Epidural Opioids for Postoperative Pain


Epidural opioids provide effective analgesia for postoperative pain. We discuss the use of both single-dose and continuous infusion for analgesia. In addition, the side effects of epidural opioids are described.


epidural, morphine, opioids, pain, postoperative


Opioids have routinely been used to manage postoperative pain, most commonly via the intravenous (IV) route; however, anesthesiologists may administer opioids epidurally, either as a single injection or a continuous infusion. The anesthesiologist can choose from a variety of available epidural opioids, each with its unique pharmacokinetic profile that gives the clinician freedom to choose the appropriate drug for the clinical scenario. Despite some of the side effects associated with epidural opioid administration, there are many advantages to using epidural opioids for analgesia. Epidural opioids are widely used to facilitate neuraxial blockade and aid in postoperative analgesia.

Pharmacology of Epidural Opioids

Opioids administered in the epidural space will diffuse into the surrounding tissues, including epidural fat and veins, and will no longer be available to bind to opioid receptors and produce analgesia. Opioids administered into the epidural space generally produce analgesia via two mechanisms: via the cerebrospinal fluid (CSF) and via supraspinal or systemic analgesia. Some epidural opioids may be absorbed into the plasma and redistributed to the brainstem via the bloodstream to produce supraspinally mediated analgesia, whereas other opioids must diffuse through the spinal meninges into the CSF to produce spinally mediated analgesia. The interactions between the physiochemical properties of the spinal meninges and epidural opioids are complex and the permeability of an opioid through the spinal meninges is dependent on many factors, including its lipid solubility. Once inside the CSF, epidural opioids interact with spinal opioid receptors located in lamina II of the dorsal horn of the spinal cord, resulting in antinociception via presynaptic reduction of afferent neurotransmitter release and postsynaptic hyperpolarization of dorsal horn neurons. The extent of the lipid solubility of the epidural opioid is one of the key pharmacologic properties that determines its analgesic and side effect profile. After single-dose epidural administration, lipophilic opioids (e.g., fentanyl, sufentanil) generally have a quicker onset but shorter duration of action when compared with opioids that are more hydrophilic (e.g., hydromorphone, morphine). In addition, the degree of lipid solubility of the epidural opioid will determine its side effect profile. The more lipid soluble opioids are more rapidly cleared from the CSF, which may limit the presence of delayed respiratory depression (>12–24 hours after administration) which may be more prevalent in hydrophilic opioids.

Epidural opioids do not consistently produce analgesia like intrathecal opioids, which are expected to produce analgesia via a direct effect on the spinal cord and redistribution within the intrathecal space. The degree to which lipophilic opioids produce analgesia via spinal or supraspinal mechanisms is still somewhat controversial. It is generally thought that lipophilic opioids will produce analgesia mostly by systemic uptake and redistribution of the opioid to brainstem opioid receptors, although some data suggest that epidural fentanyl for labor analgesia may produce a selective spinal analgesic effect. This systemic redistribution of epidurally administered lipophilic opioid is especially obvious when a continuous infusion is used for a long duration of time. Alternatively, hydrophilic opioids are primarily thought to have an analgesic site of action in the intrathecal space. After the hydrophilic opioid has penetrated the dura into the CSF after epidural administration, the opioid will remain within the CSF to produce spinal analgesia and spread cephalad or rostral in the CSF to act at the brainstem. The rostral spread of hydrophilic opioid to the brainstem may be associated with facial pruritus, nausea, and sedation.

Injection of Single-Dose Epidural Opioids

A single-dose injection of neuraxial opioids can provide effective postoperative analgesia as a sole analgesic agent. Although they may be used alone in this regard, multiple studies have shown that analgesia is more effective when they are combined with local anesthetics. However, the analgesic profile (duration of analgesia and side effects) is dependent primarily on the degree of lipophilicity (vs. hydrophilicity), with hydrophilic agents such as morphine and hydromorphone having a longer duration of action versus lipophilic agents such as fentanyl and sufentanil. The clinician should consider choosing an opioid tailored to the surgical procedure to maximize analgesia and minimize the side effects, while taking into account the pharmacokinetic differences between hydrophilic and lipophilic opioids. For example, a single injection of a hydrophilic opioid like morphine typically provides 12 to 18 hours of analgesia and would be advantageous for postoperative analgesia in surgical inpatients with appropriate monitoring. For outpatient surgery, a lipophilic opioid may be more appropriate because its analgesic onset is more rapid and duration of action is shorter.

