Intravenous paracetamol for persistent pain after endoscopic mucosal resection discriminates patients at risk of adverse events and those who can be safely discharged.

INTRODUCTION: The frequency and severity of abdominal pain after endoscopic mucosal resection (EMR) of colonic laterally spreading lesions (LSLs) of ≥ 20 mm is unknown, as are the risk factors to predict its occurrence. We aimed to prospectively characterize pain after colonic EMR , determine the rapidity and frequency of its resolution after analgesia, and estimate the frequency of needing further intervention. METHODS: Procedural and lesion data on consecutive patients with LSLs who underwent EMR at a single tertiary referral center were prospectively collected. If pain after colonic EMR, graded using a visual analogue scale (VAS), lasted > 5 minutes, 1 g of paracetamol was administered. Pain lasting > 30 minutes lead to clinical review and upgrade to opiate analgesics. Investigations and interventions for pain were recorded. RESULTS: 67/336 patients (19.9 %, 95 %CI 16.0 %-24.5 %) experienced pain after colonic EMR (median VAS 5, interquartile range 3-7). Multivariable predictors of pain were: lesion size ≥ 40 mm, odds ratio [OR] 2.15 (95 %CI 1.22-3.80); female sex, OR 1.99 (95 %CI 1.14-3.48); and intraprocedural bleeding requiring endoscopic control, OR 1.77 (95 %CI 0.99-3.16). Of 67 patients with pain, 51 (76.1 %, 95 %CI 64.7 %-84.7 %) had resolution of their "mild pain" after paracetamol and were discharged without sequelae. The remaining 16 (23.9 %) required opiate analgesia (fentanyl), after which 11/16 patients (68.8 %; "moderate pain") could be discharged. The 5/67 patients (7.5 %) with "severe pain" had no resolution despite fentanyl; all settled during hospital admission (median duration 2 days), intravenous analgesia, and antibiotics. CONCLUSION: Pain after colonic EMR occurs in approximately 20 % of patients and resolves rapidly and completely in the majority with administration of intravenous paracetamol. Pain despite opiates heralds a more serious scenario and further investigation should be considered.

Unintentional overdoses: understanding the fentanyl landscape and reducing harm.

PURPOSE OF REVIEW: Adolescent and young adult overdoses and overdose fatalities continue to increase despite reductions in self-reported substance use. This review aims to explore factors contributing to this overdose epidemic, highlight signs of overdose and the role of the overdose reversal medication naloxone, and provide recommendations for practice change to support patients and decrease their risk of unintentional overdose. RECENT FINDINGS: The potent opioid fentanyl is a common contaminant in nonopioid substances, as well as in heroin and counterfeit pills, heightening risk of fatal overdose. Adolescents and young adults who die of overdose are rarely engaged in substance use disorder treatment. Medications for opioid use disorder are effective at reducing risk of fatal overdose but are underutilized, as is the opioid reversal medication naloxone. SUMMARY: Pediatric clinician engagement in harm reduction with adolescents and young adults, starting with screening through a confidential interview, may enhance pathways to care and reduce the risk of overdose.

Opioids for procedural pain in neonates.

BACKGROUND: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. OBJECTIVES: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was December 2021. SELECTION CRITERIA: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD -2.58, 95% CI -3.12 to -2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD -1.97, 95% CI -2.46 to -1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD -0.20, 95% CI -2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI -0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD -0.83, 95% CI -2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence): with one study reporting a concerning increase in severe apnea (RR 7.44, 95% CI 0.42 to 132.95; 31 participants, 1 study; very low-certainty). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI -0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD -4.62, 95% CI -6.38 to -2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI -1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD -0.29, 95% CI -1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD -1.10, 95% CI -2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD -0.17, 95% CI -2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously). AUTHORS' CONCLUSIONS: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. The evidence is very uncertain about the effect of opioids on episodes of bradycardia, hypotension or severe apnea. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.

