Morphine: Biological Mechanisms, Clinical Applications and Adverse Effects

Morphine is the prototypical opioid drug to which all other opioids are compared.¹ Despite a century of opioid research, there is no evidence that any synthetic opioid has had more analgesic efficacy than morphine, which comes from natural sources.² Perhaps due to its origins in nature, morphine is one of the oldest medical drugs known to man.³ Ancient societies dating back to the sixth millennium B.C.E. identified the analgesic and psychoactive effects of opium, whose active ingredient is morphine.³ Morphine was chemically isolated in the early 1800s by Wilhelm Sertürner.³ In 1947, Sir Robert Robinson was granted a Nobel Prize in Chemistry for the derivation of morphine’s structural formula.³ Because morphine has been described as the “gold standard” of opioid therapy for so long,⁴ anesthesia providers should have thorough knowledge of its mechanisms of action, clinical uses and side effects.

Morphine is an opioid alkaloid isolated from the plant Papaver somniferum, with a molecular formula of C₁₇H₁₉NO₃.⁵ Like other medications in its class, morphine has an affinity for d-, k- and m-opioid receptors.⁶ It produces most of its analgesic effects through strong agonism of m-opioid receptors in the central and peripheral nervous systems.⁶ By binding to these receptors, morphine produces an overall inhibitory effect, causing reduced nociceptive (i.e., related to the sensation of pain) transmission.⁶ Morphine is hydrophilic, giving it a relatively slower onset of action and longer clinical effect than some other opioid drugs.⁴ It is metabolized in the liver by the enzyme known as UDP-glucuronosyltransferase 2B7, where it is converted into the active metabolites morphine 6-glucuronide (M6G), which is responsible for analgesia, and morphine 3-glucuronide (M3G), which is an antagonist to morphine and contributes to morphine tolerance.⁷ Both metabolites are excreted through urine.⁷ Although only 10 percent of morphine’s metabolism contributes to production of M6G, M6G has very important clinical implications.² Not only does it contribute to morphine’s analgesic effects—even in patients with normal kidney function ²—but it can also lead to respiratory depression or toxic accumulation levels.⁷ Though morphine is considered the standard opioid, it is unique from many other opioids in that it has active and potentially dangerous metabolites.

In clinical settings, morphine serves as a potent pain reliever. It is most often administered orally, intravenously, epidurally or intrathecally,⁶ though it can also be administered rectally, subcutaneously, intramuscularly or sublingually.^4,6 A study by Inui et al. even introduced a patch for transdermal administration.⁸ Oral formulations of morphine are available in immediate and extended release for treatment of acute and chronic pain.⁶ Pain that is more severe and not well controlled can be managed with a single or continuous intravenous, epidural or intrathecal dose.⁶ Clinical situations that benefit from morphine’s analgesia include palliative/end-of-life care, cancer treatment, pain from sickle cell anemia, emergency room pain and myocardial infarction (heart attack).⁶ In surgical settings, morphine is helpful in sedation and anxiolysis before a procedure or during anesthesia induction, as well as postoperative pain control.⁹ It is also used to produce anesthesia for open-heart surgery.¹⁰ Aside from its use as an analgesic, morphine can decrease heart rate and blood pressure.⁶ Morphine is effective in treating pain for many conditions and in numerous clinical settings.

Like all opioid drugs, morphine has several adverse effects, including sedation, dizziness or lightheadedness, constipation, nausea, vomiting and urinary retention.⁶ In order to prevent nausea and vomiting, morphine is often administered with an antiemetic.⁶ More severe side effects include flushing, bradycardia (slow heart rate) and respiratory depression.⁶ Because morphine releases histamines, it can cause hypotension² or urticaria (hives).¹¹ It is likely that this particular side effect has caused fentanyl to replace morphine as the most commonly used opioid in anesthesiology.² Because morphine can produce euphoria,⁶ it has a high potential for abuse and dependence and is listed as a Schedule II drug by the United States Drug Enforcement Administration.¹² For this reason, along with morphine’s other side effects and metabolite accumulation, anesthesia providers should be cautious when prescribing morphine for long-term use.⁴

Morphine, which is derived from opium, is considered the original m-opioid receptor. Morphine acts on the nervous system to produce analgesic effects, and its metabolite M6G produces further analgesia. Morphine can be used throughout the perioperative period, in the emergency room, for cancer-related pain and for treatment after a heart attack. Common side effects include nausea, vomiting, sedation, constipation and other unpleasant but minor issues. When administered in high doses, morphine can cause slow heart rate and respiratory depression, and its release of histamines can lead to hypotension or hives. Due to morphine’s adverse side effects and addictive qualities, anesthesia providers should carefully consider prescribing morphine to their patients.

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2.         Ogura T, Egan TD. Intravenous Opioid Agonists and Antagonists. In: Hemmings HC, Egan TD, eds. Pharmacology and Physiology for Anesthesia (Second Edition). Philadelphia: Elsevier; 2019:332–353.

3.         Brook K, Bennett J, Desai SP. The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. Journal of Anesthesia History. 2017;3(2):50–55.

4.         Lobo EP, Pellegrini F, Pusceddu E. 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.

5.         National Cancer Institute. Morphine (Code C62051). NCI Thesaurus. Web: U.S. Department of Health and Human Services; January 27, 2020.

6.         Murphy PB, Barrett MJ. Morphine. StatPearls. Web: StatPearls Publishing LLC; October 9, 2019.

7.         Kandasamy J, Carlo WA. Pharmacologic Therapies IV: Other Medications. In: Goldsmith JP, Karotkin EH, Keszler M, Suresh GK, eds. Assisted Ventilation of the Neonate (Sixth Edition): Elsevier; 2017:366–379.e365.

8.         Inui N, Kato T, Uchida S, et al. Novel Patch for Transdermal Administration of Morphine. Journal of Pain and Symptom Management. 2012;44(4):479–485.

9.         Morphine. PubChem Database. Web: National Center for Biotechnology Information; 2020.

10.       Rong LQ, Kamel MK, Rahouma M, et al. High-dose versus low-dose opioid anesthesia in adult cardiac surgery: A meta-analysis. Journal of Clinical Anesthesia. 2019;57:57–62.

11.       McLelland J. The Mechanism of Morphine-Induced Urticaria. Archives of Dermatology. 1986;122(2):138–139.

12.       Drug Enforcement Administration Diversion Control Division. Controlled Substance Schedules. 2020; https://www.deadiversion.usdoj.gov/schedules/.