Morphine was the first opioid approved for spinal administration by the US Food and Drugs Administration (FDA), and it has been the most widely used opioid in clinical practice via this route. Epidural morphine is useful as analgesia, as an adjunct to general anesthesia, or as a sole technique for surgical anesthesia. Morphine sulfate has FDA approval for acute or chronic moderate to severe pain. In 2004, the use of liposome-based extended-release epidural morphine (EREM) also received FDA approval. Due to its delayed peak concentration in the CSF of 3 hours after a single injection, EREM provides up to 48 hours of pain relief after a single-shot epidural administration at the lumbar level. On the other hand, epidural administration of 5 mg of morphine sulfate will provide adequate postoperative analgesia for up to 24 hours. Given its long elimination time and its potential to cause delayed adverse effects, neuraxial morphine is not a recommended therapy for ambulatory patients.
Clinical Uses of Epidural Morphine:
Opioids produce analgesia by binding to the mu-opioid receptors distributed throughout the central nervous system (CNS) and peripheral nervous system (PNS) and in many peripheral regions. More specifically, CNS mu-opioid receptors are present in the cerebellum, nucleus accumbens, caudate nucleus of the brain, putamen, cerebral cortex, substantia nigra, and spinal cord. Receptors located in the PNS which contribute to the analgesic properties of opioids include dorsal root ganglion. Opioid agonists bind to G-protein coupled receptors producing an initiation of intracellular transduction pathways that include inhibition of adenylyl cyclase, stimulation of potassium efflux, and inhibition of calcium influx. The net effect of these changes is a reduction in intracellular cAMP, hyperpolarization of the cell, and inhibition of neurotransmitter release.
Epidural morphine can be administered as a single bolus or as a continuous infusion via a catheter. Placing an epidural catheter allows for easier drug titration and seems to induce better quality analgesia. Given its hydrophilic properties, morphine has a slower onset of analgesia and a longer duration of action compared to lipophilic drugs such as fentanyl and sufentanil. The clinical dose of epidural morphine is lower than for intravenous administration due to its good spinal cord selectivity. Epidural morphine is about 5 to 10 times more potent than its intravenous form, with clinically used doses of 30 to 100 mcg/kg as a bolus or 0.2 to 0.4 mg/hour as a continuous infusion. Lower doses of morphine are recommended in patients with hepatic or renal dysfunction due to its significantly altered pharmacokinetics. To avoid inadvertent administration of epidural doses into the intrathecal space, always verify proper needle or catheter placement in the epidural space before injecting morphine.
Respiratory depression is the most potentially dangerous adverse reaction of opioid administration. The incidence is low with commonly used doses, being dose-dependent for both hydrophilic and lipophilic opioids. The overall risk of respiratory depression after neuraxial opioids is less than 1%, very similar to that of opioids administered via the parenteral route. Other adverse reactions of morphine include gastrointestinal effects (constipation, nausea, vomiting), CNS effects (sedation, dizziness), cardiovascular effects (bradycardia, hypotension), urinary retention, and pruritus; it remains unclear if these side effects are dose-related.  More specifically, the risks of epidural morphine should be considered during pregnancy, particularly if prolonged use. Although the risk of teratogenicity is low, epidural morphine during labor and delivery increases the risk of respiratory depression and bradycardia in both the mother and the neonate.
Epidural morphine, as well as intravenous morphine, should be used with extreme caution in patients with respiratory conditions such as COPD, acute bronchial asthma, or upper airway obstruction since it can further decrease the respiratory drive. Additionally, practitioners should avoid using morphine in cases of previous allergy or hypersensitivity reaction to morphine or other opioids. Since the epidural administration of morphine reduces gastroduodenal motility, it should be avoided in patients with confirmed or suspected paralytic ileus. Any absolute contraindication to neuraxial anesthesia, including coagulopathy, infection at the site of puncture, or patient refusal, are also contraindications to spinal or epidural opioids.
The therapeutic effect of epidural morphine is assessable through subjective and objective findings. Although the ultimate goal of morphine is pain control, it is important to monitor other parameters like mental status, blood pressure, or respiratory drive. Detection of opioid-induced respiratory depression after neuraxial morphine may be challenging since the respiratory rate may or may not decrease. Capnography, pulse oximetry, respiratory rate, and level of consciousness all require monitoring in all patients receiving opioids. Due to epidural morphine delay onset of action compared to fentanyl or sufentanil, patients should be monitored closely for 18 to 24 hours after neuraxial morphine.
A morphine overdose can be potentially lethal due to the risk of respiratory depression. When administered via the epidural route, morphine can cause delayed respiratory depression up to 24 hours after a single injection. If suspected, immediately stop 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 amount of opioid received. In the postoperative patient population, the starting dose of naloxone is 0.04 mg, with increments every 2 minutes if needed to a maximum of 15 mg. Supplemental oxygen should always be available in all patients receiving neuraxial opioids.
The administration of morphine via the epidural route requires an interprofessional healthcare team that includes providers, nurses, and pharmacists. Epidural morphine administration is by an anesthesiologist, nurse anesthetist, or pain specialist for perioperative pain control or chronic refractory pain. A focused history and physical examination are necessary before the administration of neuraxial opioids to identify patients at risk of respiratory depression. Given its long duration of action, patients require close monitoring for 18 to 24 hours for the adequacy of ventilation, oxygenation, and level of consciousness. [Level I] Nursing should receive proper training to identify signs of respiratory depression or opioid toxicity so they can alert the physicians when there is a need for intervention. Reversal agents like naloxone should always be available for administration in case of respiratory depression after neuraxial opioid administration. [Level I] The pharmacist should verify dosing and make recommendations for reversal agents, as well as performing medication reconciliation, and report their findings to the team. The above highlights the necessity of a properly functioning and collaborative interprofessional team approach to ensure optimal patient care when administering and monitoring epidural morphine. [Level V]
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