Acceptability of a Fentanyl Vaccine to Prevent Opioid Overdose and Need for Personalized Decision-Making.

BACKGROUND: The opioid epidemic worsened during the coronavirus disease 2019 (COVID-19) pandemic. Synthetic opioids (primarily fentanyl) comprise the most common drugs involved in overdose (OD) death. A vaccine that blocks fentanyl from reaching the brain to prevent OD is under development, and insight is needed into its acceptability. METHODS: Using a semi-structured interview guide, persons with opioid use disorder (OUD), family, professionals, and the public were interviewed about attitudes and concerns regarding a fentanyl vaccine. Reactions to fictional clinical vignettes of persons at risk of OUD because of pain and/or substance use histories were collected, analyzed, and quantified for favorability. Interviews were transcribed, coded, and analyzed thematically. RESULTS: Among N = 64 participants, (70.3% female, average age 32.4 years), attitudes were favorable toward a fentanyl vaccine, with preference for lifelong durability (76% of n = 55 asked). Perceived benefits centered on the potential for a life-saving intervention, suffering averted, healthcare dollars saved, and the utility of a passive harm reduction strategy. Concerns centered on uncertainty regarding vaccine safety, questions about efficacy, worry about implications for future pain management, stigma, and need for supportive counseling and guidance to personalize decision making. Reactions to vignettes revealed complex attitudes toward fentanyl vaccination when considering recipient age, health history, and future risks for addiction and pain. CONCLUSIONS: Positive responses to a fentanyl vaccine were found along with appreciation for the complexity of a vaccine strategy to prevent OD in the setting of pain and uncertain durability. Further research is needed to elucidate operational, ethical, and communications strategies to advance the model.

A case of buprenorphine-precipitated withdrawal managed with high-dose buprenorphine.

BACKGROUND: Buprenorphine-naloxone has a very high affinity for the mu-receptor and can cause precipitated opioid withdrawal, typically more severe than withdrawal that occurs naturally, when administered while a full mu-opioid receptor agonist remains in a person's system. To avoid precipitated withdrawal, one needs to be in mild to moderate opioid withdrawal at the time of buprenorphine-naloxone induction. Recently, there have been reported cases of precipitated withdrawal occurring in patients taking fentanyl knowingly or unknowingly, despite them being in adequate opioid withdrawal at the time of induction. When this occurs, the current recommendation is to provide 2 mg of buprenorphine-naloxone every 1-2 hours. OBJECTIVES: Describe a case of successful management of buprenorphine-precipitated withdrawal with escalation of the dose of buprenorphine and highlight implications for future management. METHODS: We present a case of a patient with a history of opioid use disorder who was in moderate opioid withdrawal at the time of buprenorphine-naloxone induction and experienced precipitated withdrawal after buprenorphine-naloxone administration. RESULTS: High-dose buprenorphine-naloxone was given to the patient and precipitated withdrawal subsided after receiving a total of 20 mg. On the next day, the patient had no symptoms of opioid withdrawal and is currently maintained on 16 mg/day. CONCLUSION: With the rising prevalence of fentanyl-laced drugs, increased instances of precipitated withdrawal are likely to be encountered. In cases of precipitated withdrawal, giving a high dose of buprenorphine-naloxone rapidly is safe and will allow rapid reversal of withdrawal symptoms.

Fentanyl and other opioid involvement in methamphetamine-related deaths.

