Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties. It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere, consequently imposing devastating social, economic, and health burdens worldwide. However, the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown, and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce. This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action, including neural circuit dysfunction and neuroinflammation. We discuss recent progress in the development of pharmacological interventions, anti-fentanyl vaccines, anti-fentanyl/heroin conjugate vaccines, and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression. However, translational studies and clinical trials are still lacking. Considering the present opioid crisis, the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.
Humans ; Fentanyl/therapeutic use* ; Opioid-Related Disorders/drug therapy* ; Drug Overdose/prevention & control* ; Analgesics, Opioid/adverse effects* ; Vaccines/therapeutic use* ; Brain

BACKGROUNDThe management of pain, agitation, and delirium (PAD) in Intensive Care Unit (ICU) is beneficial for patients and makes it widely applied in clinical practice. Previous studies showed that the clinical practice of PAD in ICU was improving; yet relatively little information is available in China. This study aimed to investigate the practice of PAD in ICUs in China.

METHODSA multicenter, nationwide survey was conducted using a clinician-directed questionnaire from September 19 to December 18, 2016. The questionnaire focused on the assessment and management of PAD by the clinicians in ICUs. The practice of PAD was compared among the four regions of China (North, Southeast, Northwest, and Southwest). The data were expressed as percentage and frequency. The Chi-square test, Fisher's exact test, and line-row Chi-square test were used.

RESULTSOf the 1011 valid questionnaire forms, the response rate was 80.37%. The clinicians came from 704 hospitals across 158 cities of China. The rate of PAD assessment was 75.77%, 90.21%, and 66.77%, respectively. The rates of PAD scores were 45.8%, 68.94%, and 34.03%, respectively. The visual analog scale, Richmond agitation-sedation scale, and confusion assessment method for the ICU were the first choices of scales for PAD assessment. Fentanyl, midazolam, and dexmedetomidine were the first choices of agents for analgesic, sedation, and delirium treatment. While choosing analgesics and sedatives, the clinicians put the pharmacological characteristics of drugs in the first place (66.07% and 76.36%). Daily interruption for sedation was carried out by 67.26% clinicians. Most of the clinicians (87.24%) used analgesics while using sedatives. Of the 738 (73%) clinicians titrating the sedatives on the basis of the proposed target sedation level, 268 (26.61%) clinicians just depended on their clinical experience. Totally, 519 (51.34%) clinicians never used other nondrug strategies for PAD. The working time of clinicians was an important factor in the management of analgesia and sedation rather than their titles and educational background. The ratios of pain score and sedation score in the Southwest China were the highest and the North China were the lowest. The ratios of delirium assessment and score were the same in the four regions of China. Moreover, the first choices of scales for PAD in the four regions were the same. However, the top three choices of agents in PAD treatment in the four regions were not the same.

CONCLUSIONSThe practice of PAD in China follows the international guidelines; however, the pain assessment should be improved. The PAD practice is a little different across the four regions of China; however, the trend is consistent.

TRIAL REGISTRATIONThe study is registered at http://www.clinicaltrials.gov (No. ChiCTR-OOC-16009014, www.chictr. org.cn/index.aspx.).

Delirium ; drug therapy ; Dexmedetomidine ; therapeutic use ; Fentanyl ; therapeutic use ; Haloperidol ; therapeutic use ; Humans ; Hypnotics and Sedatives ; therapeutic use ; Intensive Care Units ; statistics & numerical data ; Midazolam ; therapeutic use ; Pain ; drug therapy ; Pain Management ; methods ; Pain Measurement ; methods ; Surveys and Questionnaires

The objective of this study was to assess the effect of lidocaine jelly application to chest tubes on the intensity and duration of overall pain, chest tube site pain and the required analgesics for postoperative pain relief in coronary artery bypass graft (CABG) patients. For patients in group L, we applied sterile 2% lidocaine jelly on the chest tubes just before insertion, and for patients in group C, we applied normal saline. Overall visual analogue scale (VAS), maximal pain area with their VAS were documented postoperatively, and the frequency that button of patient-controlled analgesia was pressed (FPB) and total fentanyl consumption were assessed. The number of patients who complained that tube site was the most painful site was significantly higher in group C than in group L (85% vs. 30% at extubation, P<0.001). The overall VAS score was significantly higher in group C than in group L (39.14+/-12.49 vs. 27.74+/-13.76 at extubation, P=0.006). After all of the tubes were removed, the VAS score decreased more in group C (5.74+/-4.77, P<0.001) than in group L (3.05+/-2.48, P<0.001). FPB and total fentanyl consumption were significantly higher in group C than in group L (73.00, 59.00-78.00 vs. 34.00, 31.00-39.25, P<0.001; 2,214.65+/-37.01 vs. 1,720.19+/-361.63, P<0.001, respectively). Lidocaine jelly application is a very simple way to reduce postoperative pain by reducing chest tube site pain after CABG. (Clinical Trials Registry No. ACTRN 12611001215910)
Adolescent ; Adult ; Aged ; Analgesia, Patient-Controlled ; Anesthetics, Local/*therapeutic use ; Cardiac Catheters/adverse effects ; Chest Tubes/*adverse effects ; Coronary Artery Bypass ; Drainage ; Female ; Fentanyl/therapeutic use ; Humans ; Lidocaine/*therapeutic use ; Male ; Middle Aged ; Pain Management/*methods ; Pain Measurement ; Pain, Postoperative/*drug therapy ; Random Allocation ; Young Adult

