Arwen Oliva

Background: The synthetic opioid fentanyl is a key driver of drug overdose in the US.  Per the CDC, ~2,700 Americans died monthly from opioid overdose in 2024. Due to its ability to cross the blood brain barrier, fentanyl can produce rapid-onset respiratory failure, defined as a CNS-mediated decrease in respiratory rate and tidal volume.² Decreased respiratory compliance can also occur, which is associated with tetanic contraction of abdominal and lumbar muscles, contributing to Wooden Chest Syndrome (WCS) pathology.² WCS is a rarely occurring condition induced by rapid intravenous administration of opioid narcotics, which activate brain and spinal mu-opioid receptors (MORs).^1,5 Clinical features include severe thoracic wall rigidity, hypoxia, hypercapnia, and respiratory acidosis.⁵ First-line treatment is the high-affinity competitive MOR-antagonist naloxone (NLX).^4,6 Low-dose NLX (0.4 mg IV), however, can induce opioid withdrawal symptoms including tachycardia, sweating, diarrhea, pain, and agitation.⁹ Notably, while NLX effectively restores CNS respiratory drive; it fails to reverse skeletal muscle rigidity.⁸

Objective: Examine efficacy of alternative WCS treatments used in conjunction with NLX, ideally to also avoid induction of opioid withdrawal.

Search Methods: PubMed database search included case studies, reviews, and experimental trials from 2019-2026. Key words entered included: “wooden chest syndrome”, “naloxone”, “opioid overdose”, “fentanyl”, and “opioid withdrawal”.

Results: Fentanyl activates MORs in the locus coeruleus, a major catecholamine-producing region of the pons.^2,7 When bound, it inhibits voltage-gated K+ channels in pontine neuronal cells, inducing hyperexcitability and release of norepinephrine (NE).^2,7 NE, in turn, increases spinal motor neuron excitability, priming thoracic skeletal muscles to tonically contract, strongly dampening rhythmic lung ventilation. Research suggests 2-adrenergic agonists, which inhibit NE release, could treat WCS without inducing opioid withdrawal, as seen with NLX treatment alone.² Mechanically ventilated and sedated rats were administered 150 (n=10) or 300 (n=13) μg/kg of IV fentanyl.² Rats (n=13) displayed tetanic muscle contractions resulting in significant chest wall rigidity. Those administered 3 μg/kg (IV) dexmedetomidine, a potent blood brain barrier permeant 2-adrenergic agonist, experienced increased chest wall compliance, PaO₂, and skeletal muscle relaxation.² The kappa-opioid receptor (KOR) agonist, nalfurafine, likewise reduced fentanyl-mediated respiratory depression by reducing chest wall rigidity.³ Subsequent studies provided adult, non-sedated rats with IV fentanyl (150 μg/kg) over a 15s period, placing rats in a state of coma and muscle rigidity.³ After 5 minutes, those treated with 1 mg/kg nalfurafine sharply increased ventilation frequency, reaching peak ventilation (205 mL/min.) within 90s.³ Nalfurafine reversed fentanyl-induced muscle rigidity and sustained such reversal over the total 30-minute observation period.³

Conclusions: Fentanyl-induced WCS cannot be fully overcome by interfering with its MOR-mediated mechanisms; its role in the locus coeruleus also participates. While NLX provides substantial displacement of fentanyl molecules from MORs, its efficacy is limited because of its withdrawal precipitating effects. Evidence supports that KOR-agonists (e.g. nalfurafine) reduce muscular rigidity in WCS. 2-adrenergic agonists (e.g. dexmedetomidine) likewise reduce thoracic wall rigidity and promote alveolar ventilation. Perhaps, the most effective treatment for fentanyl-induced WCS is a mixture of low-dose NLX with KOR-agonists or 2-adrenergic agonists. Next steps involve comparing the efficacy of NLX alone with ratio-specific mixtures of NLX plus KOR-agonists or NLX plus 2-adrenergic agonists.

Works Cited

1. Dhaliwal A, Gupta M. Physiology, Opioid Receptor. PubMed. Published 2023. https://www.ncbi.nlm.nih.gov/books/NBK546642/
2. Haouzi P, Tubbs N. Effects of fentanyl overdose-induced muscle rigidity and dexmedetomidine on respiratory mechanics and pulmonary gas exchange in sedated rats. Journal of Applied Physiology. 2022;132(6):1407-1422. doi:https://doi.org/10.1152/japplphysiol.00819.2021
3. Lewis T, Haouzi P. Nalfurafine reverses fentanyl-induced muscle rigidity and respiratory depression without affecting sedation in rats: decoupling respiration from sedation. Journal of Applied Physiology. 2025;138(5):1161-1172. doi:https://doi.org/10.1152/japplphysiol.00952.2024
4. Pergolizzi JV, Dahan A, LeQuang JA, Raffa RB. Overdoses due to fentanyl and its analogues (F/FAs) push naloxone to the limit. Journal of Clinical Pharmacy and Therapeutics. 2021;46(6):1501-1504. doi:https://doi.org/10.1111/jcpt.13462
5. Rosal NR, Thelmo FL Jr, Tzarnas S, DiCalvo L, Tariq S, Grossman C. Wooden Chest Syndrome: A Case Report of Fentanyl-Induced Chest Wall Rigidity. J Investig Med High Impact Case Rep. 2021;9:23247096211034036. doi:10.1177/23247096211034036
6. Tammen AJ, Brescia D, Jonas D, Hodges JL, Keith P. Fentanyl-Induced Rigid Chest Syndrome in Critically Ill Patients. J Intensive Care Med. 2023;38(2):196-201. doi:10.1177/08850666221115635
7. Torralva R, Janowsky A. Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis. J Pharmacol Exp Ther. 2019;371(2):453-475. doi:10.1124/jpet.119.258566
8. Wei AD, Burgraff NJ, Oliveira LM, Moreira TS, Ramirez J. Fentanyl blockade of K+ channels contributes to wooden chest syndrome. The Journal of Physiology. 2025;604(1):582-604. doi:https://doi.org/10.1113/jp289107
9. Wong F, Edwards CJ, Jarrell DH, Patanwala AE. Comparison of lower-dose versus higher-dose intravenous naloxone on time to recurrence of opioid toxicity in the emergency department. Clinical Toxicology (Phila). 2019;57(1):19-24. doi:10.1080/15563650.2018.1490420