its less invasiveness and more positive outcomes, few complications have been reported such as local pain in 96%), diarrhea (in 44%) and hypotension (in 10%). Serious adverse effects such as neurologic  and nonneurologic symptoms  were rarely reported , 9, 13.6%, diarrThe current study is aimed to evaluate the efficacy of intraoperative chemical splanchnicectomy in cases with resectable upper abdominal masses who underwent surgical resection to provide immediate and long-life postoperative pain palliation for them. We decided to compare the result of celiac ganglion blockage during gastric and pancreatic mass resection and compare pain-relieving trend with the control group.This study aims to evaluate the effect of intraoperative chemical splanchnicectomy on pain intensity during first four months after surgical resection of gastric and pancreatic masses.In order to compare the result of chemical splanchnicectomy between those with pancreatic masses with gastric masses and separately with those who did not receive intervention, 4 subgroups of patients were expected. Calculated sample size by Altman Nomogram and comparison of two means equation equals 21 cases for each subgroup and total number of 84 .All patients with approved diagnosis of resectable pancreatic or gastric cancers who had referred to general surgery ward of Firoozgar Hospital during March 2015- September 2016 were involved.Patients with unresectable pancreatic or gastric cancer, age less than 15 or more than 80, history of prolonged consumption of opioids, NSAIDS, analgesic and antidepressant drugs or opium addiction, cardiac or pulmonary diseases, sensitivity to opioid drugs, psychological disorders, abnormal arterial blood gas analysis, and those who underwent neoadjuvant chemotherapy were not included.Patients who were dissatisfied with the procedures, expired before 4 months after operation or experienced surgical complications or any other signs that resulted in disability to complete pain scale questionnaire (such as loss of consciousness) or had prolonged postoperative hospitalization (more than 15 days) due to surgical complications were also excluded.Throughout this study, all ethical considerations were respected. Previous studies have approved that chemical splanchnicectomy cannot cause serious harms to patients and has no concerning side effect. All patients agreed to involve in the study, and informed consent was obtained for probable intervention. The project has been submitted to the Iran randomized controlled trial system with submission code of IRCT2015022821269N1. Final participants with each of gastric or pancreatic masses were randomly divided into intervention and control subgroups.The control group (including 24 cases of gastric and 19 cases of pancreatic cancers) did not receive any intervention.For the intervention subgroups (24 cases of gastric and 23 of pancreatic cancers), the surgeon applied alcohol neurolysis.While doing the procedure, surgeons had to gently find celiac ganglia on both sides of the celiac and superior mesenteric arteries which locate medial to the adrenal glands and anterior to the diaphragmatic crura. The surgeon retracted lesser curvature caudally, incised the avascular area of hepatogastric ligament, and put his left index finger on the splenic artery and the left third finger on the common hepatic artery while steadying their hand by abutting their thumb to the left lateral aspect of the aorta and straddled it and then palpated the celiac trunk to find the exact place and fixed it for injection . Then, 20 ml of a 50% ethanol  diluted in normal saline was injected to each of celiac ganglions at both sides of the suprapancreatic aorta by the right hand after aspiration of the syringe. The operation site was compressed by antibleeding packs.During injection, all vital signs were under strict control, and in the presence of changes (if any), surgeons stopped injection and anesthesiologist resuscitate patient. Adrenaline and Atropine were used in case of anaphylactic shock and bradycardia, respectively. In order to palliate postsurgical pain, all patients received 25 mg pethidine 3 times per day, and extra amount was given when necessary. During the follow-up period, all patients were under direct control and received appropriate treatments if needed.To eliminate operator bias, the study was designed as a double-blinded clinical trial so the surgeon who was not involved in the study injected solution to random cases. Neither the researcher nor the patient was aware of the injected solution. Researchers asked patients to evaluate their pain intensity at given times including one day before surgery, one, two, and four days after surgery, discharge time, one month, two months, and four months after surgery with the Visual Analogue Scale (VAS) for pain. To increase accuracy of their answers, the Wonge–Baker Face Pain Scale was also used.At each interval, reported scores were then analyzed by SPSS version 22 by the repeated measure ANOVA test. To eliminate the bias effect, we subtracted before surgery pain scores from all follow-up times.p > 0.05) . The 90 were allocated in four surgery/intervention subgroups . Male to > 0.05) .p=0.57) and Gastrectomy (p=0.12) groups. Mean pain scores in each follow-ups for the intervention subgroups are displayed in p < 0.001). The pain modifying effect of the injection was not different between Whipple and gastrectomy groups (p=0.125) (p=0.875).Before the surgery, there were no differences between the