Background: Methamphetamine-related deaths have been rising along with those involving synthetic opioids, mostly fentanyl and fentanyl analogs (FAs). However, the extent to which methamphetamine involvement in deaths differs from those changes occurring in synthetic opioid involvement is unknown.Objectives: To determine the patterns and temporal changes in methamphetamine-related deaths with and without other drug involvement.Methods: Data from all methamphetamine-related deaths in West Virginia from 2013 to 2018 were analyzed. Quasi-Poisson regression analyses over time were conducted to compare the rates of change in death counts among methamphetamine and fentanyl//FA subgroups.Results: A total of 815 methamphetamine-related deaths were analyzed; 572 (70.2%) were male and 527 (64.7%) involved an opioid. The proportion of methamphetamine only deaths stayed relatively flat over time although the actual numbers of deaths increased. Combined fentanyl/FAs and methamphetamine were involved in 337 deaths (41.3%) and constituted the largest increase from 2013 to 2018. The modeling of monthly death counts in 2017-2018 found that the average number of deaths involving fentanyl without methamphetamine significantly declined (rate of change -0.025, p < .001), while concomitant fentanyl with methamphetamine and methamphetamine only death counts increased significantly (rate of change 0.056 and 0.057, respectively, p < .001).Conclusions: Fentanyl and FAs played an increasingly significant role in methamphetamine-related deaths. The accelerating number of deaths involving fentanyl/FAs and methamphetamine indicates the importance of stimulants and opioids in unintentional deaths. Comprehensive surveillance efforts should continue to track substance use patterns to ensure that appropriate prevention programs are undertaken.

"It wasn't here, and now it is. It's everywhere": fentanyl's rising presence in Oregon's drug supply.

BACKGROUND: Illicit fentanyl has contributed to a drastic increase in overdose drug deaths. While fentanyl has subsumed the drug supply in the Northeastern and Midwestern USA, it has more recently reached the Western USA. For this study, we explored perspectives of people who use drugs (PWUD) on the changing drug supply in Oregon, experiences of and response to fentanyl-involved overdose, and recommendations from PWUD to reduce overdose risk within the context of illicit fentanyl's dramatic increase in the recreational drug supply over the past decade. METHODS: We conducted in-depth interviews by phone with 34 PWUD in Oregon from May to June of 2021. We used thematic analysis to analyze transcripts and construct themes. RESULTS: PWUD knew about fentanyl, expressed concern about fentanyl pills, and were aware of other illicit drugs containing fentanyl. Participants were aware of the increased risk of an overdose but remained reluctant to engage with professional first responders due to fear of arrest. Participants had recommendations for reducing fentanyl overdose risk, including increasing access to information, harm reduction supplies (e.g., naloxone, fentanyl test strips), and medications for opioid use disorder; establishing drug checking services and overdose prevention sites; legalizing and regulating the drug supply; and reducing stigma enacted by healthcare providers. CONCLUSION: PWUD in Oregon are aware of the rise of fentanyl and fentanyl pills and desire access to tools to reduce harm from fentanyl. As states in the Western USA face an inflection point of fentanyl in the drug supply, public health staff, behavioral health providers, and first responders can take action identified by the needs of PWUD.

Improving postoperative analgesia in hallux valgus surgery: oral opioids suppression by addition of a single transdermal fentanyl patch: a prospective evaluation.

The last decade there is an exponential increase in opioid related deaths. This is proven to be correlated with the rising medical prescription rates of strong opioids. We investigated whether pain after hallux valgus surgery under popliteal nerve block could be adequately controlled without the prescription of oral opioids, with a single transdermal fentanyl patch. In this prospective observational study with 100 patients undergoing corrective first metatarsal osteotomies we prospectively investigated the adverse effects and need for extra pain medication. The transdermal fentanyl patch was applied one hour before surgery, prior to the ultrasound guided popliteal nerve block. Patients filled out a questionnaire every 6 hours to evaluate the pain [VAS-score], nausea [PONV-score], activity [acivity and ambulation score] and the intake of extra medication. Postoperative pain was well controlled [Mean VAS 2,53]. The maximum mean VAS score [3.93] was recorded 36 hours postoperatively. 63.8% of patients had less pain than expected. No major adverse effects were reported by the patients. Nausea was mainly mild and the majority of patients reported 'no effect' or 'sometimes' effect on daily activities. In an era where surgeons need to be aware of the threat of overuse of strong opioids, the use of a single transdermal fentanyl patch in combination with an ultrasound guided nerve block can be a good alternative in hallux valgus surgery. The use of the patch seems to obviate the need for oral opioids after discharge. Nausea and vomiting were a concern - as expected -, but only at 24 and 36 hours. On the other hand nausea did not seem to affect activity, as there was a gradual increase in activity score over time.

