Pub Date : 2025-12-12DOI: 10.1097/ALN.0000000000005803
Michael S Avidan, Jon Cohen, Jessica L Saleska
The poem Cassandra's Curse, accompanied by a brief commentary, explores the psychological and existential terrain of routine medical surveillance through the lens of a patient who is also a physician and has stage IV leiomyosarcoma. Using the medium of poetry, the author hopes to offer clinicians, as well as a broader audience, deeper insight into the dread patients with life-limiting illness repeatedly face, even in relation to apparently mundane procedures, such as computed axial tomography scans.
{"title":"Cassandra's Curse.","authors":"Michael S Avidan, Jon Cohen, Jessica L Saleska","doi":"10.1097/ALN.0000000000005803","DOIUrl":"https://doi.org/10.1097/ALN.0000000000005803","url":null,"abstract":"<p><p>The poem Cassandra's Curse, accompanied by a brief commentary, explores the psychological and existential terrain of routine medical surveillance through the lens of a patient who is also a physician and has stage IV leiomyosarcoma. Using the medium of poetry, the author hopes to offer clinicians, as well as a broader audience, deeper insight into the dread patients with life-limiting illness repeatedly face, even in relation to apparently mundane procedures, such as computed axial tomography scans.</p>","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1097/aln.0000000000005824
Adam J Milam,Zakaria Sharif,Molly B Kraus,David Warner
{"title":"Suzetrigine for the Treatment of Acute Pain: Comment.","authors":"Adam J Milam,Zakaria Sharif,Molly B Kraus,David Warner","doi":"10.1097/aln.0000000000005824","DOIUrl":"https://doi.org/10.1097/aln.0000000000005824","url":null,"abstract":"","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":"120 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1097/aln.0000000000005825
Todd Bertoch,Carmen Bozic,Scott G Weiner
{"title":"Suzetrigine for the Treatment of Acute Pain: Reply.","authors":"Todd Bertoch,Carmen Bozic,Scott G Weiner","doi":"10.1097/aln.0000000000005825","DOIUrl":"https://doi.org/10.1097/aln.0000000000005825","url":null,"abstract":"","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":"6 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Suzetrigine for the Treatment of Acute Pain: Comment.","authors":"Bingbing Xiang,Chaoyi Deng,Han Yang,Wensheng Zhang","doi":"10.1097/aln.0000000000005823","DOIUrl":"https://doi.org/10.1097/aln.0000000000005823","url":null,"abstract":"","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":"43 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1097/aln.0000000000005894
Simone Jansen,Erik Olofsen,Laurence Moss,Joseph C Grieco,Marc L Lesnick,James C Hackworth,Monique van Velzen,Albert Dahan,Elise Sarton,Geert Jan Groeneveld,Marieke Niesters,Rutger van der Schrier
BACKGROUNDThe novel analgesic cebranopadol targets the nociceptin (NOP) and mu-opioid (MOP) receptor, acting as a novel full dual NOP-MOP-receptor agonist, with possible differences in respiratory effects compared to selective MOP-opioids like oxycodone.METHODSIn this randomized, double-blind, placebo-controlled study, 30 healthy volunteers received oral placebo (n=20), cebranopadol (600 µg, n=20; 800 µg, n=20; or 1000 µg, n=20) or oxycodone (30 mg, n=20; or 60 mg, n=20) on 4 occasions in a partial-crossover design. On each occasion ventilation at an extrapolated isohypercapnic level of 55 mmHg (V̇E55) derived from hypercapnic ventilatory responses and electrical pain tolerance tests were obtained at regular intervals before and for 24 h after drug intake. Mixed model analyses on respiratory endpoints was performed (primary endpoint) as well as an exploratory population pharmacokinetic/pharmacodynamic analyses on respiratory and analgesic endpoints.RESULTSOxygen desaturations (to ∼80%) were observed in 65% of subjects after oxycodone 60 mg versus cebranopadol 1000 µg in 25% of subjects (all occurring in between respiratory or pain testing). A significant main effect and a significant separation of all cebranopadol and oxycodone doses versus placebo (all p<0.0001) was observed with cebranopadol 600 μg producing less respiratory depression than oxycodone 30 mg (p=0.022). Pharmacokinetic/pharmacodynamic analyses showed that respiratory C50 values (drug concentration causing 50% effect) was 0.20±0.54 for cebranopadol versus 36±6 ng/mL for oxycodone. Cebranopadol was more potent than oxycodone in producing analgesia.CONCLUSIONSThe primary endpoint showed separation between the respiratory effects of cebranopadol and oxycodone, with 25% less respiratory depression at equianalgesia, as observed in the pharmacokinetic/pharmacodynamic analysis.