pain of the injected and not-injected subjects in both Whipple (p=0.125) . There wAlmost 70% of patients suffering from end-stage malignancies are complaining about intolerable moderate to very severe chronic discomfort. Most of patients with any advanced cancer experience episodes of visceral or bone pain .In patients with pancreatic cancer, widening of pancreatic capsule due to mass lesion results in midepigastric pain, with radiation to the mid-back or lower-back region in up to 90 percent of patients.According to the few times of life expectancy, palliation of symptoms is assumed as the primary goal of treatment for both operable and inoperable patients of these cancers .Based on latest the World Health Organization guideline for pain management in pancreatic cancer palliation, use of analgesic drugs is the first-line treatment while recent studies revealed that complete pain relief cannot be achieved without invasive procedures. Nowadays, by addition of celiac plexus blocks and neurolysis, splanchnicectomy, and intrathecal therapies, overuse of drugs and their unwanted side effects decrease , 9.There are two prominent reasons for choosing celiac ganglion to block: first, the role of thoracic splanchnic nerves in conducting pain sensation caused by the upper abdominal masses around the celiac ganglion; second, the splanchnic nerves are accessible and have a more predictable anatomical location and are not as closely associated with vital vascular and neurological structures , 15.This study was designed to evaluating the effects of intraoperative chemical splanchnicectomy on relieving pain from gastric and pancreatic masses, and to achieve this goal, we applied this method in cases with operable masses to avoid the bias effect of pain control resulted by tumor resection itself.Three sets of the sympathetic ganglia of celiac plexus constitute a relay station for visceral afferent nerve fibers are responsible for transferring pain signals from all pelvic and abdominal viscera. Outcomes and efficacy of celiac ganglion block in pain management are discussed in numerous studies , 16, 17.The early experiences with image-guided celiac block were aided by angiography and fluoroscopy; later, the CT-guided chemical splanchnicectomy was emerged as the modality of choice for this procedure because it improves both precision in accuracy of injection and decreases risk of unintended faults .Mallet-Guy performed the first left splanchnicectomy in 1942 through laparotomy in order to cure intractable pain due to chronic pancreatitis.The first randomized controlled double-blinded trial estimating the benefits of intraoperative splanchnicectomy through laparotomy was performed by Lillemoe et al. in unresectable pancreatic masses. They significantly approve longer duration of pain relieving in the intervention group , 9.Flanigan et al. also recommended open phenol splanchnicectomy at the time of initial laparotomy in patients with advanced intra-abdominal neoplasm .A meta-analysis of 24 studies including 1145 patients conducted by Eisenberg E et al. showed 87% of pain relief in the short-term period (first 3 months). Most studies were able to provide long-term outcomes (≥3 months) from fewer patients , 13.Raj et al. also applied celiac ganglion ablation patients with poor controlled chronic benign or malignancy-related abdominal pain and achieved short-term and long-term pain reduction in 85% of their cases .Garcea et al. showed statistically significant benefits as well, including decrease in pain degree, opioid use, and hospital admissions for pain control, healthier mental status, and better perception of general well being .Here, we applied intraoperative alcohol neurolysis with 50% ethanol injection to celiac ganglions with its safety and efficacy has approved in previous studies. By applying this easy and inexpensive intervention during the surgery, no further procedures are needed after massive abdominal surgeries.Unfortunately, reported effects of alcohol splanchnicectomy are not permanent. Most of our patients had experienced moderate to severe pain recurring before death. Regarding that, these poor prognoses are susceptible to malnutrition, pneumonia, deep vein thrombosis, and other complication of immobility; relieving pain through much of their limited life expectancy is worth this invasive procedure .It is expected that improving quality of life in patients with end-stage gastric or pancreatic cancers with controlling pain and a decreasing the demand on narcotic analgesics prolong their survival.There are few self-limiting complications reported such as prolonged recovery period, mild and transient orthostatic hypotension, diarrhea, complications caused by trauma during the procedure, and local pain. The major uncommon but concerning complications include pneumothorax, chest pain, hematuria, hiccoughing, and neurological symptoms such as epidural anesthesia, weakness, and paresthesia of the lower limbs that need further workups and attention.A case report in Japan suggested not applying alcohol neurolysis in cases with atherosclerosis of collaterals arteries or history of spinal cord infarction .This method would not benefit those with alternative pathway carrying abdominal pain and anatomical variations, and predicted outcome does not achieve if the amount of alcohol injection or the placement of needle are not correct .Besides all achievements in splanchnicectomy, there is still controversy surrounding this method. Some authors believe significant