Improvements on a chemically contiguous hapten for a vaccine to address fentanyl-contaminated heroin.

Unintentional overdose deaths related to opioids and psychostimulants have increased in prevalence due to the adulteration of these drugs with fentanyl. Synergistic effects between illicit compounds and fentanyl cause aggravated respiratory depression, leading to inadvertent fatalities. Traditional small-molecule therapies implemented in the expanding opioid epidemic present numerous problems since they interact with the same opioid receptors in the brain as the abused drugs. In this study, we report an optimized dual hapten for use as an immunopharmacotherapeutic tool in order to develop antibodies capable of binding to fentanyl-contaminated heroin in the periphery, thus impeding the drugs' psychoactive effects on the central nervous system. This vaccine produced antibodies with nanomolar affinities and effectively blocked opioid analgesic effects elicited by adulterated heroin. These findings provide further insight into the development of chemically contiguous haptens for broad-spectrum immunopharmacotherapies against opioid use disorders.

Comparison of Chloroprocaine Versus Lidocaine With Epinephrine, Sodium Bicarbonate, and Fentanyl for Epidural Extension Anesthesia in Elective Cesarean Delivery: A Randomized, Triple-Blind, Noninferiority Study.

BACKGROUND: For emergent intrapartum cesarean delivery (CD), the literature does not support the use of any particular local anesthetic solution to extend epidural analgesia to cesarean anesthesia. We hypothesized that 3% chloroprocaine (CP) would be noninferior to a mixture of 2% lidocaine, 150 µg of epinephrine, 2 mL of 8.4% bicarbonate, and 100 µg of fentanyl (LEBF) in terms of onset time to surgical anesthesia. METHODS: In this single-center randomized noninferiority trial, adult healthy women undergoing CD were randomly assigned to epidural anesthesia with either CP or LEBF. Sensory blockade (pinprick) to T10 was established before operating room (OR) entry for elective CD. On arrival to the OR, participants received the epidural study medications in a standardized manner to simulate the conversion of "epidural labor analgesia to surgical anesthesia." The primary outcome was the time to loss of touch sensation at the T7 level. A noninferiority margin was set at 3 minutes. The secondary outcome was the need for intraoperative analgesia supplementation. RESULTS: In total, 70 women were enrolled in the study. The mean onset time to achieve a bilateral sensory block to touch at the T7 dermatome level was 655 (standard deviation [SD] = 258) seconds for group CP and 558 (269) seconds for group LEBF, a difference in means of 97 seconds (90% confidence interval [CI], SD = -10.6 to 204; P = .10 for noninferiority). The upper limit of the 90% CI for the mean difference exceeded the prespecified 3-minute noninferiority margin. There was no meaningful difference in the requirement for intraoperative analgesia between the 2 groups. CONCLUSION: Both anesthetic solutions have a rapid onset of anesthesia when used to extend low-dose epidural sensory block to surgical anesthesia. Data from the current study provide insufficient evidence to confirm that CP is noninferior to LEBF for rapid epidural extension anesthesia for CD, and further research is required to determine noninferiority.

Efficacy of an Oxycodone-Propofol Combination versus a Fentanyl-Propofol Combination in Conscious Sedation during Therapeutic Endoscopic Retrograde Cholangiopancreatography in Elderly Patients.