{"title":"Respiratory and antinociceptive effects of NOP-MOP agonist cebranopadol versus full opioid receptor agonist oxycodone: a comparison in healthy volunteers.","authors":"Simone Jansen,Erik Olofsen,Laurence Moss,Joseph C Grieco,Marc L Lesnick,James C Hackworth,Monique van Velzen,Albert Dahan,Elise Sarton,Geert Jan Groeneveld,Marieke Niesters,Rutger van der Schrier","doi":"10.1097/aln.0000000000005894","DOIUrl":"https://doi.org/10.1097/aln.0000000000005894","url":null,"abstract":"BACKGROUNDThe novel analgesic cebranopadol targets the nociceptin (NOP) and mu-opioid (MOP) receptor, acting as a novel full dual NOP-MOP-receptor agonist, with possible differences in respiratory effects compared to selective MOP-opioids like oxycodone.METHODSIn this randomized, double-blind, placebo-controlled study, 30 healthy volunteers received oral placebo (n=20), cebranopadol (600 µg, n=20; 800 µg, n=20; or 1000 µg, n=20) or oxycodone (30 mg, n=20; or 60 mg, n=20) on 4 occasions in a partial-crossover design. On each occasion ventilation at an extrapolated isohypercapnic level of 55 mmHg (V̇E55) derived from hypercapnic ventilatory responses and electrical pain tolerance tests were obtained at regular intervals before and for 24 h after drug intake. Mixed model analyses on respiratory endpoints was performed (primary endpoint) as well as an exploratory population pharmacokinetic/pharmacodynamic analyses on respiratory and analgesic endpoints.RESULTSOxygen desaturations (to ∼80%) were observed in 65% of subjects after oxycodone 60 mg versus cebranopadol 1000 µg in 25% of subjects (all occurring in between respiratory or pain testing). A significant main effect and a significant separation of all cebranopadol and oxycodone doses versus placebo (all p<0.0001) was observed with cebranopadol 600 μg producing less respiratory depression than oxycodone 30 mg (p=0.022). Pharmacokinetic/pharmacodynamic analyses showed that respiratory C50 values (drug concentration causing 50% effect) was 0.20±0.54 for cebranopadol versus 36±6 ng/mL for oxycodone. Cebranopadol was more potent than oxycodone in producing analgesia.CONCLUSIONSThe primary endpoint showed separation between the respiratory effects of cebranopadol and oxycodone, with 25% less respiratory depression at equianalgesia, as observed in the pharmacokinetic/pharmacodynamic analysis.","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":"7 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1097/aln.0000000000005822
Ammar Siddiqui,Jeff L Xu,Apolonia E Abramowicz
{"title":"Suzetrigine for the Treatment of Acute Pain: Comment.","authors":"Ammar Siddiqui,Jeff L Xu,Apolonia E Abramowicz","doi":"10.1097/aln.0000000000005822","DOIUrl":"https://doi.org/10.1097/aln.0000000000005822","url":null,"abstract":"","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":"111 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1097/aln.0000000000005808
David O Warner,Randall P Flick,Juraj Sprung,Robert T Wilder
Melissa L. Coleman, M.D., Editor Early Exposure to Anesthesia and Learning Disabilities in a Population-based Birth Cohort. By Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, and Warner DO. A nesthesiology 2009; 110:796-804. Reprinted with permission. Anesthetic drugs administered to immature animals may cause neurohistopathologic changes and alterations in behavior. The authors studied association between anesthetic exposure before age 4 yr and the development of reading, written language, and math learning disabilities. This was a population-based, retrospective birth cohort study. The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota, from 1976 to 1982 and who remained in the community at 5 yr of age were reviewed to identify children with learning disabilities. Cox proportional hazards regression was used to calculate hazard ratios for anesthetic exposure as a predictor of learning disabilities, adjusting for gestational age at birth, sex, and birth weight. Of the 5,357 children in this cohort, 593 received general anesthesia before age 4 yr. Compared with those not receiving anesthesia (n = 4,764), a single exposure to anesthesia (n = 449) was not associated with an increased risk of learning disabilities (hazard ratio, 1.0; 95% CI, 0.79 to 1.27). However, children receiving two anesthetics (n = 100) or three or more anesthetics (n = 44) were at increased risk for learning disabilities (hazard ratio, 1.59; 95% CI, 1.06 to 2.37; and hazard ratio, 2.60; 95% CI, 1.60 to 4.24, respectively). The risk for learning disabilities increased with longer cumulative duration of anesthesia exposure (expressed as a continuous variable; P = 0.016). Exposure to anesthesia was a significant risk factor for the later development of learning disabilities in children receiving multiple but not single anesthetics. These data cannot reveal whether anesthesia itself may contribute to learning disabilities or whether the need for anesthesia is a marker for other unidentified factors that contribute to learning disabilities.