PURPOSE: We evaluated the incidence and risk factors of postoperative nausea and vomiting (PONV) in patients with fentanyl-based intravenous patient-controlled analgesia (IV-PCA) and single antiemetic prophylaxis of 5-hydroxytryptamine type 3 (5 HT3)-receptor antagonist after the general anesthesia. MATERIALS AND METHODS: In this retrospective study, incidence and risk factors for PONV were evaluated with fentanyl IV-PCA during postoperative 48 hours after various surgeries. RESULTS: Four hundred-forty patients (23%) of 1878 had showed PONV. PCA was discontinued temporarily in 268 patients (14%), mostly due to PONV (88% of 268 patients). In multivariate analysis, female, non-smoker, history of motion sickness or PONV, long duration of anesthesia (>180 min), use of desflurane and intraoperative remifentanil infusion were independent risk factors for PONV. If one, two, three, four, five, or six of these risk factors were present, the incidences of PONV were 18%, 19%, 22%, 31%, 42%, or 50%. Laparoscopic surgery and higher dose of fentanyl were not risk factors for PONV. CONCLUSION: Despite antiemetic prophylaxis with 5 HT3-receptor antagonist, 23% of patients with fentanyl-based IV-PCA after general anesthesia showed PONV. Long duration of anesthesia and use of desflurane were identified as risk factors, in addition to risk factors of Apfel's score (female, non-smoker, history of motion sickness or PONV). Also, intraoperative remifentanil infusion was risk factor independent of postoperative opioid use. As the incidence of PONV was up to 50% according to the number of risk factors, risk-adapted, multimodal or combination therapy should be applied.
Adult ; Aged ; Analgesia, Patient-Controlled/*adverse effects ; Analgesics, Opioid/*adverse effects/therapeutic use ; Antiemetics/administration & dosage/therapeutic use ; Female ; Fentanyl/*adverse effects/therapeutic use ; Humans ; Incidence ; Isoflurane/adverse effects/*analogs & derivatives/therapeutic use ; Male ; Middle Aged ; Piperidines/*adverse effects/therapeutic use ; Postoperative Nausea and Vomiting/chemically induced/*epidemiology ; Retrospective Studies ; Risk Factors

PURPOSE: Opioids improve pain from knee and hip osteoarthritis (OA) and decrease the functional impairment of patients. However, there is a possibility that opioids induce analgesia and suppress the physiological pain of OA in patients, thereby inducing the progression of OA changes in these patients. The purpose of the current study was to investigate the possibility of progressive changes in OA among patients using opioids. MATERIALS AND METHODS: Two hundred knee or hip OA patients were evaluated in the current prospective, randomized, active-controlled study. Patients were randomized 1:1:1 into three parallel treatment groups: loxoprofen, tramadol/acetaminophen, and transdermal fentanyl groups. Medication was administered for 12 weeks. Pain scores and progressive OA changes on X-ray films were evaluated. RESULTS: Overall, pain relief was obtained by all three groups. Most patients did not show progressive OA changes; however, 3 patients in the transdermal fentanyl group showed progressive OA changes during the 12 weeks of treatment. These 3 patients used significantly higher doses than others in the transdermal fentanyl group. Additionally, the average pain score for these 3 patients was significantly lower than the average pain score for the other patients in the transdermal fentanyl group. CONCLUSION: Fentanyl may induce progressive changes in knee or hip OA during a relatively short period, compared with oral Non-Steroidal Anti-Inflammatory Drugs or tramadol.
Aged ; Aged, 80 and over ; Analgesics, Opioid/*adverse effects/therapeutic use ; Disease Progression ; Female ; Fentanyl/*adverse effects/therapeutic use ; Humans ; Male ; Middle Aged ; Osteoarthritis, Hip/*drug therapy/radiography ; Osteoarthritis, Knee/*drug therapy/radiography ; Pain/drug therapy