BACKGROUND: With a rapidly aging population, the need for endoscopic retrograde cholangiopancreatography (ERCP) is increasing. The commonly used sedation anesthesia in ERCP is a combination of propofol and fentanyl, even though fentanyl may cause some adverse reactions such as respiratory depression. OBJECTIVES: This study aimed to evaluate the efficacy of oxycodone combined with propofol versus fentanyl combined with propofol for sedation anesthesia during ERCP. METHODS: A total of 193 patients aged from 65 to 80 years undergoing ERCP were enrolled and randomized into two groups: an "oxycodone combined with propofol" group (group OP, n = 97) and a "fentanyl combined with propofol" group (group FP, n = 96). The rate of perioperative adverse events as well as the recovery time, patients' satisfaction, and endoscopists' satisfaction were noted. RESULTS: There was no difference in the frequency of hypotension or bradycardia between the two groups, but there were more episodes of desaturation (SpO2 <90% for >10 s in 8.3%), postoperative nausea (7.3%), and vomiting (5.2%) in group FP than in group OP. Patients' satisfaction in group FP was lower than that in group OP. The recovery time was longer in group FP than in group OP. CONCLUSIONS: Oxycodone combined with propofol was effective in ERCP, with a low incidence of perioperative adverse events.

Oral Ondansetron to Reduce Vomiting in Children Receiving Intranasal Fentanyl and Inhaled Nitrous Oxide for Procedural Sedation and Analgesia: A Randomized Controlled Trial.

STUDY OBJECTIVE: Intranasal fentanyl and inhaled nitrous oxide are increasingly combined to provide procedural sedation and analgesia in the pediatric emergency setting. This regimen is attractive because of its nonparenteral administration, but is associated with a higher incidence of vomiting than nitrous oxide alone. We seek to assess whether prophylactic oral ondansetron use could reduce the incidence of vomiting associated with intranasal fentanyl and nitrous oxide for procedural sedation compared with placebo. METHODS: This was a double-blind, randomized controlled trial of oral ondansetron versus placebo conducted at a single tertiary care pediatric emergency department. Children aged 3 to 18 years with planned sedation with intranasal fentanyl and nitrous oxide were randomized to receive oral ondansetron or placebo 30 to 60 minutes before nitrous oxide administration. The primary outcome was early vomiting associated with procedural sedation, defined as occurring during or up to 1 hour after nitrous oxide administration. Secondary outcomes included vomiting 1 to 24 hours after procedural sedation, procedural sedation duration, adverse events, and quality of sedation across the 2 groups. RESULTS: We recruited 442 participants and 436 were included for analysis. There was no significant difference in the primary outcome, early vomiting associated with procedural sedation, between the groups: ondansetron 12% versus placebo 16%, with a difference in proportions of -4.6% (95% confidence interval -11% to 2.0%; P=.18). Most sedations were reported as optimal by treating clinicians (91%). Only 2 minor adverse events occurred, both in the placebo group. CONCLUSION: Oral ondansetron does not significantly reduce vomiting during or shortly after procedural sedation with combined intranasal fentanyl and inhaled nitrous oxide.

Sedation and Analgesia for Liver Cancer Percutaneous Radiofrequency Ablation: Fentanyl and Oxycodone Comparison.

Background: Sedation and analgesia use in percutaneous radiofrequency ablation (RFPA) for liver cancer is a necessary part of the procedure; however, the optimal medicine for sedation and analgesia for PRFA remains controversial. The aim of this study was to compare the perioperative pain management, haemodynamic stability and side effects between oxycodone (OXY) and fentanyl (FEN) use in patients under dexmedetomidine sedation. Methods: Two hundred and five adults with an American Society of Anaesthesiologists physical status score of I to II were included in this study. Patients were assigned to the OXY (n=101) or FEN (n=104) group. Radiofrequency ablation was performed under spontaneous breathing and with painless anaesthesia administered intravenously. The outcomes included fluctuations in mean arterial pressure, heart rate, side effects and the perioperative numerical rating scale (NRS). Results: Radiofrequency ablation was successfully performed in 205 patients. No significant differences were observed in mean blood pressure fluctuations between the two groups despite the longer durations of ablation and total sedation time in the OXY group. The highest NRS score during the surgery and 1 hour and 2 hours after the surgery were significantly lower in the OXY group than in the FEN group. Heart rate fluctuations were significantly lower in the OXY group than in FEN group throughout the surgery. More patients in the FEN group displayed unwanted body movement and respiratory depression. Conclusions: Both oxycodone and fentanyl can be applied for liver cancer percutaneous radiofrequency ablation; however, oxycodone provides a better patient experience, lower postoperative pain, less respiratory depression and stable haemodynamic fluctuations.