decrease in narcotic consumption is not reported following celiac block, and this probable outcome is not worth applying such invasion .An Italian clinical trial study compared efficacy of celiac plexus blockage versus analgesics, decreasing of pain score was seen in both groups but there was no statistically significant difference between the two.Through a double-blinded, randomized, controlled trial, Wong et al. reported long-term pain relief after celiac ganglion block but could not significantly demonstrate its effect on quality of life, opioid drug use, and survival .Even though in one published study, bilateral chemical splanchnicectomy was not recommended since it seemed to have no effect or its effect may have been masked by the surgery .A review of articles persist that neurolytic block should apply only when opioids fail to control the pain or side effects of opioids consumption leads to more organ damage .This study was undertaken to confirm the efficacy of intraoperative chemical splanchnicectomy and suggest this method as an efficient, safe, and inexpensive way to palliate pain after upper abdominal major surgeries. The efficacy was approved for Whipple surgery. Regarding that celiac ganglions are also known as the origin of pain caused by gastric masses, we aimed to compare the result for total gastrectomy and Whipple.The result of this study revealed the significant effect of pain palliation in both groups in comparison with the control group of each, but the difference was a bit more at Whipple surgery. During first four months, the difference disappeared slightly and reported pain degree in both the control and intervention group seemed the same. There are two main descriptions for this evidence; first is local recurrence of tumor and the second is unfortunate nonpermanent effect of chemical splanchnicectomy. Since higher pain intensity is expected for local recurrence than observed, the first reason seems less accurate. Assuredly, tumor resection itself can cure the pain after few months . However, since the life expectancy for end-stage patients is not much more than few months, we urge surgeons to provide them with safe, dignified, and reliable palliative care.For further researches, it is suggested to follow long-time outcomes and its possible complications for other gastrointestinal massive surgeries. For more reliable outcomes, it is recommended to exclude cases whose pain relates to previous surgery or endoscopic procedures.Intraoperative bilateral celiac ganglion ablation by injection of 20 cc 50% ethanol to each ganglion is an easy, effective, warranted safe, and inexpensive procedure recommended for all operable gastric or pancreatic masses to palliate the pain degree. Although this method has short-time effect, it can be helpful for patients suffering from postsurgical pain and more preferred than undergoing percutaneous or endoscopic chemical splanchnicectomy after surgeries.


Since patients often experience pain and unpleasantness during a colonoscopy, the present study aimed to evaluate the efficacy and safety of sublingually administered fentanyl tablets for pain treatment. Furthermore, since the use of intravenous drugs significantly increases colonoscopy costs, sublingual tablets could be a cost-effective alternative to intravenous sedation. We conducted a prospective placebo-controlled randomized study of 158 patients to evaluate the analgesic effect of a 100 µg dose of sublingual fentanyl administered before a colonoscopy. Pain, sedation, nausea, and satisfaction were assessed during the colonoscopy by the patients as well as the endoscopists and nurses. Respiratory rate and peripheral arteriolar oxygen saturation were monitored throughout the procedure. There were no differences between the fentanyl and placebo groups in any of the measured variables. The median pain intensity values, as measured using a numerical rating scale, were 4.5 in the fentanyl group and 5 in the placebo group. The sedation and oxygen saturation levels and the respiratory rate did not differ between the groups. The majority of the colonoscopies were completed.Our results indicate that a 100 µg dose of sublingual fentanyl is not beneficial compared to the placebo in the treatment of procedural pain during a colonoscopy. Even though a colonoscopy can be successfully performed with drugs that do not alter the patient’s level of consciousness or cause nociception4, the use of intravenous sedation or analgesia has become the standard practice in many countries6.A colonoscopy is an invasive procedure that can cause pain and discomfort in patients. Various drugs are used to prevent and treat discomfort during a colonoscopy, but the optimal drugs and dosing regimens are still unknown. Patients want to have a painless colonoscopy8. Repeated dosing of sedatives can cause prolonged sedation, hypoxia, and respiratory depression by decreasing the patient’s respiratory response to carbon dioxide9. Since oxygenation monitoring is required in such cases, patient follow-up is essential, and intravenously sedated patients cannot be discharged immediately after the colonoscopy.Most patients find procedural sedation effective, but it may increase the risks and costs of the procedure10. A recent meta-analysis suggested that propofol is superior to other sedative agents; recovery and discharge times were shorter and patient satisfaction scores were greater than with benzodiazepines11. However, sedation with propofol is associated with longer recovery