Hydromorphone: Biology, Clinical Uses and Side Effects

February 21, 2020

Hydromorphone is a semi-synthetic opioid drug with analgesic effects, and a more potent derivative of morphine.1 Hydromorphone is classified by the United States Drug Enforcement Administration (DEA) as a Schedule II drug,2 meaning it is considered dangerous “with a high potential for abuse, with use potentially leading to severe psychological or physical dependence.”3 Hydromorphone was first synthesized in the 1920s and is now sold under the brand name Dilaudid.4 Because of hydromorphone’s ubiquity in pain management, anesthesia providers should be knowledgeable of its biological mechanisms, clinical applications and side effects.

Hydromorphone is a hydrogenated ketone analog of morphine that can be formed by the N-demethylation of hydrocodone.5 The differences in chemical structure between hydromorphone and morphine allow hydromorphone to be more potent with a similar side effect profile.6 Hydromorphone is an opioid agonist that can bind to a variety of opioid receptors, including k- and d-opioid receptors, though its analgesic effect is suggested to be related to its agonism of the m-opioid receptor.6 Its actions in the medulla oblongata, which is responsible for cardiovascular and respiratory function,7 allow it to depress the respiratory system and suppress cough.8 Like morphine, but unlike many other opioid drugs, hydromorphone is hydrophilic, which impairs its ability to cross the blood-brain barrier.5 It is 10 times as lipid-soluble as morphine and more potent, allowing for effective doses to be infused subcutaneously.5 Hydromorphone undergoes metabolism in the liver into hydromorphone-3-glucuronide (H3G), and both hydromorphone and H3G are excreted in the urine.5,9 Though H3G is an active metabolite, it lacks analgesic efficacy and is produced in negligible amounts.5 Hydromorphone mainly acts as an opioid receptor agonist and undergoes significant first-pass hepatic metabolism.6

Due to its greater potency and faster onset of action (five to 10 minutes) than morphine, hydromorphone has become the drug of choice for use with patient-controlled analgesia.10,11 Side effects also occur less frequently with hydromorphone than with morphine, making it even more preferable.10 However, a study by Gulur et al. found that though hydromorphone led to quicker discharge from the hospital than did morphine, it was also associated with higher readmission rates, calling into question the advantages over morphine.12 Hydromorphone is commonly used when prolonged analgesia is required, particularly in patients who have renal insufficiency and may suffer from the accumulation of morphine metabolites.13 Hydromorphone is prescribed as tablets or rectal suppositories.4 In a surgical setting, it can be administered through intravenous, epidural or intrathecal injection for perioperative or postoperative pain management.5

More recently, hydromorphone has also been administered intranasally.13 Overall, hydromorphone offers analgesia with a quick onset and long duration (two to four hours)9 of action, limited renal side effects and multiple forms of administration.

Like all opioid, hydromorphone is associated with some side effects. Unlike morphine, hydromorphone releases very little histamine and is thus safe for patients with asthma.9 Similar to other opioids, hydromorphone is associated with side effects such as sedation and drowsiness, nausea, vomiting, urinary retention, constipation and other gastrointestinal upsets.4,14 It can also cause respiratory depression, temporary impairment of mental status, bradycardia or even death.15 Research has shown that hydromorphone may be suitable for patients who do not tolerate the side effects of morphine,16 though evidence of reduced side effects is limited.4 As with other opioids, hydromorphone should be used with caution due to its side effects, which include abuse potential.

Hydromorphone is a morphine derivative with higher potency and quicker onset of action, making it a useful analgesic drug. Hydromorphone primarily acts on the m-opioid receptor to cause analgesia, though it may also serve as an agonist of k- and d-opioid receptors. Because hydromorphone creates fewer active metabolites and is more lipid-soluble than morphine, it can be a preferred option. Hydromorphone is administered orally, through injection, intranasally or with rectal suppositories. Like all opioids, hydromorphone can cause nausea, vomiting and sedation, with more severe side effects including respiratory depression, bradycardia and death. Because of its addictive properties and unpleasant side effects, anesthesia providers should carefully consider prescribing hydromorphone.

1.         Hydromorphone. PubChem Database. Web: National Center for Biotechnology Information; 2020.

2.         Drug & Chemical Evaluation Section. Hydromorphone (Trade name: Dilaudid®; Street Names: Dust, Juice, Smack, D, Footballs). Springfield, VA: United States Drug Enforcement Administration; July 2013.

3.         United States Drug Enforcement Administration. Drug Scheduling. Drug Information 2020; https://www.dea.gov/drug-scheduling.

4.         Koyyalagunta D. Chapter 113—Opioid Analgesics. In: Waldman SD, Bloch JI, eds. Pain Management. Philadelphia: W.B. Saunders; 2007:939–964.

5.         Sheth S, Holtsman M, Mahajan G. Chapter 42—Major Opioids in Pain Management. In: Benzon HT, Raja SN, Liu SS, Fishman SM, Cohen SP, eds. Essentials of Pain Medicine (Fourth Edition): Elsevier; 2018:373–384.e372.

6.         Hydromorphone. DrugBank February 11, 2020; https://www.drugbank.ca/drugs/DB00327.

7.         Medulla Oblongata. ScienceDirect: Neuroscience 2020; https://www.sciencedirect.com/topics/neuroscience/medulla-oblongata.

8.         Abi-Aad KR, Derian A. Hydromorphone. StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.

9.         Chapter 25—Pharmacology. In: Malamed SF, ed. Sedation (Sixth Edition): Mosby; 2018:319–358.

10.       Lobo EP, Pellegrini F, Pusceddu E. Chapter 1—Anesthesia Complications in Head and Neck Surgery. In: Eisele DW, Smith RV, eds. Complications in Head and Neck Surgery (Second Edition). Philadelphia: Mosby; 2009:3–27.

11.       Chang AK, Bijur PE, Meyer RH, Kenny MK, Solorzano C, Gallagher EJ. Safety and Efficacy of Hydromorphone as an Analgesic Alternative to Morphine in Acute Pain: A Randomized Clinical Trial. Annals of Emergency Medicine. 2006;48(2):164–172.

12.       Gulur P, Koury K, Arnstein P, et al. Morphine versus Hydromorphone: Does Choice of Opioid Influence Outcomes? Pain Research and Treatment. 2015;2015:6.

13.       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.

14.       Shaiova L. The management of opioid-related sedation. Current Pain and Headache Reports. 2005;9(4):239–242.

15.       Simmons B, Kuo A. 40—Analgesics, Tranquilizers, and Sedatives. In: Brown DL, ed. Cardiac Intensive Care (Third Edition). Philadelphia: Elsevier; 2019:421–431.e425.

16.       Kumar MG, Lin S. Hydromorphone in the management of cancer-related pain: An update on routes of administration and dosage forms. Journal of Pharmacy and Pharmaceutical Sciences. 2007;10(4):504–518.