Emergence of xylazine as a public health threat: what does the anesthesiologist need to know for perioperative care?

This paper explores the rapid emergence of xylazine exposure in the USA and its implications for anesthesiologists. Xylazine, a non-opioid sedative and analgesic often used in veterinary medicine, has increasingly been found as an adulterant in the illicit substance supply, leading to serious health implications. The pharmacological properties of xylazine, its clinical effects, and the challenges it poses for clinicans will be discussed. Perioperative strategies for anesthesiologists to manage these potential cases are provided. Furthermore, this paper necessitates an epidemiological understanding for detection and multidisciplinary collaboration in addressing this emerging public health threat. The manuscript concludes by emphasizing the role anesthesiologists will have to play in managing the clinical implications of xylazine and contributing to public health strategies aimed at curbing its misuse.

Observational study of the effect of ketamine infusions on sedation depth, inflammation, and clinical outcomes in mechanically ventilated patients with SARS-CoV-2.

Severely ill patients with COVID-19 are challenging to sedate and often require high-dose sedation and analgesic regimens. Ketamine can be an effective adjunct to facilitate sedation of critically ill patients but its effects on sedation level and inflammation in COVID-19 patients have not been studied. This retrospective, observational cohort study evaluated the effect of ketamine infusions on inflammatory biomarkers and clinical outcomes in mechanically ventilated patients with SARS-CoV-2 infection. A total of 186 patients were identified (47 received ketamine, 139 did not). Patients who received ketamine were significantly younger than those who did not (mean (standard deviation) 59.2 (14.2) years versus 66.3 (14.4) years; P = 0.004), but there was no statistically significant difference in body mass index (P = 0.25) or sex distribution (P = 0.91) between groups. Mechanically ventilated patients who received ketamine infusions had a statistically significant reduction in Richmond Agitation-Sedation Scale score (-3.0 versus -2.0, P < 0.001). Regarding inflammatory biomarkers, ketamine was associated with a reduction in ferritin (P = 0.02) and lactate (P = 0.01), but no such association was observed for C-reactive protein (P = 0.27), lactate dehydrogenase (P = 0.64) or interleukin-6 (P = 0.87). No significant association was observed between ketamine administration and mortality (odds ratio 0.971; 95% confidence interval 0.501 to 1.882; P = 0.93). Ketamine infusion was associated with improved sedation depth in mechanically ventilated COVID-19 patients and provided a modest anti-inflammatory benefit but did not confer benefit with respect to mortality or intensive care unit length of stay.

Caring for Our Patients With Opioid Use Disorder in the Perioperative Period: A Guide for the Anesthesiologist.

Opioid use disorder (OUD) is a rising public health crisis, impacting millions of individuals and families worldwide. Anesthesiologists can play a key role in improving morbidity and mortality around the time of surgery by informing perioperative teams and guiding evidence-based care and access to life-saving treatment for patients with active OUD or in recovery. This article serves as an educational resource for the anesthesiologist caring for patients with OUD and is the second in a series of articles published in Anesthesia & Analgesia on the anesthetic and analgesic management of patients with substance use disorders. The article is divided into 4 sections: (1) background to OUD, treatment principles, and the anesthesiologist; (2) perioperative considerations for patients prescribed medications for OUD (MOUD); (3) perioperative considerations for patients with active, untreated OUD; and (4) nonopioid and nonpharmacologic principles of multimodal perioperative pain management for patients with untreated, active OUD, or in recovery. The article concludes with a stepwise approach for the anesthesiologist to support OUD treatment and recovery. The anesthesiologist is an important leader of the perioperative team to promote these suggested best practices and help save lives.

Real-world study of intranasal ketamine for use in patients with refractory chronic migraine: a retrospective analysis.

