Continuing Education Activity

Epidural morphine is a medication used for analgesia, whether as an adjunct to general anesthesia or as the sole technique for surgical anesthesia. This medication is the first opioid approved for neuraxial administration by the U.S. Food and Drug Administration (FDA). Epidural morphine has been the most widely utilized opioid in clinical practice when administered via this route. In 2004, liposome-based extended-release epidural morphine (EREM) also received FDA approval. This activity describes the indications, action, and contraindications for epidural morphine as a valuable agent for treating acute and chronic moderate-to-severe pain. Furthermore, this activity will highlight the mechanism of action, adverse event profile, and other crucial factors, such as dosing, pharmacokinetics, monitoring, contraindications, and toxicity, pertinent for interprofessional team members in managing epidural morphine in patients receiving the medication.

Objectives:

• Identify appropriate indications and risks associated with epidural morphine administration for patients in various clinical settings, including perioperative analgesia and management of chronic moderate-to-severe pain.
• Differentiate between the pharmacological profile and potential adverse effects of epidural morphine from other opioid analgesics to make informed prescribing decisions.
• Select the most suitable epidural morphine formulation and delivery method based on patient characteristics and surgical procedures to ensure adequate analgesia and minimize potential adverse effects.
• Collaborate with pain management specialists, anesthesiologists, and pharmacists to ensure optimal safety and efficacy of epidural morphine therapy throughout the treatment course.

Indications

Morphine was the first opioid approved by the U.S. Food and Drug Administration (FDA) for spinal administration. Epidural morphine has been the most extensively utilized opioid in clinical practice when administered via this route.[1] This medication is used for analgesia, whether as an adjunct to general anesthesia or as the sole technique for surgical anesthesia. Furthermore, morphine sulfate has also obtained FDA approval for treating acute or chronic moderate-to-severe pain.

In 2004, liposome-based extended-release epidural morphine (EREM) also received FDA approval. Owing to the delayed peak concentration of epidural morphine in the cerebrospinal fluid (CSF), occurring 3 hours after a single injection, EREM provides more prolonged pain relief for up to 48 hours after a single-shot epidural administration at the lumbar level.[2] 

On the other hand, the epidural administration of 5 mg of morphine sulfate provides sufficient postoperative analgesia, lasting up to 24 hours. However, due to the drug's extended elimination time and its potential to cause delayed adverse effects, neuraxial morphine therapy is not recommended for ambulatory patients.[3] Notably, continuous microinfusion devices have obtained FDA approval for the epidural administration of morphine.[4]

Clinical Uses of Epidural Morphine

Epidural morphine finds application in various clinical scenarios, as listed below.

• Perioperative analgesia for several procedures, including:
  • Abdominal surgeries
  • Thoracic surgeries
  • Vascular surgeries
  • Gynecological surgeries
  • Orthopedic procedures of the lower extremities, such as knee replacement surgery and hip arthroplasty
• Obstetrics settings, including:
  • Cesarean section
  • Labor pain
• Moderate-to-severe chronic pain, which is refractory to conservative treatment.

Mechanism of Action

Opioids induce analgesia by binding to the mu-opioid receptors distributed throughout the central nervous system (CNS), peripheral nervous system (PNS), and various peripheral regions. More specifically, CNS mu-opioid receptors are present in various crucial regions, including the cerebellum, nucleus accumbens, the caudate nucleus of the brain, putamen, cerebral cortex, substantia nigra, and spinal cord.[5] 

Receptors located in the PNS that contribute to the analgesic properties of opioids include the dorsal root ganglion. Opioid agonists bind to G-protein–coupled receptors, initiating intracellular transduction pathways that involve inhibiting adenylyl cyclase, stimulating potassium efflux, and inhibiting calcium influx. Consequently, these changes reduce intracellular cyclic adenosine monophosphate (cAMP), cell hyperpolarization, and neurotransmitter release inhibition.[6]

Pharmacokinetics

Absorption: When morphine is administered in the epidural space, it is rapidly absorbed into the systemic circulation. Peak plasma concentrations are reached within 10 to 15 minutes, whereas peak CSF concentrations are achieved within 60 to 90 minutes after injection.