times than sedation with midazolam and fentanyl, especially in the elderly12. Meanwhile, previous studies have interestingly demonstrated that patient comfort appears to be unrelated to the use of sedatives or analgesics13. Obviously, further studies are needed on procedural sedation during colonoscopy.Typically, intravenous midazolam is used to induce sedation for a colonoscopy. However, it has been shown that low-dose midazolam neither relieves discomfort nor produces amnesia in patients16. Fentanyl is rather short acting compared to other strong opioids  that are commonly used during the intraoperative period. Transmucosal sublingual fentanyl has been developed to improve the management of breakthrough pain in cancer patients. Achieving analgesia using a transmucosal tablet during colonoscopy is a novel approach, and a recent study reported promising results that indicated that oral transmucosal fentanyl is a safe and effective premedication in patients undergoing surgery under general anesthesia17. Similarly, low doses of intravenous fentanyl seem to be effective in achieving a satisfactory level of comfort during a colonoscopy14. Sublingual administration is an easy and non-invasive method of fentanyl administration prior to a colonoscopy. Furthermore, a single dose of sublingual fentanyl does not require follow-up after the procedure. The only limitation is that the patient is not allowed to drive a vehicle after the administration of strong opioids.Although many patients report pain during a colonoscopy, only a few studies have focused on the use of opioid analgesics during this procedureThe purpose of the present study was to compare the efficacy and safety of sublingually administered fentanyl and a placebo in patients undergoing a colonoscopy. We hypothesized that sublingual fentanyl would provide sufficient analgesia and increase patient satisfaction during the colonoscopy.In this randomized, double-blind, and placebo-controlled study, 158 patients undergoing a diagnostic or therapeutic colonoscopy were randomly given 100 µg dose of sublingual fentanyl  or the placebo before the procedure. The dose was based on a small pilot study of 35 patients prior to the initiation of the current study. In the pilot study, a 100 µg dose of sublingual fentanyl appeared to be a useful alternative to analgesia and sedation during an endoscopic procedure. The patients were randomized into two groups using the sealed envelope technique, and all patients, investigators, and staff members involved in the study were blinded to the treatment assignment.This study was approved by the institutional review board (IRB) of the Hospital District of Southwest Finland (IRB number: 140/2011). The trial was registered before patient enrollment at clinicaltrials.gov  and in the EudraCT database . All research was performed in accordance with relevant guidelines and regulations. Written informed consent was obtained from each patient.2 < 90%, who were pregnant or nursing, or who were undergoing concomitant drug therapy known to cause significant enzyme induction or CYP3A4 inhibition were excluded from the study. Additional exclusion criteria were a history of intolerance to fentanyl or related compounds; a history of or current alcoholism or drug abuse; and a history of and psychiatric, psychological, or other emotional problems that were likely to invalidate informed consent.Male and female patients between 18 and 80 years old who were scheduled for a routine diagnostic or therapeutic colonoscopy and had an American Society of Anesthesiologists (ASA) physical status classification of I–III, a body mass index (BMI) < 35, and a weight of more than 50 kg were deemed eligible for the present study. Patients who had a previous gastrointestinal surgery, sleep apnea, chronic obstructive pulmonary disease, or SpOConsecutive ambulatory colonoscopy patients were randomized to receive a sublingual fentanyl tablet  or a matching placebo tablet 10 min before the procedure. The patients were instructed not to swallow the tablet but to allow it to completely dissolve in the sublingual cavity without chewing or sucking. The patients were not allowed to eat or drink anything until the sublingual tablet was completely dissolved. The patients did not receive any other sedative or analgesic drug during the colonoscopy.2 and the respiratory rate were followed throughout the procedure. If SpO2 decreased below 90% or the respiratory rate decreased below eight per minute, additional oxygen was given. In the case of excessive opioid effects, 0.1 mg of intravenous naloxone was given.The patients assessed their average pain intensity using a numerical rating scale (NRS 0–10) during and at the end of the colonoscopy. Adverse opioid effects and subjective effects were recorded at the end of the colonoscopy. The following adverse opioid effects were evaluated using NRS (0–10): drowsiness , pleasantness (very unpleasant/very pleasant feeling), and nausea/vomiting (no nausea/very strong nausea). At the end of the colonoscopy, the endoscopists and the assisting nurses used NRS to evaluate whether the patient seemed to have pain or nausea and judged the level of sedation and the overall flow of the procedure. The endoscopists also estimated any technical difficulties associated with the colonoscopy. SpOThe patients scored their overall satisfaction with the procedure prior to discharge. In addition, they were interviewed by telephone one day after the procedure. At this time, they assessed their