INTRODUCTION: Subanesthetic ketamine infusion has been used for managing refractory headache in inpatient or outpatient infusion settings. Intranasal ketamine may be an alternative option for outpatient care. METHODS: A retrospective study was conducted at a single tertiary headache center to assess the clinical effectiveness and tolerability of intranasal ketamine in patients with refractory chronic migraine. Candidates who received intranasal ketamine between January 2019 and February 2020 were screened through an electronic medical record query. Manual chart reviews and structured telephone interviews were conducted on obtaining informed consent. RESULTS: Of 242 subjects screened, 169 (79.9% women) of median (IQR) age 44 (22) years were interviewed. They reported a median (IQR) of 30 (9) monthly headache days and tried 4 (1) classes of preventive medications. Overall, they used 6 (6) sprays per day, with a median (IQR) of spray use of 10 (11) days per month. Intranasal ketamine was reported as 'very effective' in 49.1% and the quality of life was considered 'much better' in 35.5%. At the time of the interview, 65.1% remained current intranasal ketamine users and 74.0% reported at least one adverse event. CONCLUSION: In this descriptive study, intranasal ketamine served as an acute treatment for refractory chronic migraine by reducing headache intensity and improving quality of life with relatively tolerable adverse events. Most patients found intranasal ketamine effective and continued to use it despite these adverse events. Given the potential for overuse, it should be reserved for those clearly in need of more effective rescue treatment with appropriate safety precautions. Well-designed prospective placebo-controlled trials are necessary to demonstrate the efficacy and safety of intranasal ketamine in patients with migraine.

Population pharmacokinetic and safety analysis of ropivacaine used for erector spinae plane blocks.

INTRODUCTION: Erector spinae plane blocks have become popular for thoracic surgery. Despite a theoretically favorable safety profile, intercostal spread occurs and systemic toxicity is possible. Pharmacokinetic data are needed to guide safe dosing. METHODS: Fifteen patients undergoing thoracic surgery received continuous erector spinae plane blocks with ropivacaine 150 mg followed by subsequent boluses of 40 mg every 6 hours and infusion of 2 mg/hour. Arterial blood samples were obtained over 12 hours and analyzed using non-linear mixed effects modeling, which allowed for conducting simulations of clinically relevant dosing scenarios. The primary outcome was the Cmax of ropivacaine in erector spinae plane blocks. RESULTS: The mean age was 66 years, mean weight was 77.5 kg, and mean ideal body weight was 60 kg. The mean Cmax was 2.5 ±1.1 mg/L, which occurred at a median time of 10 (7-47) min after initial injection. Five patients developed potentially toxic ropivacaine levels but did not experience neurological symptoms. Another patient reported transient neurological toxicity symptoms. Our data suggested that using a maximum ropivacaine dose of 2.5 mg/kg based on ideal body weight would have prevented all toxicity events. Simulation predicted that reducing the initial dose to 75 mg with the same subsequent intermittent bolus dosing would decrease the risk of toxic levels to <1%. CONCLUSION: Local anesthetic systemic toxicity can occur with erector spinae plane blocks and administration of large, fixed doses of ropivacaine should be avoided, especially in patients with low ideal body weights. Weight-based ropivacaine dosing could reduce toxicity risk. TRIAL REGISTRATION NUMBER: NCT04807504; clinicaltrials.gov.

ASRA Pain Medicine consensus guidelines on the management of the perioperative patient on cannabis and cannabinoids.

BACKGROUND: The past two decades have seen an increase in cannabis use due to both regulatory changes and an interest in potential therapeutic effects of the substance, yet many aspects of the substance and their health implications remain controversial or unclear. METHODS: In November 2020, the American Society of Regional Anesthesia and Pain Medicine charged the Cannabis Working Group to develop guidelines for the perioperative use of cannabis. The Perioperative Use of Cannabis and Cannabinoids Guidelines Committee was charged with drafting responses to the nine key questions using a modified Delphi method with the overall goal of producing a document focused on the safe management of surgical patients using cannabinoids. A consensus recommendation required ≥75% agreement. RESULTS: Nine questions were selected, with 100% consensus achieved on third-round voting. Topics addressed included perioperative screening, postponement of elective surgery, concomitant use of opioid and cannabis perioperatively, implications for parturients, adjustment in anesthetic and analgesics intraoperatively, postoperative monitoring, cannabis use disorder, and postoperative concerns. Surgical patients using cannabinoids are at potential increased risk for negative perioperative outcomes. CONCLUSIONS: Specific clinical recommendations for perioperative management of cannabis and cannabinoids were successfully created.

Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: A phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: Celecoxib-tramadol co-crystal (CTC) is a first-in-class analgesic co-crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co-crystal structure, compared with its active constituents administered alone/concomitantly. AIM: We evaluated CTC in moderate-to-severe acute postoperative pain. MATERIALS AND METHODS: This randomized, double-blind, factorial, active- and placebo-controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate-to-severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac-tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0-48 h sum of pain intensity differences (SPID0-48) in all randomized patients. Pain intensity was assessed on a 0-10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals. RESULTS: In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0-48 (least-squares mean: -139.1 [95% confidence interval: -151.8, -126.5]) than tramadol (-109.1 [-121.7, -96.4]; p < 0.001), celecoxib (-103.7 [-116.4, -91.0]; p < 0.001), or placebo (-74.6 [-92.5, -56.6]; p < 0.001). Total treatment-emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug-related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths. CONCLUSION: CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States.

A critical review of oliceridine injection as an IV opioid analgesic for the management of severe acute pain.

INTRODUCTION: Oliceridine is a G protein-selective (biased) agonist at the µ-opioid receptor, with less recruitment of ß-arrestin-2, a signaling pathway associated with opioid-related adverse events. Nonclinical evidence showed that oliceridine elicits a rapid systemic analgesic effect while attenuating opioid-related adverse events. AREAS COVERED: Three pivotal studies in patients with moderate-to-severe acute pain, including two randomized, double-blind, placebo- and morphine-controlled efficacy studies following either orthopedic surgery-bunionectomy or plastic surgery-abdominoplasty; and an open-label safety study following a surgical procedure or due to a medical condition. EXPERT OPINION: Poorly controlled acute postoperative pain is associated with poorer recovery, longer hospitalization, increased complications, and worse healthcare outcomes. Recently, oliceridine intravenous injection was approved for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Introduction of this new IV opioid provides a valuable option to manage postoperative pain.

The demographics of pain after spinal cord injury: a survey of our model system.

STUDY DESIGN: Survey OBJECTIVES: Better understand the demographics of pain after spinal cord injury (SCI). SETTING: Academic Level 1 trauma center and SCI Model System. METHODS: A survey including general demographic questions, questions of specific interest to the authors, the standardized SCI Pain Instrument (SCIPI), International SCI Pain Data Set, Basic form (ISCIPDS:B), Patient Reported Outcomes Measurement Information System (PROMIS) neuropathic 5a (PROMIS-Neur), and PROMIS nociceptive 5a (PROMIS-No). RESULTS: 81% of individuals with SCI experience chronic pain and 86% of individuals with pain have neuropathic pain. 55% of individuals had shoulder pain. Females and those who recall >5/10 pain during initial hospital stay had significantly higher PROMIS-Neur scores. Completeness of injury correlates inversely with the degree of neuropathic pain. Those who recall >5 pain during the initial hospital stay and those who reported the worst or second worst pain as being shoulder pain had significantly higher PROMIS-No scores. Lumbosacral injuries trended towards higher PROMIS-No scores and had the highest PROMIS-Neur scores. Those with tetraplegia were more likely to develop shoulder pain and those with shoulder pain had higher PROMIS-No scores. CONCLUSIONS: Chronic pain is almost universal in patients with SCI. Pain is more commonly reported as neuropathic in nature and females reported more neuropathic pain than males. Physicians should monitor for nociceptive shoulder pain, particularly in those with tetraplegia. Patients with incomplete injuries or lumbosacral injuries are more likely to report higher levels of neuropathic pain and pain levels should be monitored closely. Those with more neuropathic and nociceptive pain recall worse pain at initial hospitalization. Better understanding pain demographics in this population help screen, prevent and manage chronic pain in these patients.

Ketamine in the Past, Present, and Future: Mechanisms, Metabolites, and Toxicity.

PURPOSE OF REVIEW: While ketamine's analgesia has mostly been attributed to antagonism of N-methyl-D-aspartate receptors, evidence suggests multiple other pathways are involved in its antidepressant and possibly analgesic activity. These mechanisms and ketamine's role in the nociplastic pain paradigm are discussed. Animal studies demonstrating ketamine's neurotoxicity have unclear human translatability and findings from key rodent and human studies are presented. RECENT FINDINGS: Ketamine's metabolites, and (2R,6R)-hydroxynorketamine in particular, may play a greater role in its clinical activity than previously believed. The activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the mammalian target of rapamycin by ketamine are mechanisms that are still being elucidated. Ketamine might work best in nociplastic pain, which involves altered pain processing. While much is known about ketamine, new studies will continue to define its role in clinical medicine. Evidence supporting ketamine's neurotoxicity in humans is lacking and should not impede future ketamine clinical trials.