Comparing the different oxycodone doses of prevent oxycodone for prevention of preventing fentanyl-induced cough during induction of general anaesthesia.

BACKGROUND: Fentanyl-induced cough (FIC) usually occurs after the intravenous administration of fentanyl during general anaesthesia induction. It is a transient condition depending on the fentanyl administration dose and injection speed. Oxycodone can also prevent FIC because it has been proven to treat coughing. This study aimed to evaluate the efficacy of different oxycodone doses to prevent FIC during general anaesthesia induction. METHODS: In a double-blind randomised controlled trial, 210 adult patients who were undergoing elective surgery, classified as American Society of Anaesthesiologists physical status I-II, and aged 20-65 years were randomly assigned into five equally sized groups: Sham group, Group Ⅰ, Group II, Group III and Group IV. Groups Ⅰ-IV were each intravenously injected with oxycodone 0.025, 0.05, 0.075 and 0.100 mg/kg, while an equal volume of normal saline was given instead of oxycodone in the Sham group. Five minutes later, fentanyl 3 µg/kg was intravenously injected within 5 seconds, then, 2 minutes later the other drugs were administered for general anaesthesia induction. The occurrence and severity of coughing were observed within 2 minutes of the fentanyl injection. Vital signs and intensities of coughing were recorded and analysed. RESULTS: Coughing incidences were each 57.1, 50, 42.8, 33.3 and 21.4% in the Sham group and Groups Ⅰ-IV. Significant differences were found in the incidences of coughing between the Sham group and Groups III-IV. No significant differences in FIC incidences have been detected between the Sham group and Groups Ⅰ-II. However, no significant difference in FIC incidence existed between Group III and Group IV. Cough severities in Groups III and IV were significantly lower than in Groups Ⅰ and II (P < .05). No significant differences existed in the hypotension or severe bradycardia incidences during anaesthesia induction among the five groups (P > .05). CONCLUSION: Oxycodone 0.075 mg/kg provided more effective FIC prevention during general anaesthesia induction.

The fentanyls: pharmacological and clinical aspects relevant to Australia.

OBJECTIVE: North American and other jurisdictions have seen an alarming rise in the abuse of the fentanyls, with related overdose deaths. We sought to review this group of drugs to alert Australian psychiatrists and drug and alcohol clinicians to their clinical effects and potential harms. CONCLUSIONS: The extreme potency of the fentanyls underlie their lethality. Vigilance and investment from both policy makers and health care providers are required to mitigate harm from a possible future Australian fentanyl epidemic.

Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis.

