Physostigmine is a drug that inhibits the action of cholinesterase, which breaks down acetylcholine, a neurotransmitter that plays an important role in muscle movement and the function of brain neurons. It is useful across a range of conditions in which a deficiency of acetylcholine is present or in which it is useful to promote an increase in acetylcholine in nerve synapses. For instance, physostigmine can be used to treat certain types of glaucoma by increasing the levels of acetylcholine available to the ciliary muscle of the eye, enabling it to contract, which subsequently increases the circulation of fluid in the eye and reduces pressure.¹ It can also cross the blood-brain barrier, so it is used to treat overdoses of anticholinergic drugs like atropine.² Notably, physostigmine is also useful in managing a wide range of conditions in the perioperative setting.

One use of physostigmine in perioperative care is in the management of septic shock. Because physostigmine has been observed to reduce the inflammatory response via the cholinergic anti-inflammatory pathway, researchers have initiated trials to determine whether physostigmine might accordingly mitigate the effects of septic shock. One study found that in patients undergoing septic shock from an intra-abdominal infection, physostigmine was safe and lowered patients’ Sequential Organ Failure Assessment (SOFA) score, which is used to assess organ dysfunction in patients with sepsis.³ Studies in rats have shown that treatment with physostigmine lowered the production of harmful reactive oxygen species and improved survival times.⁴

Cholinesterase inhibitors like physostigmine have been shown to affect the anti-nociceptive pathways, the nervous system response that inhibits or reduces the perception of pain. This characteristic can be leveraged to manage perioperative pain and lower patients’ dependency on opioids, which are highly addictive. In one randomized controlled trial, patients who received a physostigmine infusion combined with morphine postoperatively had less dependency on opioids but a higher degree of pain relief compared with patients who only received morphine.⁵ Patients who received physostigmine had lower production of inflammatory cytokines, which may account for the enhanced pain relief. A more recent study showed that sensitivity to pain was lower after surgery in patients who received intraoperative physostigmine, though there was no difference between the two groups in opioid consumption.⁶

There are reports in the medical literature of physostigmine exerting a positive effect on postoperative delirium, a common side effect of surgery marked by confusion, restlessness, and agitation that can prolong hospital stays and introduce new complications. These case studies involve patients presenting with central anticholinergic syndrome,⁷ a disruption of acetylcholine in the brain that can manifest as delirium. In these instances, physostigmine likely reduces the observed symptoms by restoring acetylcholine production and availability. However, a 2021 study showed that physostigmine had no effect on postoperative delirium or cognitive dysfunction in patients who received the drug during liver surgery.⁸ The discrepancy might be a function of delirium caused by factors other than a disruption to acetylcholine, as postoperative delirium can also result from infection, neuroinflammation, and electrolyte imbalance. Regardless, there are several applications for physostigmine in perioperative care, and future research may uncover even more.

References

1. Andrade, O. A. & Zafar Gondal, A. Physostigmine (Archived). in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
2. Blackstone, N. G., Olson, A. & Ainapurapu, B. Physostigmine in Anticholinergic Poisoning: An Old Antidote With Resurgence. Cureus 12, e11739 (2020), DOI: 10.7759/cureus.11739
3. Pinder, N. et al. Effect of physostigmine on recovery from septic shock following intra-abdominal infection – Results from a randomized, double-blind, placebo-controlled, monocentric pilot trial (Anticholium® per Se). J Crit Care 52, 126–135 (2019), DOI: 10.1016/j.jcrc.2019.04.012
4. Bitzinger, D. I. et al. In Vivo Effects of Neostigmine and Physostigmine on Neutrophil Functions and Evaluation of Acetylcholinesterase and Butyrylcholinesterase as Inflammatory Markers during Experimental Sepsis in Rats. Mediators of Inflammation 2019, 8274903 (2019), DOI: 10.1155/2019/8274903
5. Beilin, B., Bessler, H., Papismedov, L., Weinstock, M. & Shavit, Y. Continuous physostigmine combined with morphine-based patient-controlled analgesia in the postoperative period. Acta Anaesthesiol Scand 49, 78–84 (2005), DOI: 10.1111/j.1399-6576.2004.00548.x
6. Klivinyi, C. et al. Perioperative use of physostigmine to reduce opioid consumption and peri-incisional hyperalgesia: a randomised controlled trial. Br J Anaesth 126, 700–705 (2021), DOI: 10.1016/j.bja.2020.10.039
7. Moos, D. D. Central anticholinergic syndrome: a case report. J Perianesth Nurs 22, 309–321 (2007), DOI: 10.1016/j.jopan.2007.05.006
8. Spies, C. D. et al. Physostigmine for prevention of postoperative delirium and long-term cognitive dysfunction in liver surgery: A double-blinded randomised controlled trial. Eur J Anaesthesiol 38, 943–956 (2021), DOI: 10.1097/EJA.0000000000001456