Effect of difelikefalin, a selective kappa opioid receptor agonist, on respiratory depression: A randomized, double-blind, placebo-controlled trial.

Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, small-peptidic structure limits CNS entry, minimizing potential CNS-mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single-center, randomized, double-blind, placebo-controlled, three-way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg/kg i.v.) or placebo on sequential days with an intervening 24 (±2) h washout period. The primary end points included incidence of increased end-tidal carbon dioxide (ETCO2 ) greater than or equal to 10 mm Hg versus baseline or a level greater than 50 mm Hg sustained greater than or equal to 30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO2 ) to less than 92% sustained greater than or equal to 30 seconds. Secondary end points included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO2 or reduced SpO2 primary end point criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4-h postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO2 , SpO2 , or respiratory rate. The most commonly reported treatment-emergent AEs (TEAEs; ≥20% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg/kg i.v. did not produce respiratory depression.

An anesthesiologist-led inpatient buprenorphine initiative.

Hospitalized patients with opioid use disorder who present with acute pain are challenging to manage. Without any treatment, their mortality in the first 28 days after discharge is substantially increased. Unlike extended-release naltrexone, which requires a period of withdrawal, or methadone, which can cause prolonged corrected QT (QTc) and carries a higher risk of respiratory depression, buprenorphine provides potent analgesia with low respiratory risk. Hospitalization provides a unique opportunity for clinicians to perform buprenorphine induction, which could potentially reduce mortality without affecting analgesia. Our acute pain management service uses multimodal analgesia to maintain adequate analgesia and minimize withdrawal during buprenorphine induction in the hospital. With the assistance of narcotics addiction rehabilitation program specialists, we help link patients to outpatient buprenorphine providers and maximize the chance of successful recovery. The primary outcome of this study was to determine the percentage of patients who filled an outpatient buprenorphine prescription after undergoing inpatient induction.

Peripherally Acting µ-Opioid Receptor Antagonists in the Management of Postoperative Ileus: a Clinical Review.

Postoperative ileus (POI) and constipation are common secondary effects of opioids and carry significant clinical and economic impacts. µ-Opioid receptors mediate opioid analgesia in the central nervous system (CNS) and gastrointestinal-related effects in the periphery. Peripherally acting µ-opioid receptor antagonists (PAMORAs) block the peripheral effects of opioids in the gastrointestinal tract, while maintaining opioid analgesia in the CNS. While most are not approved for POI or postoperative opioid-induced constipation (OIC), PAMORAs have a potential role in these settings via their selective effects on the µ-opioid receptor. This review will discuss recent clinical trials evaluating the safety and efficacy of PAMORAs, with a focus on alvimopan (Entereg®) and methylnaltrexone (Relistor®) in patients with POI or postoperative OIC. We will characterize potential factors that may have impacted the efficacy observed in phase 3 trials and discuss future directions for the management and treatment of POI.

Neuraxial and peripheral misconnection events leading to wrong-route medication errors: a comprehensive literature review.

We conducted a search of the literature to identify case reports of neuraxial and peripheral nervous system misconnection events leading to wrong-route medication errors. This narrative review covers a 20-year period (1999-2019; English-language publications and abstracts) and included the published medical literature (PubMed and Embase) and public access documents. Seventy-two documents representing 133 case studies and 42 unique drugs were determined relevant. The most commonly reported event involved administering an epidural medication by an intravenous line (29.2% of events); a similar proportion of events (27.7%) involved administering an intravenous medication by an epidural line. Medication intended for intravenous administration, but delivered intrathecally, accounted for 25.4% of events. In the most serious cases, outcomes were directly related to the toxicity of the drug that was unintentionally administered. Patient deaths were reported due to the erroneous administration of chemotherapies (n=16), muscle relaxants (n=4), local anesthetics (n=4), opioids (n=1), and antifibrinolytics (n=1). Severe outcomes, including paraplegia, paraparesis, spinal cord injury, and seizures were reported with the following medications: vincristine, gadolinium, diatrizoate meglumine, doxorubicin, mercurochrome, paracetamol, and potassium chloride. These case reports confirm that misconnection events leading to wrong-route errors can occur and may cause serious injury. This comprehensive characterization of events was conducted to better inform clinicians and policymakers, and to describe an emergent strategy designed to mitigate patient risk.