Distribution: CSF concentrations of morphine are significantly higher (ranging from 50 to 250 times) than plasma concentrations. Specifically, CSF concentration accounts for approximately 4% of the epidurally injected dose. The efflux of morphine from the CNS is influenced significantly by ABCB1, a member of the ATP-binding cassette transporter family.[7]

Metabolism: The primary clearance pathway involves hepatic glucuronidation facilitated by UDP-glucuronosyltransferase (UGT) enzymes, leading to the formation of morphine-3-glucuronide, which is pharmacologically inactive. However, the pharmacologically active metabolite is morphine-6-glucuronide, which can effectively cross the blood-brain barrier.[8]

Excretion: The elimination half-life for epidural administration ranges from 39 to 249 minutes. Morphine and its metabolites are primarily excreted via the kidneys. Approximately 10% of the administered dose is eliminated in the feces. Notably, the elimination of morphine metabolites is affected in patients with obesity and those who are critically ill.[9][10]

Administration

Epidural morphine can be administered either as a single bolus or through a continuous infusion using a catheter. The placement of an epidural catheter enables more precise drug titration and provides better-quality analgesia.[2] Morphine exhibits a slower onset of analgesia and a longer action duration than lipophilic drugs, such as fentanyl and sufentanil, owing to its hydrophilic properties. The clinical dose of epidural morphine is lower than intravenous administration because of its good spinal cord selectivity.[1][3] 

Epidural morphine is approximately 5 to 10 times more potent than its intravenous form, and it is commonly administered at clinically used doses of 30 to 100 mcg per kg as a bolus or as a continuous infusion at 0.2 to 0.4 mg per hour. Physicians should always ensure proper needle or catheter placement in the epidural space before injecting morphine to prevent any inadvertent administration of epidural doses into the intrathecal space. The recommended initial epidural dosage for patients not tolerant to opioids ranges from 3.5 to 7.5 mg per day.

The recommended starting dosage for continuous epidural infusion in patients with opioid tolerance is 4.5 to 10 mg per day. Caution should be exercised when administering dosages above 20 mg per day due to the increased risk of adverse drug reactions. Recommendations strongly advise against abruptly discontinuing epidural morphine in patients with physical dependence. Instead, gradual tapering of the dose is recommended while carefully observing for any signs and symptoms of withdrawal.

Specific Patient Populations

Patients with hepatic impairment: Patients with hepatic impairment may experience prolonged elimination of epidurally administered morphine due to reduced liver function. Therefore, it is advisable to use caution when administering epidural morphine to such patients.

Patients with renal impairment: Patients with renal impairment often exhibit reduced clearance and higher concentrations of morphine. Furthermore, the active metabolite, morphine-6-glucuronide, tends to accumulate in patients with impaired renal function, leading to significantly higher concentrations in the CSF of dialysis patients. As a result, lower doses of morphine are recommended in this population to avoid potential adverse effects.[11]

Pregnancy considerations: During pregnancy, it is essential to carefully evaluate the risks associated with epidural morphine, especially if prolonged use is being considered. Although the risk of teratogenicity is low, administering epidural morphine during labor and delivery can increase the likelihood of respiratory depression and bradycardia in both the mother and the neonate. Chronic use of epidural morphine during pregnancy can lead to life-threatening neonatal opioid withdrawal syndrome (NOWS). Therefore, if prolonged epidural morphine use is deemed necessary for a pregnant woman, it is crucial to provide counseling regarding the potential risks and hazards associated with NOWS.[12]

Breastfeeding considerations: Epidural morphine for postcesarean section analgesia results in lower concentrations of morphine in colostrum and milk than oral and intravenous morphine. However, it is essential to note that there is a potential for sedation and respiratory depression in the nursing infant while using epidural morphine. Therefore, it is necessary to conduct a careful risk-benefit analysis before considering epidural morphine in nursing mothers.[13]

Pediatric patients: The safety and efficacy of epidural morphine have not been established in the pediatric population, and its use is not recommended, as stated in the product labeling.