PURPOSE: This analysis was done to investigate the optimal regimen for fentanyl-based intravenous patient-controlled analgesia (IV-PCA) by finding a safe and effective background infusion rate and assessing the effect of adding adjuvant drugs to the PCA regimen. MATERIALS AND METHODS: Background infusion rate of fentanyl, type of adjuvant analgesic and/or antiemetic that was added to the IV-PCA, and patients that required rescue analgesics and/or antiemetics were retrospectively reviewed in 1827 patients who underwent laparoscopic abdominal surgery at a single tertiary hospital. RESULTS: Upon multivariate analysis, lower background infusion rates, younger age, and IV-PCA without adjuvant analgesics were identified as independent risk factors of rescue analgesic administration. Higher background infusion rates, female gender, and IV-PCA without additional 5HT3 receptor blockers were identified as risk factors of rescue antiemetics administration. A background infusion rate of 0.38 microg/kg/hr [area under the curve (AUC) 0.638] or lower required rescue analgesics in general, whereas, addition of adjuvant analgesics decreased the rate to 0.37 microg/kg/hr (AUC 0.712) or lower. A background infusion rate of 0.36 microg/kg/hr (AUC 0.638) or higher was found to require rescue antiemetics in general, whereas, mixing antiemetics with IV-PCA increased the rate to 0.37 microg/kg/hr (AUC 0.651) or higher. CONCLUSION: Background infusion rates of fentanyl between 0.12 and 0.67 microg/kg/hr may safely be used without any serious side effects for IV-PCA. In order to approach the most reasonable background infusion rate for effective analgesia without increasing postoperative nausea and vomiting, adding an adjuvant analgesic and an antiemetic should always be considered.
Adult ; Aged ; Analgesia, Patient-Controlled/*adverse effects/*methods ; Female ; Fentanyl/administration & dosage/therapeutic use ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Sex Factors

PURPOSE: Opioid-based intravenous patient-controlled analgesia (IV PCA) is popular method of postoperative pain control, but many patients suffer from IV PCA-related postoperative nausea and vomiting (PONV). In this retrospective observational study, we have determined independent predictors of IV PCA-related PONV and predictive values of the Apfel's simplified risk score in pursuance of identifying high-risk patients. MATERIALS AND METHODS: We analyzed 7000 patients who received IV PCA with background infusion after elective surgery. Patients who maintained IV PCA for a postoperative period of 48 hr (completion group, n=6128) were compared with those who have discontinued IV PCA within 48 hr of surgery due to intractable PONV (cessation group, n=872). Patients, anesthetics, and surgical factors known for predicting PONV were evaluated by logistic regression analysis to identify independent predictors of IV PCA related intractable PONV. RESULTS: In a stepwise multivariate analysis, weight, background infusion dose of fentanyl, addition of ketolorac to PCA, duration of anesthesia, general anesthesia, head and neck surgery, and Apfel's simplified risk score were revealed as independent risk factors for intractable PONV followed by the cessation of IV PCA. In addition, Apfel's simplified risk score, which demonstrated the highest odds ratio among the predictors, was strongly correlated with the cessation rate of IV PCA. CONCLUSION: Multimodal prophylactic antiemetic strategies and dose reduction of opioids may be considered as strategies for the prevention of PONV with the use of IV PCA, especially in patients with high Apfel's simplified risk scores.
Adult ; Analgesia, Patient-Controlled/*adverse effects ; Anesthetics, Intravenous/administration & dosage/adverse effects/therapeutic use ; Antiemetics/administration & dosage/therapeutic use ; Female ; Fentanyl/administration & dosage/adverse effects/therapeutic use ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Postoperative Nausea and Vomiting/*drug therapy ; Retrospective Studies ; Risk Assessment/methods ; Risk Factors

PURPOSE: To investigate the analgesic effect and incidence of postoperative nausea and vomiting (PONV) between the opioid fentanyl and the non-steroidal anti-inflammatory drug ketorolac in patients who underwent eye amputation surgery. METHODS: Retrospective observational case series. Eighty-two patients underwent evisceration or enucleation surgery by one surgeon over a 2-year period. Fentanyl by intravenous patient-controlled analgesia (IV-PCA) at 20 microg/kg with 12 mg/kg ondansetron or intravenous ketorolac at 2 mg/kg/day was administered to patients at postoperative days 0, 1, and 2. The pain score was measured using an 11-point visual analog scale (VAS). The incidence of severe nausea requiring anti-emetics and the incidence of vomiting were reviewed. RESULTS: The mean postoperative VAS in the fentanyl group was significantly lower than that in the ketorolac group on the day of operation for both types of surgery (p = 0.001 and p = 0.004, respectively). At postoperative days 1 and 2, the mean VAS was not different between the two groups for either surgical type (p > 0.05 for both days). The mean VAS was significantly higher in eviscerated patients than in enucleated patients at postoperative days 0 and 1 in the fentanyl group (p = 0.023 and p = 0.016, respectively). However, this was not observed in the ketorolac group. The incidence of PONV was higher in the fentanyl group than in the ketorolac group, although this was not statistically significant for either surgical type (p > 0.05 for both groups). CONCLUSIONS: Fentanyl was more effective as an analgesic than was ketorolac on the day of operation for both surgical types. There was no difference between the two analgesics on postoperative day 1. The analgesic effect of fentanyl in enucleated patients was significantly higher than in eviscerated patients at postoperative days 0 and 1. The use of fentanyl by IV-PCA was associated with greater PONV despite co-administration with anti-emetics, although this finding was not significant.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Opioid/therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; *Eye Enucleation ; *Eye Evisceration ; Female ; Fentanyl/*therapeutic use ; Humans ; Ketorolac/*therapeutic use ; Male ; Middle Aged ; Pain, Postoperative/*drug therapy ; Retrospective Studies ; Treatment Outcome ; Young Adult