anxiety before the procedure using a scale from 1 to 4  and evaluated how well they could remember events during and after the colonoscopy using a scale from 1 to 4 . Their level of abdominal pain was assessed using a scale from 1 to 4 . The patients were also asked whether they had any adverse effects during the day after the procedure, such as abnormal tiredness, nausea, or dizziness; they evaluated these effects using a scale from 1 to 4 . Finally, patients assessed the unpleasantness of the colonoscopy from 1 to 4 .18, it was calculated that 87 patients would be needed per group to demonstrate a 30% decrease in the worst experienced pain at a level of significance 0.05 and power of 90%. The standard deviation of the worst experienced pain was assumed to be 50% of the mean pain score in the placebo group. Because of possible dropouts, 100 patients were planned to be recruited to both groups. However, because it was unexpectedly difficult to recruit suitable patients, we decided to settle for a smaller power. We estimated that we needed 73 patients each in the fentanyl and placebo groups to demonstrate, using NRS, a 25% difference in the worst experienced pain at a significance level of 0.05 and a power of 85%. Because of possible dropouts, 75 patients were planned to be recruited to both groups. The primary efficacy analysis was summarized descriptively for overall success evaluated by the patients, endoscopists and nurses and by treatment group. We performed the chi-square test or the Fisher’s exact test where appropriate and used the analysis of variance model with treatment as the main effect for overall and pairwise comparisons.Based on previous studyA total of 158 patients at Turku University Hospital were recruited between April 2012 and December 2018. Fourteen patients were excluded from the study because of missing data. As such, there were 72 patients in each group. Descriptive data are summarized in Table 9 in the placebo group, respectively. The fentanyl group had a median pain intensity value of 4.5, and the placebo group had a median pain intensity value of 5. The female patients had a median pain intensity value of 5 in both groups, and the male patients of 3 and 4 in the fentanyl and placebo groups, respectively. There was no statistical difference between the groups in male and female patients (p = 0.124). Both groups had a median self-reported degree of sedation of 0. The results are summarized in Table There were no differences in pain intensity or degree of sedation between the fentanyl and placebo groups. The maximum pain experienced by patients was 7 [4.75–8] in the fentanyl group and 8s p = 0.14. Both gThree procedures (one in the fentanyl group and two in the placebo group) were interrupted due to excessive pain. Both groups had a median time interval between the end of the colonoscopy and hospital discharge of 25 min  Table .Oxygen saturation was in the normal range in both groups, and there were no desaturation events. Respiratory rates were above eight per minute, and naloxone was not needed in any of the patients. Post-procedural interviews the day after the colonoscopy showed no differences in patient experience reminiscence between the fentanyl and placebo groups Table .Table 3PThe study findings indicate that a 100 µg dose of sublingual fentanyl did not affect colonoscopy-related pain intensity compared to the placebo. The sublingual fentanyl did not cause significant adverse effects or sedation, and patient hospital stays were not prolonged. Although patients reported moderate pain, nearly all of the procedures were completed successfully. The fentanyl did not have a significant effect on the satisfaction of the endoscopists. Finally, there were no differences between the fentanyl and placebo groups on the day after the procedure when the patients were asked to assess their anxiety level before the procedure.17, we found no difference between the fentanyl and placebo groups when pain during the colonoscopy was assessed using NRS. Similarly, a previous study evaluating the effect of a 200 µg dose of sublingual fentanyl as a premedication before bone marrow aspiration and biopsy19 found the fentanyl to be inadequate in relieving patients’ pain.The primary aim of this study was to evaluate the efficacy of a single sublingual dose of fentanyl in relieving pain during a colonoscopy. Sublingual administration was chosen to avoid the need for intravenous access. Although Singh et al. showed that a 200 µg dose of transmucosal fentanyl as a premedication in surgical patients undergoing general anesthesia caused effective anxiolysis with minimal adverse effects14. Meanwhile, when the effects of administering 1,000 mg of intravenous paracetamol and 0.5–1 µg/kg of intravenous fentanyl to colonoscopy patients were compared, the mean pain assessments were 4.00 and 3.77, respectively20. Thus, in our study, the median pain scores were similar to previous findings.In the present study, the median NRS pain values were 4.5 in the fentanyl group and 5 in the placebo group, which is commonly considered moderate pain. In a study by Lazaraki et al., patients received a small dose of intravenous fentanyl or midazolam, and the mean pain scores  were 2.59 in the fentanyl group and 4.43 in the midazolam group23. Regarding the intravenous route, a single 36 µg dose of intravenous fentanyl has been shown to be sufficient prior to colonoscopy14. In the pilot study, the 100 µg dose of sublingual fentanyl did not delay home readiness