Both lipophilic and hydrophilic opioids may provide effective postoperative analgesia when administered as a single dose. In comparison to IV fentanyl boluses, epidural fentanyl boluses have been shown to provide adequate pain relief and inhibit physiologic, hormonal, and metabolic responses observed in the postoperative period, as shown by lower blood glucose and plasma cortisol levels for the first 20 hours after surgery. Administering a single epidural bolus of lipophilic opioid like fentanyl may provide a rapid onset (5–10 minutes) but relatively transient postoperative analgesia (up to 4 hours). Diluting the epidural dose of fentanyl (typically 50–100 μg) in at least 10 mL of preservative-free normal saline may hasten onset and prolong analgesia. Administering a single epidural bolus of hydrophilic opioid like morphine may provide a slower onset but provide a relatively longer postoperative analgesia window, which is very useful for certain procedures, including cesarean deliveries and major abdominal vascular surgery. Combining a hydrophilic and lipophilic opioid in a single epidural injection will combine the side effect profile of the short onset time and long duration of analgesia of both a lipophilic and hydrophilic opioid, respectively.

Epidural analgesia is also very convenient because administering analgesia before the onset of surgical nociceptive stimuli may prevent initiation of the feedback loop, which allows for preventive analgesia. If the epidural site is not congruent with the site of surgical incision (e.g., upper thoracic catheter for a lower abdominal surgery), a hydrophilic opioid administered into the epidural space will be very effective (either as a single shot or continuous infusion) in providing analgesia via its action in the CSF. Commonly used dosages for epidural administration of opioids are provided in Table 15.1 . The doses of epidural morphine may need to be decreased for elderly patients and thoracic catheter sites, so as to avoid respiratory depression and other side effects.

TABLE 15.1

Common Doses of Epidural Opioids a

Single Dose
Fentanyl 50–100 μg
Sufentanil 10–50 μg
Alfentanil 0.5–1 mg
Morphine 1–5 mg
Diamorphine 4–6 mg
Hydromorphone 0.5–1 mg
Meperidine 20–60 mg
Methadone 4–8 mg

a Doses based on use of neuraxial opioid alone. Lower doses may be effective when administered to the elderly or when injected in the cervical or thoracic region.

Continuous Infusion of Epidural Opioids

The main difference between single boluses of epidural opioids and continuous infusions of epidural opioids is that, when epidural opioids are used alone for postoperative pain control, analgesic infusions of epidural opioids will not generally cause motor block or hypotension due to sympathetic blockade, as may be seen with patients receiving local anesthetic via their epidural catheter. Otherwise, the similar principles apply for infusions of lipophilic (fentanyl, sufentanil) and hydrophilic (morphine, hydromorphone) opioids as they do for single-bolus doses. Although the exact site of analgesic action (spinal vs. supraspinal/systemic) for continuous epidural infusions of lipophilic opioids has not yet been well characterized, epidural infusions of lipophilic opioids produce analgesia primarily via a supraspinal/systemic mechanism. In these trials, there were no differences in plasma concentrations, side effects, or pain scores between those receiving either IV or epidural infusions of fentanyl. The overall advantage of administering continuous epidural infusions of lipophilic opioids alone is minimal.

Alternatively, continuous infusions of hydrophilic opioids produce analgesia via opioid receptors in the spinal cord. Epidural infusions of hydrophilic opioids are just as effective as single-bolus doses in providing postoperative pain control in cases in which the epidural catheter is located at a site not ideal for the location of the surgical incision or when side effects (e.g., hypotension, motor block) limit the utility of a local anesthetic-only epidural analgesic solution. A continuous epidural infusion of morphine may provide superior analgesia when compared with systemic opioids or intermittent boluses of epidural morphine.

In common clinical practice, continuous infusions of epidural opioids are administered with a local anesthetic rather than just epidural opioids alone. This combination may provide analgesic advantages over infusions of either opioid or local anesthetic alone, although the incidence of side effects may or may not be diminished. The choice of opioid varies among anesthesiologists and clinicians: Many will choose to use a lipophilic opioid (fentanyl 2–5 μg/mL or sufentanil 0.5–1 μg/mL) as part of a patient-controlled epidural analgesia (PCEA) regimen to allow for rapid titration of analgesia; however, use of a hydrophilic opioid (morphine 0.05–0.1 mg/mL or hydromorphone 0.01–0.05 mg/mL) as part of a local anesthetic–opioid epidural analgesic regimen may also provide effective postoperative analgesia.