{"title":"Anesthesia and Babies' Brains: Lessons from the Lounge.","authors":"David O Warner,Randall P Flick,Juraj Sprung,Robert T Wilder","doi":"10.1097/aln.0000000000005808","DOIUrl":"https://doi.org/10.1097/aln.0000000000005808","url":null,"abstract":"Melissa L. Coleman, M.D., Editor Early Exposure to Anesthesia and Learning Disabilities in a Population-based Birth Cohort. By Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, and Warner DO. A nesthesiology 2009; 110:796-804. Reprinted with permission. Anesthetic drugs administered to immature animals may cause neurohistopathologic changes and alterations in behavior. The authors studied association between anesthetic exposure before age 4 yr and the development of reading, written language, and math learning disabilities. This was a population-based, retrospective birth cohort study. The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota, from 1976 to 1982 and who remained in the community at 5 yr of age were reviewed to identify children with learning disabilities. Cox proportional hazards regression was used to calculate hazard ratios for anesthetic exposure as a predictor of learning disabilities, adjusting for gestational age at birth, sex, and birth weight. Of the 5,357 children in this cohort, 593 received general anesthesia before age 4 yr. Compared with those not receiving anesthesia (n = 4,764), a single exposure to anesthesia (n = 449) was not associated with an increased risk of learning disabilities (hazard ratio, 1.0; 95% CI, 0.79 to 1.27). However, children receiving two anesthetics (n = 100) or three or more anesthetics (n = 44) were at increased risk for learning disabilities (hazard ratio, 1.59; 95% CI, 1.06 to 2.37; and hazard ratio, 2.60; 95% CI, 1.60 to 4.24, respectively). The risk for learning disabilities increased with longer cumulative duration of anesthesia exposure (expressed as a continuous variable; P = 0.016). Exposure to anesthesia was a significant risk factor for the later development of learning disabilities in children receiving multiple but not single anesthetics. These data cannot reveal whether anesthesia itself may contribute to learning disabilities or whether the need for anesthesia is a marker for other unidentified factors that contribute to learning disabilities.","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":"61 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDNoradrenergic projections from the locus coeruleus (LC) to the thalamus and anterior cingulate cortex (ACC) contribute to pain‒like behaviors, yet their hierarchical organization remains unclear. Here, we examined how LC‒derived norepinephrine (NE) inputs to the paraventricular thalamic nucleus (PVA) and ACC differentially regulate nociceptive sensitization.METHODSIn adult male and female mice, complete Freund's adjuvant (CFA) was used to induce pain‒like behaviors. To examine functional connectivity among LC, PVA, and ACC, we combined targeted recombination in active populations (Fos‒TRAP), in vivo recordings, and viral tracing. We used optogenetic and chemogenetic tools to selectively manipulate LC projections and assess their impact on neural activity and pain behaviors.RESULTSCFA led to enhanced c‒Fos expression in LC, PVA, and ACC (Cells per microscopic field; LC: 13.60 ± 2.24 vs. 44.50 ± 7.72; PVA: 8.00 ± 1.58 vs. 66.40 ± 9.45; ACC: 12.80 ± 2.28 vs. 36.70 ± 2.59; p < 0.001), alongside increased gamma‒band activity and single‒unit firing rates. Monosynaptic LC-ACC and polysynaptic LC-PVA-ACC circuits were identified. Notably, nociception‒related LC neurons preferentially projected to PVA, which subsequently targeted hyperactive ACC neurons. Under inflammatory pain conditions, activation of the LC-PVA-ACC circuits evoked greater ACC firing (Hz; LC-PVA-ACC vs. LC-ACC: 15.75 ± 2.88 vs. 9.72 ± 2.06; P < 0.001) and tactile‒evoked responses (Hz; 22.98 ± 2.60 vs. 15.34 ± 1.86; P < 0.001) than direct LC-ACC activation. Consistently, optogenetic or chemogenetic manipulation of the LC-PVA-ACC circuit produced stronger modulation of mechanical and thermal pain sensitivity than direct LC-ACC stimulation.CONCLUSIONSWe identify the LC-PVA-ACC pathway as a hierarchical noradrenergic circuit that modulates nociceptive sensitization via a thalamocortical relay, thereby revealing a circuit‒specific mechanism by which the LC-NE system regulates pain processing.