following the endoscopic procedure. For safety and ethical reasons, we wanted to keep the dose of fentanyl relatively low, especially since most patients were opioid naïve. Furthermore, although, according to its summary of product characteristics, Abstral is contraindicated for opioid intolerant patients and the treatment of acute pain, we considered its off-label use in procedural sedation under the supervision of a senior anesthesiologist trained to use fentanyl to be acceptable for the present study purposes.The bioavailability of sublingual fentanyl is approximately 70%, and a 100 µg dose of sublingual fentanyl—as used in the present study—has been shown to be effective and safe in average-sized adults and in elderly patients with comorbidities24. The patients in either group did not feel sedated, indicating that pain is probably the worst part of a colonoscopy and that pain, anxiety, and discomfort should be treated together.Our results indicate that a single sublingual low-dose opioid is not an ideal premedication for patients having a colonoscopy. Furthermore, we hypothesize that pain is seldom the only limiting factor for success in a colonoscopy; discomfort and anxiety might also be of importance. Although pain is a subjective experience, we evaluated analgesia by recording self-reported pain ratings using NRS, which is a reliable and validated method for quantifying pain25. However, since there are very few studies in which analgesics alone have been used to treat pain during a colonoscopy, comparing sedation levels to those in other studies is difficult. Most studies used a combination of an opioid and midazolam to achieve sedation27. In the present study, the endoscopists and the assisting nurses assessed the patients’ sedation levels using NRS and determined the median level of sedation to be 0 in both groups. The median time between the end of the colonoscopy and hospital checkout was very short in both groups: 25 (range 5–90) minutes in the placebo group and 25 (range 9–60) minutes in the fentanyl group. To ensure the smooth operation of a colonoscopy unit, it is important that patients recover rapidly from sedation. The time required to reach home discharge readiness was found to be lower in patients who received only intravenous fentanyl for sedation than those who received only midazolam14. Routinely given conscious sedation does not benefit patients or make a colonoscopy technically easier4, and premedication or sedation should only be offered to very anxious patients.Moderate or conscious sedation is safer and more cost efficient than deep sedation28. However, the peak concentration of sublingual fentanyl in the blood was reached 39.7 min after the 100 µg dose of sublingual fentanyl was administered. Since the median length of the colonoscopy in the current study was short (15 min in the placebo group and 20 min in the fentanyl group), the patients could have had better pain relief during the procedure if the time interval between the administration of the drug and the beginning of colonoscopy had been longer. Meanwhile, although the 100 µg dose of sublingual fentanyl was considered adequate based on previous reports14, the lack of difference in the efficacy of the fentanyl and the placebo is a strong indication that the dose of fentanyl was probably insufficient.Our study has limitations, one of which is the long recruitment period. The main reasons for this were patients’ unwillingness to undergo a colonoscopy without sedation and the proscription of driving a car after the administration of the study drugs. Another limitation was the timing of the fentanyl dose. Patients received the drug 10 min before the procedure, which coincides with the first detectable concentrations and reported onset of effectIn conclusion, a single 100 µg dose of sublingual fentanyl as a monotherapy administered 10 min before the start of an endoscopic procedure was not found to be beneficial compared to the placebo in the treatment of procedural pain during a colonoscopy. Current ambulatory practice requires fast patient turnover, an efficient and short-acting analgesic, and the rapid discharge of patients. It remains to be elucidated whether a combination of fentanyl and oral benzodiazepine would be more effective, equally safe, and able to eliminate the need for deeper intravenous sedation during a colonoscopy.


Radiculopathy due to lumbar or cervical disc disease is the most common chronic neuropathic pain in adults. The aim of present study was evaluation of low dose of sodium valproate (VPA) on radicular pain and determining VPA pharmacokinetics.In this double blind randomized placebo control clinical study, 80 patients with established lumbar or cervical radicular pain, have been randomly allocated into two study groups: 40 have received sodium valproate 200 mg/day and Celecoxib 100 mg/day and acetaminophen 500 mg PRN as rescue medication, and second group has received placebo, Celecoxib and acetaminophen. Quantitative assessment of pain was done by visual analogue scale (VAS) prior to perform the intervention and after ten days (treatment duration). Blood sample has been taken for determining mean through concentration after five half-lives. Evaluation of plasma concentration of VPA and that of efficacy on pain score relationship by comparing VAS before and after the therapy was done.Group A and B have demonstrated significant alleviation in mean VAS score; −21.97 ± 25.41, −14.39 ± 23.03 respectively (P < 0.001). The mean plasma concentration of VPA in group A was: 26.9 ± 13.5 mg/L. Moreover, no significant correlation was seen between pain score with age, gender, and weight (p > 0.05).Low dose of sodium valproate especially together with NSAIDs demonstrated good efficacy in lumbar and cervical radicular pain management. Radicular pain is the main manifestation of radiculopathy that lancinating and traveling on a narrow band which it maybe repetitive episode or paroxysmal. The main cause of this form of pain is ectopic activation of ischemic damaged nerve roots or inflamed dorsal root ganglion , 2. The The present double-blind randomized placebo controlled study was conducted in 80 patients  who have suffered from cervical and or lumbar radicular pain . 