Side Effects of Epidural Opioids

Epidural opioids exhibit the same side effects of pruritus, respiratory depression, nausea, and vomiting as opioids administered systematically. The side effect profile varies between hydrophilic and lipophilic opioids, and the severity of the side effects is usually dose dependent. Unlike local anesthetics given via the epidural space, epidural opioids are rarely directly responsible for hypotension and have little effect on heart rate or mean arterial blood pressure in comparison with being given systemically. It is essential to consider other etiologies for the side effects, and it is important to have standing orders and nursing protocols for the monitoring of neurologic status (e.g., sensory and motor functions) and side effects with clinician notification of critical parameters.

Respiratory Depression

The risk of respiratory depression with epidural opioids is not elevated when compared with systemic opioids and is typically reported to be from 0.1% to 0.9%. Still, it is one of the side effects that is most concerning, especially in patients who are elderly, have an underlying pulmonary disease or decreased respiratory reserve, have underwent thoracic surgery, and/or are also taking systemic opioids and sedatives.

There are differences in the respiratory depressant profile between epidural lipophilic and hydrophilic opioids. Lipophilic opioids administered in the epidural space are associated with early (typically within 2–4 hours of administration) rather than late (more than 2–4 hours after administration) respiratory depression. Lipophilic opioids are rapidly absorbed systemically from the epidural venous plexus and delivered to the brain and respiratory centers. Hence the onset and resolution of respiratory depression from lipophilic opioids occur relatively quickly. Alternatively, the onset of respiratory depression after epidural administration of hydrophilic opioids is generally slower than that seen with epidural administration of lipophilic opioids. Hydrophilic epidural opioids are primarily delivered to the brain via relatively slower rostral migration in the CSF rather than the more rapid systemic absorption and redistribution of lipophilic opioids. Cephalad spread of hydrophilic opioids typically occurs within 12 hours following injection. Respiratory depression from epidural administration of hydrophilic opioids can therefore occur later, typically within 6–12 hours after injection. Administration of naloxone (increments of 0.1–0.4 mg) is generally effective in reversing respiratory depression; however, a continuous infusion of naloxone (0.5–5 μg/kg per hour) may be needed because the duration of action of naloxone is shorter than the respiratory depressant effect of epidural opioids. Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration have been published.

Nausea and Vomiting

The physiology behind nausea and vomiting associated with opioids results from interactions with opioid receptors in the area postrema and chemotactic trigger zone of the medulla.

The occurrence of nausea and vomiting after a single-bolus dose of epidural opioids has been recorded to be between 20% and 50%, and the overall incidence of nausea and vomiting with a continuous epidural infusion appears to be between 45% and 80%. For epidurally administered hydrophilic opioids, nausea and vomiting may be related to the cephalad migration of opioid within the CSF to the area postrema in the medulla. Common treatment of epidural opioid–induced nausea and vomiting includes naloxone, droperidol, metoclopramide, ondansetron, dexamethasone, transdermal scopolamine, and sometimes even a small dose of propofol.


The etiology of epidural opioid–induced pruritus is unclear and may be related to activation of an “itch center” in the medulla, interaction with opioid receptors in the trigeminal nucleus or nerve roots, or changes in the sensory modulation of the trigeminal and upper cervical spinal cord due to cephalad migration of the opioid. It is important to note that opioid-induced pruritus does not appear to be associated with peripheral histamine release. Pruritus from epidural opioids occurs in up to 60% of patients exposed, compared with an incidence of 15%–18% in patients exposed to IV opioids. Some systematic data show no evidence of a dose-dependent relationship with epidural opioid–induced pruritus, whereas other studies suggest a relationship. It continues to be uncertain whether there is a relationship, but it is certain that naloxone, naltrexone, nalbuphine, and droperidol appear to be effective in managing epidural opioid–induced pruritus. Interestingly, studies have shown that there is a relation between the severity of epidural opioid–induced pruritus and the A118G polymorphisms of the human opioid receptor gene. For patients being managed for postcesarean analgesia with epidural morphine, the severity of epidural opioid–induced pruritus was significantly lower in individuals with the homogenous recessive allele in the A118G polymorphism, in comparison with individuals with the homogenous dominant allele or heterozygous genotype.

Urinary Retention

The physiology behind urinary retention associated with administration of epidural opioids stems from activation of spinal opioid receptors leading to an increase in detrusor muscle strength contraction. The incidence of urinary retention with epidurally administered opioids appears to be fairly high (70%–80%), especially in comparison with systematically administered opioids, for which the occurrence of urinary retention is only 18%. The development of urinary retention does not appear to be dose dependent. Low-dose naloxone may be effective in treating epidural opioid–induced urinary retention but at the risk of reversing analgesia.

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Sep 21, 2019 | Posted by in PAIN MEDICINE | Comments Off on Epidural Opioids for Postoperative Pain

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