从蓝斑（LC）到丘脑和前扣带皮层（ACC）的去甲肾上腺素能投射有助于疼痛样行为，但其等级组织尚不清楚。在这里，我们研究了lc来源的去甲肾上腺素（NE）输入到室旁丘脑核（PVA）和ACC是如何不同地调节伤害性致敏的。方法用完全弗氏佐剂（CFA）诱导成年雌雄小鼠的疼痛样行为。为了研究LC、PVA和ACC之间的功能连通性，我们结合了活性群体中的靶向重组（Fos-TRAP）、体内记录和病毒追踪。我们使用光遗传学和化学遗传学工具来选择性地操纵LC投射，并评估它们对神经活动和疼痛行为的影响。结果scfa导致LC、PVA和ACC中c-Fos表达增强（细胞/显微镜视野；LC: 13.60±2.24 vs. 44.50±7.72;PVA: 8.00±1.58 vs. 66.40±9.45;ACC: 12.80±2.28 vs. 36.70±2.59;p < 0.001），同时增加γ波段活性和单单位放电率。发现了单突触LC-ACC和多突触LC-PVA-ACC回路。值得注意的是，伤害感觉相关的LC神经元优先投射到PVA， PVA随后靶向过度活跃的ACC神经元。在炎症性疼痛条件下，LC-PVA-ACC回路激活比LC-ACC直接激活诱发更大的ACC放电（Hz; LC-PVA-ACC vs LC-ACC: 15.75±2.88 vs 9.72±2.06,P < 0.001）和触觉诱发反应（Hz; 22.98±2.60 vs 15.34±1.86,P < 0.001）。与此一致，光遗传学或化学遗传学操作LC-PVA-ACC电路比直接LC-ACC刺激产生更强的机械和热痛敏感性调制。我们发现LC-PVA-ACC通路是一个分层的去肾上腺素能回路，通过丘脑皮质中继调节伤害性敏化，从而揭示了LC-NE系统调节疼痛加工的电路特异性机制。
{"title":"Modulation of pain sensitivity by the locus coeruleus-paraventricular thalamic nucleus-anterior cingulate cortex pathway in mice.","authors":"Shihui Kuai,Zijie Li,Ziyi Wu,Yongda Liu,Xuejiao Wang,Xueru Wang,Kaiwen Tang,Nanjue Cao,Shiyue Fan,Xu Yang,Pingting Yang,Ling Qin,Ping Zhao","doi":"10.1097/aln.0000000000005897","DOIUrl":"https://doi.org/10.1097/aln.0000000000005897","url":null,"abstract":"BACKGROUNDNoradrenergic projections from the locus coeruleus (LC) to the thalamus and anterior cingulate cortex (ACC) contribute to pain‒like behaviors, yet their hierarchical organization remains unclear. Here, we examined how LC‒derived norepinephrine (NE) inputs to the paraventricular thalamic nucleus (PVA) and ACC differentially regulate nociceptive sensitization.METHODSIn adult male and female mice, complete Freund's adjuvant (CFA) was used to induce pain‒like behaviors. To examine functional connectivity among LC, PVA, and ACC, we combined targeted recombination in active populations (Fos‒TRAP), in vivo recordings, and viral tracing. We used optogenetic and chemogenetic tools to selectively manipulate LC projections and assess their impact on neural activity and pain behaviors.RESULTSCFA led to enhanced c‒Fos expression in LC, PVA, and ACC (Cells per microscopic field; LC: 13.60 ± 2.24 vs. 44.50 ± 7.72; PVA: 8.00 ± 1.58 vs. 66.40 ± 9.45; ACC: 12.80 ± 2.28 vs. 36.70 ± 2.59; p < 0.001), alongside increased gamma‒band activity and single‒unit firing rates. Monosynaptic LC-ACC and polysynaptic LC-PVA-ACC circuits were identified. Notably, nociception‒related LC neurons preferentially projected to PVA, which subsequently targeted hyperactive ACC neurons. Under inflammatory pain conditions, activation of the LC-PVA-ACC circuits evoked greater ACC firing (Hz; LC-PVA-ACC vs. LC-ACC: 15.75 ± 2.88 vs. 9.72 ± 2.06; P < 0.001) and tactile‒evoked responses (Hz; 22.98 ± 2.60 vs. 15.34 ± 1.86; P < 0.001) than direct LC-ACC activation. Consistently, optogenetic or chemogenetic manipulation of the LC-PVA-ACC circuit produced stronger modulation of mechanical and thermal pain sensitivity than direct LC-ACC stimulation.CONCLUSIONSWe identify the LC-PVA-ACC pathway as a hierarchical noradrenergic circuit that modulates nociceptive sensitization via a thalamocortical relay, thereby revealing a circuit‒specific mechanism by which the LC-NE system regulates pain processing.","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":"8 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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