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.

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.