Older patients: Older patients generally exhibit higher sensitivity to and increased adverse events from epidural morphine. Consequently, the initial dose should be lower, considering the reduced renal and hepatic clearance in this population. Moreover, close monitoring for CNS depression is essential when older patients receive epidural morphine.

Adverse Effects

Respiratory depression is the most potentially dangerous adverse reaction to opioid administration. However, the incidence of respiratory depression is generally low with commonly used doses, and it is dose-dependent for both hydrophilic and lipophilic opioids. The overall risk of respiratory depression after neuraxial opioids is less than 1%, which is similar to opioids administered via the parenteral route.[2][3] 

Other adverse reactions of morphine include gastrointestinal effects, such as constipation, nausea, and vomiting; CNS effects, such as sedation and dizziness; cardiovascular effects, such as bradycardia and hypotension; urinary retention and pruritus. However, it remains uncertain whether these adverse effects are related to morphine dosages.[14] 

Exacerbation of chronic pain and medical device site infection has been reported.[15] In addition, suppressing the hypothalamic-pituitary-adrenal (HPA) axis by opioids can lead to adrenal insufficiency.[16][17]

Drug-Drug Interactions 

Monoamine oxidase inhibitors (MAOIs): MAOIs have the potential to intensify the effects of morphine, resulting in respiratory depression, confusion, and coma. Therefore, the use of morphine is contraindicated in patients taking MAOIs. MAOIs should be discontinued at least 14 days before initiating epidural morphine to avoid any adverse interactions.[18]

Serotonergic drugs: The concurrent use of opioids, including morphine, with drugs that influence the serotonergic neurotransmitter systems, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and linezolid, can potentially result in serotonin syndrome. In the event of suspected serotonin syndrome, it is crucial to discontinue epidural morphine promptly.[19][20]

Mixed agonist/antagonist and partial opioid agonist: Epidural morphine should not be concomitantly used with partial agonists (such as buprenorphine) or mixed agonists/antagonists (such as pentazocine, butorphanol, and nalbuphine). Such combinations can reduce the analgesic effects of epidural morphine and may even precipitate withdrawal symptoms.[21]

Oral P2Y12 inhibitors: Morphine can potentially delay the absorption of these oral P2Y12 inhibitors, such as clopidogrel, thereby delaying the onset of their antiplatelet effect.[22]

Anticholinergic drugs: Concurrent administration of epidural morphine with anticholinergic medications increases the risk of urinary retention and paralytic ileus. Therefore, monitoring for signs of urinary retention or decreased gastric motility is essential to ensure patient safety in these cases.[23]

Contraindications

Clinicians administering epidural morphine or intravenous morphine should exercise extreme caution in patients with respiratory conditions such as chronic obstructive pulmonary disease (COPD), acute bronchial asthma, or upper airway obstruction, as it can further decrease the respiratory drive. In addition, Furthermore, practitioners should avoid using morphine in cases of previous allergy or hypersensitivity reactions to morphine or other opioids.

As epidural administration of morphine can reduce gastroduodenal motility, clinicians should refrain from using it in patients with confirmed or suspected paralytic ileus. In addition, any absolute contraindication to neuraxial anesthesia, including coagulopathy, infection at the puncture site, uncontrolled bleeding diathesis, or patient refusal, should also be considered as contraindications to spinal or epidural opioids.[24]

Boxed Warning

• Neuraxial administration of morphine can result in acute or delayed respiratory depression lasting up to 24 hours. Given the potential for severe adverse reactions when morphine is administered via the epidural route, it is imperative to observe patients in a hospital setting for at least 24 hours after the initial dose. Patients should be closely monitored, especially during the initiation of epidural morphine or following an increase in the dose.[25]

• Epidural morphine carries the risk of addiction and abuse, potentially leading to drug overdose and even death. Therefore, it is crucial to thoroughly assess the risk factors before considering epidural morphine.

