Butorphanol: Biological Mechanisms, Applications and Perioperative Uses

Butorphanol is a synthetic opioid drug that is used for analgesia, often as an adjunct to other anesthetic drugs.¹ Butorphanol is a derivative of morphinan that was developed in the 1970s for use as an analgesic and for antagonism of narcotic drugs,² and is now sold under the brand name Stadol.³ Butorphanol is about four to seven times as potent as morphine.⁴ Because anesthesiology professionals often use opioids, they should have thorough knowledge of butorphanol’s biological mechanisms, uses and perioperative implications.

Butorphanol, also known as butorphanol tartrate, has a molecular formula of C₂₁H₂₉NO₂.³ Though the exact mechanisms of its action are unknown, it is believed to interact with opioid receptors in the central nervous system.¹ Butorphanol is a partial m-opioid receptor antagonist and k-opioid receptor agonist,⁵ and may even have agonistic effects at the σ-opioid receptor.¹ Its antagonism of the m-opioid receptor may result from competitive inhibition or could be due to other mechanisms.¹ According to research, butorphanol is equally as analgesic as another opioid agonist-antagonist nalbuphine.⁶ Butorphanol binds to serum proteins at approximately 80 percent, which is a lower rate than drugs like buprenorphine but higher than many other opioids.¹ Its protein-binding rate affects its elimination half-life of 18 hours; higher protein binding leads to slower elimination.¹ Butorphanol is extensively metabolized in the liver, and while its metabolites have not been studied in humans, they show some analgesic properties in animals.¹ Because of the liver’s role in its metabolism, butorphanol’s elimination—which occurs by excretion through urine and feces—is slowed by hepatic impairment.¹ In general, butorphanol is more potent than morphine and has a shorter duration of action with minimal sedation.⁷

The uses of butorphanol vary widely, ranging from producing analgesia in veterinary medicine to serving as an antitussive (anti-cough) medication in humans.⁸ It provides poor-to-moderate pain relief that is better for visceral (i.e., organ) pain than somatic (i.e., skin, muscles and soft tissue) pain.⁸ Though it was first launched as a parenteral formulation, it can now be used in intranasal form for noninvasive analgesia for moderate to severe pain.¹ When administered parenterally, butorphanol serves as a narcotic analgesic on its own or as an adjunct to general anesthesia.⁹ As a nasal spray, it is most often used for treatment of migraine headaches.⁹

Several researchers have approached the uses of butorphanol during the perioperative period. An older study by Bowdle et al. found that intravenous butorphanol improved ventilation after fentanyl anesthesia.¹⁰ Laffey and Kay’s study found that butorphanol premedication was as effective as morphine in reducing pain during abdominal hysterectomy, with the advantage of fewer side effects.¹¹ Meanwhile, Vogelsang and Hayes’ review recognizes the uses of butorphanol as a preoperative sedative and analgesic, a supplement to balanced anesthesia, an obstetric analgesic and a suppressant of post-anesthesia shaking and post-labor pain.¹² Its receptor specificity limits respiratory depression, gastrointestinal side effects and risk of dependency when compared to morphine and meperidine.¹² Other studies have found that compared to other opioids, butorphanol is associated with less cardiovascular or respiratory depression, though there is species variability.⁴ While butorphanol may have fewer adverse effects than other opioids, it may also cause undesired sedation when used as an analgesic.⁶ Additionally, it can cause confusion, euphoria, agitation, itching, sweating, abdominal bloating, nausea, vomiting and constipation, though gastrointestinal side effects may be less intense than with other opioids.⁹ More serious adverse effects—like those of other opioids—include hypoventilation, cardiovascular insufficiency, respiratory depression, coma and death.^1,9

Butorphanol is a synthetic opioid drug that is more potent than morphine, but without many of the adverse side effects. Butorphanol is usually administered parenterally or intranasally, and can be used for veterinary or human medicine for pain control, or even as an antitussive. Though butorphanol has relatively fewer side effects than other opioid drugs and is less likely to result in overdose, it can still be accompanied by sedation, euphoria, nausea, vomiting, gastrointestinal symptoms, respiratory depression, cardiovascular issues or even death. Anesthesia providers should thoroughly evaluate patients who may benefit from pain control with butorphanol.

1. Butorphanol. DrugBank February 10, 2020; https://www.drugbank.ca/drugs/DB00611.
2. Pircio AW, Gylys JA, Cavanagh RL, Buyniski JP, Bierwagen ME. The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic. Archives Internationales de Pharmacodynamie et de Therapie. 1976;220(2):231–257.
3. Butorphanol. PubChem Database. Web: National Center for Biotechnology Information; 2020.
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6. Coté CJ, Lerman J, Ward RM, Lugo RA, Goudsouzian N. Chapter 6—Pharmacokinetics and Pharmacology of Drugs Used in Children. In: Coté CJ, Lerman J, Todres ID, eds. A Practice of Anesthesia for Infants and Children (Fourth Edition). Philadelphia: W.B. Saunders; 2009:89–146.
7. Aarnes TK, Muir WW. Chapter 26—Pain Assessment and Management. In: Peterson ME, Kutzler MA, eds. Small Animal Pediatrics. Saint Louis: W.B. Saunders; 2011:220–232.
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9. Butorphanol. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; April 29, 2019.
10. Bowdle TA, Greichen SL, Bjurstrom RL, Schoene RB. Butorphanol improves CO2 response and ventilation after fentanyl anesthesia. Anesthesia and Analgesia. 1987;66(6):517–522.
11. Laffey DA, Kay NH. Premedication with butorphanol: A comparison with morphine. British Journal of Anaesthesia. 1984;56(4):363–367.
12. Vogelsang J, Hayes SR. Butorphanol tartrate (stadol): A review. Journal of Postanesthesia Nursing. 1991;6(2):129–135.