In December 2018, the Centers for Disease Control declared fentanyl the deadliest drug in America. Opioid overdose is the single greatest cause of death in the United States adult population (ages 18-50), and fentanyl and its analogs [fentanyl/fentanyl analogs (F/FAs)] are currently involved in >50% of these deaths. Anesthesiologists in the United States were introduced to fentanyl in the early 1970s when it revolutionized surgical anesthesia by combining profound analgesia with hemodynamic stability. However, they quickly had to master its unique side effect. F/FAs can produce profound rigidity in the diaphragm, chest wall and upper airway within an extremely narrow dosing range. This clinical effect was called wooden chest syndrome (WCS) by anesthesiologists and is not commonly known outside of anesthesiology or to clinicians or researchers in addiction research/medicine. WCS is almost routinely fatal without expert airway management. This review provides relevant clinical human pharmacology and animal data demonstrating that the significant increase in the number of F/FA-induced deaths may involve α-adrenergic and cholinergic receptor-mediated mechanical failure of the respiratory and cardiovascular systems with rapid development of rigidity and airway closure. Although morphine and its prodrug, heroin, can cause mild rigidity in abdominal muscles at high doses, neither presents with the distinct and rapid respiratory failure seen with F/FA-induced WCS, separating F/FA overdose from the slower onset of respiratory depression caused by morphine-derived alkaloids. This distinction has significant consequences for the design and implementation of new pharmacologic strategies to effectively prevent F/FA-induced death. SIGNIFICANCE STATEMENT: Deaths from fentanyl and F/FAs are increasing in spite of availability and awareness of the opioid reversal drug naloxone. This article reviews literature suggesting that naloxone may be ineffective against centrally mediated noradrenergic and cholinergic effects of F/FAs, which clinically manifest as severe muscle rigidity and airway compromise (e.g., wooden chest syndrome) that is rapid and distinct from respiratory depression seen with morphine-derived alkaloids. A physiologic model is proposed and implications for new drug development and treatment are discussed.

Deep sedation for transvenous lead extraction: a large single-centre experience.

AIMS: Transvenous lead extraction for cardiac implantable electronic devices (CIED) is of growing importance. Nevertheless, the optimal anaesthetic approach, general anaesthesia vs. deep sedation (DS), remains unresolved. We describe our tertiary centre experience of the feasibility and safety of DS. METHODS AND RESULTS: Extraction procedures were performed in the electrophysiology (EP) laboratory by two experienced electrophysiologists. We used intravenous Fentanyl, Midazolam, and Propofol for DS. A stepwise approach with locking stylets, dilator sheaths, and mechanical sheaths via subclavian, femoral, or internal jugular venous access was utilized. Patient characteristics and procedural data were collected. Logistic regression models were used to identify parameters associated with sedation-related complications. Extraction of 476 leads (dwelling time/patient 88 ± 49 months, 30% ICD leads) was performed in 220 patients (64 ± 17 years, 80% male). Deep sedation was initiated with bolus administration of Fentanyl, Midazolam, and Propofol; mean doses 0.34 ± 0.12 µg/kg, 24.3 ± 6.8 µg/kg, and 0.26 ± 0.13 mg/kg, respectively. Deep sedation was maintained with continuous Propofol infusion (initial dose 3.7 ± 1.1 mg/kg/h; subsequently increased to 4.7 ± 1.2 mg/kg/h with 3.9 ± 2.6 adjustments) and boluses of Midazolam and Fentanyl as indicated. Sedation-related episodes of hypotension, requiring vasopressors, and hypoxia, requiring additional airway management, occurred in 25 (11.4%) and 5 (2.3%) patients, respectively. These were managed without adverse consequences. Five patients (2.3%) experienced major intraprocedural complications; there were no procedure-related deaths. All of our logistic regression models indicated intraprocedural support was associated with administration higher Fentanyl doses. CONCLUSION: Transvenous lead extraction under DS in the EP laboratory is a safe procedure with high success rates when performed by experienced staff.

Fentanyl and Drug Overdose: Perceptions of Fentanyl Risk, Overdose Risk Behaviors, and Opportunities for Intervention among People who use Opioids in Baltimore, USA.