• The concurrent use of epidural morphine with alcohol, benzodiazepines, or other CNS depressants can result in profound sedation, severe respiratory depression, coma, and even death. Therefore, it is essential to reserve concurrent prescribing for patients with inadequate alternative treatment options. When using concurrent therapy, it is recommended to lower the dosages and durations of epidural morphine and CNS depressants to the lowest possible level. In addition, patients should be monitored for signs of sedation and respiratory depression.[26]

Monitoring

The therapeutic effect of epidural morphine can be evaluated through both subjective and objective findings. Although pain control is the primary goal of morphine, it is also essential to monitor additional parameters such as mental status, blood pressure, and respiratory drive. Identifying respiratory depression caused by opioid use after administering neuraxial morphine can be difficult as the respiratory rate may or may not decrease.[2] 

In all patients receiving opioids, including epidural morphine, monitoring of capnography, pulse oximetry, respiratory rate, and level of consciousness is essential. Considering the delayed onset of action of epidural morphine compared to fentanyl or sufentanil, close monitoring for 18 to 24 hours after neuraxial morphine administration is recommended to ensure patient safety.[27][28] 

The use of epidural morphine poses the risk of dependence, even under appropriate medical care. Vigilance is necessary to monitor for signs of misuse, considering morphine is classified as a Schedule II controlled drug.[29] Therefore, clinicians should diligently monitor patients for neurological deficits as a precautionary measure.[30]

Toxicity

A morphine overdose can be life-threatening, primarily due to the risk of respiratory depression. When morphine is administered through the epidural route, it can cause delayed respiratory depression, even up to 24 hours after a single injection. In case of suspicion of overdose, it is imperative to promptly discontinue opioids or sedatives and administer intravenous naloxone to reverse the effects of morphine. Naloxone is an opioid antagonist, and its effective dose depends on the opioid dose received. For postoperative patients, the initial dosage of naloxone is typically 0.04 mg, with the option to administer additional increments every 2 minutes if necessary, up to a maximum of 15 mg.[31]

Supplemental oxygen should always be readily available for all patients receiving neuraxial opioids. In cases of adrenal insufficiency, treatment with corticosteroids and gradual tapering of the drug are necessary.[32]

Enhancing Healthcare Team Outcomes

The administration of morphine via the epidural route necessitates the involvement of an interprofessional healthcare team, including prescribing physicians, advanced practice practitioners, nursing staff, and pharmacists. Typically, epidural morphine is administered by an anesthesiologist, nurse anesthetist, or pain specialist to manage perioperative pain or chronic refractory pain in patients.

A focused history and physical examination of patients are necessary before administering neuraxial opioids to identify patients at risk of respiratory depression. In the case of a morphine overdose, emergency medicine physicians should promptly stabilize the patient. According to the guidelines set by the American Society of Anesthesiology and the American Society of Regional Anesthesia and Pain Medicine, patients should undergo monitoring every hour during the first 24 hours and every 4 hours from 24 to 48 hours to ensure adequate ventilation, oxygenation, and level of consciousness.[25]

Nursing staff should undergo comprehensive training to recognize signs of respiratory depression or opioid toxicity, enabling them to alert physicians when intervention is required promptly. As a safety measure, reversal agents such as naloxone should always be readily available for administration in the event of respiratory depression following neuraxial opioid administration.

Pharmacists play a crucial role in verifying dosing, recommending reversal agents, conducting medication reconciliation, checking for drug-drug interactions, and reporting their findings to the healthcare team. These responsibilities underscore the importance of a well-coordinated and collaborative interprofessional approach to ensure optimal patient care and prevent adverse events while administering and monitoring epidural morphine.