Oliceridine is Associated with Reduced Risk of Vomiting and Need for Rescue Antiemetics Compared to Morphine: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials.

INTRODUCTION: Use of parenteral opioids is a major risk factor for postoperative nausea and vomiting. Conventional opioids bind to µ-opioid receptors (MOR), stimulate both the G-protein signaling (achieving analgesia); and the ß-arrestin pathway (associated with opioid-related adverse effects). Oliceridine, a next-generation IV opioid, is a G-protein selective MOR agonist, with limited recruitment of ß-arrestin. In two randomized, placebo- and morphine-controlled phase 3 studies of patients with moderate-to-severe acute pain following bunionectomy or abdominoplasty, oliceridine at demand doses of 0.1, 0.35, and 0.5 mg provided rapid and sustained analgesia vs. placebo with favorable gastrointestinal (GI) tolerability. In this exploratory analysis, we utilized a clinical endpoint assessing gastrointestinal tolerability, "complete GI response" defined as the proportion of patients with no vomiting and no use of rescue antiemetic to characterize the GI tolerability profile of oliceridine vs. morphine. METHODS: A logistic regression model was utilized to compare oliceridine (pooled regimens) vs. morphine, after controlling for analgesia (using the sum of pain intensity difference [SPID]-48/24 [bunionectomy/abdominoplasty] with pre-rescue scores carried forward for 6 h). This analysis excluded patients receiving placebo and was performed for each study separately and for pooled data from both studies. RESULTS: In the unadjusted analysis, a significantly greater proportion of patients in the placebo (76.4%), oliceridine 0.1 mg (68.0%), and 0.35 mg (46.2%) demand dose achieved complete GI response vs. morphine 1 mg (30.8%), p ≤ 0.005. In the adjusted analysis, after controlling for analgesia, the odds ratio of experiencing a complete GI response with oliceridine (pooled regimens) vs. morphine was 3.14 (95% CI: 1.78, 5.56; p < 0.0001) in bunionectomy study and 1.92 (95% CI: 1.09, 3.36; p = 0.024) in abdominoplasty study. CONCLUSIONS: When controlled for the analgesic effects (constant SPID-48/24), the odds ratio for complete GI response was higher with oliceridine than morphine, suggesting better GI tolerability with oliceridine.

Blood-brain barrier: mechanisms governing permeability and interaction with peripherally acting µ-opioid receptor antagonists.

The blood-brain barrier (BBB) describes the unique properties of endothelial cells (ECs) that line the central nervous system (CNS) microvasculature. The BBB supports CNS homeostasis via EC-associated transport of ions, nutrients, proteins and waste products between the brain and blood. These transport mechanisms also serve as physiological barriers to pathogens, toxins and xenobiotics to prevent them from contacting neural tissue. The mechanisms that govern BBB permeability pose a challenge to drug design for CNS disorders, including pain, but can be exploited to limit the effects of a drug to the periphery, as in the design of the peripherally acting µ-opioid receptor antagonists (PAMORAs) used to treat opioid-induced constipation. Here, we describe BBB physiology, drug properties that affect BBB penetrance and how data from randomized clinical trials of PAMORAs improve our understanding of BBB permeability.

Meeting the Challenge of Analgesia in a Pregnant Woman With Burn Injury Using Subanesthetic Ketamine: A Case Report and Literature Review.

Pain management guidelines for burn injury in pregnant women are scarce. Maternal and fetal morbidity and mortality in pregnant burn patients have been shown to be higher than that of the general population, especially in severe burns. Early intervention and interdisciplinary treatment are critical to optimize maternal and fetal outcomes. Proper pain management is central to wound treatment, as poor control of pain can contribute to delayed healing, re-epithelialization, as well as persistent neuropathic pain. We present this case of a 34-year-old female patient who suffered an 18% total body surface area burn during the third trimester of pregnancy to demonstrate that ketamine can be considered as an adjunct for procedural and background analgesia during the third trimester, as part of a multimodal strategy in a short-term, monitored setting after a thorough and complete analysis of risks and benefits and careful patient selection.