BACKGROUND: Fentanyl-related mortality has skyrocketed among people who use opioids (PWUO) in North America. The current study of PWUO aims to examine the perceived fentanyl risk and training needs; fatal overdose prevention behaviors; and, feasibility of a peer education approach to reducing fentanyl-related fatal overdoses in Baltimore, Maryland, USA. METHODS: 316 street-recruited PWUO were interviewed about fentanyl in Baltimore, MD. RESULTS: Most participants (56%) reported that "all" or "almost all" heroin in Baltimore was adulterated with fentanyl and were worried (75%) about their drug buddies overdosing on fentanyl. Half (54%) the participants felt that they needed more training to respond to an overdose. Many participants (66%) reported receiving naloxone or a prescription for it, yet only 17% carried naloxone with them "often" or "always." Among people who inject drugs (PWID) only 13% had naloxone available "often" or "always" when they injected with others, and 51% "often" or "always" injected alone. Almost half of participants (47%) were "very willing" to talk with people in their neighborhood about fentanyl. CONCLUSIONS: The majority of PWUO perceived that most heroin in Baltimore was adulterated with fentanyl, yet most did not carry naloxone and PWID often did so alone. Given the high perceived risk of fentanyl and relatively low uptake of fatal overdose prevention behaviors, there is an urgency for safe injection facilities, access to medically assisted treatment, and programs that work with the drug-using community to deliver overdose prevention training as well as promote behaviors to carry naloxone and not use drugs alone.

Changes in consumption of opioid analgesics in Israel 2009 to 2016: An update focusing on oxycodone and fentanyl formulations.

PURPOSE: The purpose of the study is to assess opioid (morphine, methadone, oxycodone, pethidine, and fentanyl) consumption in Israel during 2009 to 2016 and identify recent trends. METHODS: Data for all treatment settings, private and public, for the years 2009 to 2016, were extracted from the Israel Ministry of Health's Pharmaceutical Administration database. The data were used to calculate defined daily doses (DDD) per 1000 inhabitants per day, of the various drugs. RESULTS: Consumption of the 5 opioids increased by 68%, from 3.40 DDD/1000 inhabitants/day in 2009 to 5.72 DDD/1000 inhabitants/day in 2016. This trend resulted mostly from increases in oxycodone consumption from 0.50 DDD/1000 inhabitants/day to 2.03 DDD/1000 inhabitants/day (namely, 4-fold) and in fentanyl consumption, from 1.09 DDD/1000 inhabitants/day to 2.33 DDD/1000 inhabitants/day (about 2-fold). The use of the 3 remaining opioids decreased substantially as follows: pethidine from 0.03 DDD/1000/day in 2009 to 0.007 DDD/1000 inhabitants/day in 2016 (-67%), methadone from 1.61 DDD/1000 inhabitants/day to 1.20 DDD/1000 inhabitants/day (-25%), and morphine from 0.17 DDD/1000 inhabitants/day to 0.15 DDD/1000 inhabitants/day (-12%). An increasing trend was also observed in the use of oxycodone/naloxone (Targin) and oxycodone/acetaminophen (Percocet) combinations, while a decrease was observed in the use of pure oxycodone formulations. CONCLUSIONS: The increase in opioid consumption persisted throughout the years 2009 to 2016. This has been associated with substantial changes in the patterns of prescribing opioids, characterized by increases in oxycodone and fentanyl prescriptions and decreases in morphine, methadone, and pethidine prescriptions. A national program aiming to ensure safe use of opioids in the treatment of chronic pain is warranted.

The fentanyl family: A distinguished medical history tainted by abuse.

WHAT IS KNOWN AND OBJECTIVE: Beginning in the 1950s, a family of potent opioids was synthesized and developed (fentanyl and analogues). They continue to serve as valuable analgesic agents. But the recent spike and notoriety of their abuse has raised alarm, even calls for tighter control. We review the trajectory of these compounds. COMMENT: To rectify shortcomings of the then available opioid analgesics, an analogue family of compounds was synthesized having a piperidine ring (presumptive principal active moiety in morphine and meperidine). The result was more potent and rapid-acting compounds, including alfentanil, carfentanil, fentanyl, sufentanil and others. These properties, plus availability in formulations for multiple routes of administration, impart broad therapeutic utility. They also unfortunately favour abuse. WHAT IS NEW AND CONCLUSION: The abuse of fentanyl and its analogues (legal and illicit) serves as a case study for the dilemma and difficulties balancing a medical need against psychosocial realities. The fentanyl family provides relief for severe pain, but their very properties also engender abuse.