20–70 yDiagnosis was based on history of the symptoms and physical examination, straight leg raise test have been used to recognize a lumbar radiculopathy by rheumatologist.The selected Patients had been allowed time to ask questions before written informed consent was taken.All patients were randomly divided into 2 groups, randomization was done by the use of random numbers table, treatment plan of group A comprised of sodium valproate 200 mg/day, Celecoxib 200 mg/day and acetaminophen 500 mg PRN , group B or control group’s treatment plan contained placebo once a day, Celecoxib 200 mg/day and acetaminophen 500 mg PRN, duration of treatment was ten days, meanwhile all patients were emphasized that Valproate must be administered on 12 AM before meal and Celecoxib must be administered at night after dinner, except for treatment with sodium valproate, target therapy groups and control group were similar in all respects. The placebo tablets were identical in shape and color with that of valproate sodium tablets. All patients, who had been enrolled for group A, took valproate tablets in the same batch number from the same manufacturer company. All patients were monitored for adverse events  during the course of treatment. Each patient was rated his/her pain intensity on the visual analog scale (VAS) from 0–100  before beginning and after the end of intervention (VAS assessment occurred at baseline and day ten). The number of consuming acetaminophens as a rescue medication was recorded in a personal diary during ten days by each subjects and was documented in individuals relevant information file after the end of therapy by the member of research team. After collecting data, all of them were evaluated by blinded statistician and then the outcomes were decoded and divided the same into target therapy group (A), group (B) and then were compared to each other.Inclusion criteria: 1. Diagnosis of lumbar or cervical radicular by the rheumatologist. 2. Age between 20 and 70 years. 3. No possibility of health risk or confounding by other diseases, e.g., pregnancy, hepatic or kidney disorders, congestive heart failure. 4. Normal liver function 5. Patients hadn’t used valproate sodium or if they had been using, they must remember pain intensity before using valproate sodium and can compare with current pain intensity. 6. Weight between 50 and 90 kg. Exclusion criteria: 1. Intolerance to sodium valproate side effects. 2. Allergic history to VPA or NSAIDs. 3. Patients would be forced to administered medicines that change protein binding or clearance of valproate sodium. 3. Patients would be given diseases that affect the results of study.Gas chromatography method.All blood samples were stored in −20°C till analyzed. 0.5 ml of each serum was separated and four drops perchloric acid 60% was added in order to protein precipitation and achievement to desire PH (1), this was followed by five min shaking to complete deproteination, after centrifugation at 3000 rpm for ten min the supernatant fluid was transferred to a ten ml volumetric flask, after 20 min break time (in order to complete acidification process) deionized water was added to ten ml gradually, this samples were stored in 2–8°c following 3 min mixing until analyzed.The serial dilution of spiking solutions were made up by adding the different amounts of the stock solution (10 mg/ml) to 0.5 ml drug free serum, deproteinating and the rest of process have been done according what was mentioned in sample preparation method, diluting with deionized water up to ten ml in order to obtain different concentrations from 2–100 μg/ml  was performed. All spiking samples were analyzed by gas chromatography/flame ionization detector (GC/ FID) in the same constant thermal ramping with the unknown samples, calibration curve and linear regression were performed then the Y-intercept and the slope of plotted curve were calculated and replaced in linear equation.Analyte have been extracted by solid phase micro extraction (SPME) method. For creating a partitioning between the sample matrix and the fibre coating the needle of SPME set was passed through the septum which sealed sample vial and the polyacrylate fibre was entered to headspace above the sample in this meantime the glass vial of sample was heated and stirred by the hotplate Labtron model L-50; magnet stirrer speed was set on point one and temperature on 60°C. sample extraction and desorption time were 20 and five min respectively.All groups were similar in demographic features like mean age, mean weight, and primary and secondary pain scores as summarized in Formula 1:Similarly, the population half-life for valproate sodium was calculated using Formula 2:The differences in the primary and secondary pain scores between two groups were compared. Also, the