PURPOSE: Chronic low back pain is a common clinical problem. As medication, non-steroidal anti-inflammatory drugs are generally used; however, they are sometimes non-effective. Recently, opioids have been used for the treatment of chronic low back pain, and since 2010, transdermal fentanyl has been used to treat chronic non-cancer pain in Japan. The purpose of the current study was to examine the efficacy of transdermal fentanyl in the treatment of chronic low back pain. MATERIALS AND METHODS: This study included patients (n=62) that suffered from chronic low back pain and were non-responsive to non-steroidal anti-inflammatory drugs. Their conditions consisted of non-specific low back pain, multiple back operations, and specific low back pain awaiting surgery. Patients were given transdermal fentanyl for chronic low back pain. Scores of the visual analogue scale and the Oswestry Disability Index, as well as adverse events were evaluated before and after therapy. RESULTS: Overall, visual analogue scale scores and Oswestry Disability Index scores improved significantly after treatment. Transdermal fentanyl (12.5 to 50 microg/h) was effective in reducing low back pain in 45 of 62 patients; however, it was not effective in 17 patients. Patients who experienced the most improvement were those with specific low back pain awaiting surgery. Adverse events were seen in 40% of patients (constipation, 29%; nausea, 24%; itching, 24%). CONCLUSION: Disability Index scores in 73% of patients, especially those with specific low back pain awaiting surgery; however, it did not decrease pain in 27% of patients, including patients with non-specific low back pain or multiple back operations.
Administration, Cutaneous ; Adult ; Aged ; Aged, 80 and over ; Chronic Disease ; Female ; Fentanyl/*administration & dosage/*therapeutic use ; Humans ; Low Back Pain/*drug therapy ; Male ; Middle Aged ; Young Adult

PURPOSE: The aim of this prospective, double-blind, randomized study was to investigate the analgesic effects of low-dose ketamine on intravenous patient-controlled analgesia (IV-PCA) with fentanyl for pain control in pediatric patients following the Nuss procedure for pectus excavatum. MATERIALS AND METHODS: Sixty pediatric patients undergoing the Nuss procedure were randomly assigned to receive fentanyl (Group F, n=30) or fentanyl plus ketamine (Group FK, n=30). Ten minutes before the end of surgery, following the loading dose of each solution, 0.5 microg/kg/hr of fentanyl or 0.5 microg/kg/hr of fentanyl plus 0.15 mg/kg/hr of ketamine was infused via an IV-PCA pump (basal rate, 1 mL/hr; bolus, 0.5 mL; lock out interval, 30 min). Fentanyl consumption, pain score, ketorolac use, nausea/vomiting, ondansetron use, pruritus, respiratory depression, hallucination, dreaming, and parent satisfaction with pain control were measured throughout the 48 hours following surgery. RESULTS: The pain scores, ketorolac use, and fentanyl consumption of Group FK were significantly lower than in Group F (p<0.05). The incidence of nausea/vomiting and ondansetron use in Group FK was significantly lower than in Group F (p<0.05). There were no reports of respiratory depression, hallucination or dreaming. Parent satisfaction with pain control was similar between the two groups. CONCLUSION: We concluded that low-dose ketamine added to IV-PCA with fentanyl after the Nuss procedure in pediatric patients can reduce pain scores, consumption of fentanyl, and incidence of nausea/vomiting without increasing side effects.
Analgesia, Patient-Controlled/*methods ; Analgesics/*therapeutic use ; Child ; Double-Blind Method ; Female ; Fentanyl/*therapeutic use ; Funnel Chest/surgery ; Humans ; Injections, Intravenous ; Ketamine/*therapeutic use ; Male ; Pain, Postoperative/drug therapy