mean number of patients’ consumed Acetaminophen tablets during ten days of treatment period was estimated and compared for the two groups. Patients in Group B took an average number of 5.08 rescue medication which was a bit greater compared to Group A (3.08) though it was not significant (p = 0.597). Also, no significant difference was observed between the difference of pain scores of groups after treatment and the number of Acetaminophen taken by Group A and Group B. Finally, the correlation between age, gender, and weight with pain score difference was investigated indicating no significant correlation.Sodium valproate is an anticonvulsant drug –28 widelIn this study, the group receiving VPA and Celecoxib simultaneously reported a maximum reduction of 79 units and a minimum reduction of 35 units in pain score . Also, tIn the study by Drews et al. (1994), 1200–2400 mg/ day valproate sodium was administered to 20 spinal injury patients on the basis of their response to treatment (the mean plasma concentration of the patients was 614 μmol/L). The response to treatment and pain reduction in patients were investigated by McGill pain questionnaire. No statistically significant difference was found at the end of the treatment period between the patients who received this medicine and those who received placebo despite a %33 reduction in pain .Kochar et al., assessed the role of sodium valproate for treating of pain in diabetic neuropathy. In this regard, they assessed pain via Visual Analogue score McGill Questionnaire at beginning, after 1 and 3 months of study and observed that sodium valproate provides significant improvement in reducing pain in patients with diabetic neuropathy, which was consistent with our study . Hardy eIn addition, clinical observations on our population race demonstrated that for some medicines, the doses administered to patients on the basis of medical references exceeded the needs of the patients. The clinical study has been done on Iranian race indicated that Iranian patients have different pharmacokinetic parameters of Phenytoin from the reported mean values in other population, according to this study; Iranian population demonstrated higher Michaelis-Menten constant (Km) and lower maximum rate of metabolism (Vm) than other races and ignoring this issue could lead to increasing risk of adverse reactions. E. Salehifar and et al claimed that our population may have a lower metabolic capacity for phenytoin metabolism and lower expression of CYP2C9 and CYP2C19 that these data could help the specialists to optimization and individualize antiepileptic therapy . CYP-medAlso, in surveying the number of Acetaminophen tablets taken by each group, it was observed that, patients in Group A had taken 3.08 ± 5.16 tablets on average while those in Group B had consumed 5.08 ± 8.07 Acetaminophen tablets on average being greater than Group A. The two groups under study were not significantly different in this parameter . It should be pointed out that during the orientation session when the procedures of drug administration were explained to each patients, it was observed that the majority of patients had a negative attitude towards Acetaminophen consumption showing no inclination for taking this tablet even in the presence of pain. This can justify the low mean of Acetaminophen consumption in the Placebo Group and even the intervention group. The pharmacokinetic parameters obtained from the intervention group receiving VPA are significantly different from those obtained for population studies . These sThis indicates that our study population demands its own pharmacodynamic and pharmacokinetic investigations and that making judgments on the basis of studies on other populations would be misleading and inaccurate. The half-life obtained from kinetic estimations for the consumption of the drug once per day was averagely 29.6 h for its simultaneous consumption with Celecoxib , while tA wide fluctuation was observed in trough concentration among the patients in Group A so that an SD of 13.53 was obtained for this group. This could be probably attributed to the effect of Celecoxib in the metabolism and clearance of drug which varies from individual to individual . An incrChronic pains such as pains of neuropathic nature may have several simultaneous causes, all of which are able to play a role in the course of patient’s healing. Consequently, these pains may be considered to be multifactorial among which are anxiety disorders, depression, insomnia, and low energy levels or lethargies. Hence, chronic pain control is not possible just with eliminating the inducing factor, rather it demands some multilateral approach . MoreoveOn the basis of the interventions conducted in this study, we may conclude that:Low doses of valproate sodium specifically along with NSAIDs demonstrate very pronounced therapeutic effects on reduction and even removal of radicular chronic pains.The half-life, elimination constant and true clearance of drug for each patient was significantly different from the equivalent parameters obtained from population studies .Lower true clearance in our patients in comparison of population studies results proved that not only drug efficacy assessment but also therapeutic drug monitoring (TDM) and drug plasma concentration determination is necessary for prescription.Hence, it is recommended that supplementary studies on pharmacokinetics and their NSAIDs interactions be carried out with a focus on eliminated metabolites of drugs.