Mechanism of Action of Intrathecal Opioids

Nociceptive information is transmitted by multiple afferent neurons that play a major role in the transmission of pain. These neurons consist of small-diameter unmyelinated fibers and thinly myelinated fibers (C fibers and Aδ fibers, respectively). Once activated they release excitatory transmitters such as substance P and ultimately contribute to the perception of pain. Central terminals of small unmyelinated fibers are located in Rexed laminae I, II, and III. Opioid receptors exist in Rexed laminae I, II, and V in the dorsal horn of the spinal cord. This location provides the anatomic basis for selective opioid analgesia in the cerebrospinal fluid (CSF). IT morphine injected into the CSF blocks the transmission of substance P and is mediated by gamma-aminobutyric acid (GABA) presynaptically and glycine postsynaptically.

The pharmacologic properties of various opioids determine their speed of onset, duration of action, and side effect profile ( Table 14.1 ). Lipophilicity (vs. hydrophilicity) is the key property affecting the speed of onset and duration of action. Highly lipid-soluble drugs (i.e., fentanyl and sufentanil) have a faster onset but shorter duration of action when used intrathecally. Shortly after injection, CSF levels are barely detectible because the drug is quickly distributed to the spinal cord. This may result in a more segmental spread of analgesia and a lower concentration reaching the brain, decreasing the risk of delayed respiratory depression (e.g., 12–24 hours after injection). In contrast, hydrophilic opioids, such as morphine, have a slower onset of action and longer duration of action and remain detectable in the CSF long after injection. Delayed respiratory depression may be more likely with morphine than with other lipophilic drugs, as morphine remains in the CSF long enough to circulate rostrally to the brainstem and respiratory centers.

An exception to these general rules is IT meperidine, exhibiting both local anesthetic properties and IT opioid receptor–binding properties that allow it to be used as a sole agent for surgery. It produces spinal anesthesia that is qualitatively similar to that achieved with conventional local anesthetics. The onset of action for meperidine is similar to that of fentanyl despite being significantly less lipid soluble; however, its duration is longer than that of fentanyl. In contrast to morphine, meperidine has a shorter duration of action because it dissipates from the CSF four times faster than morphine.

Advantages of Intrathecal Opioids

There are several advantages inherent to the use of IT opioids compared with other either intravenous (IV)/epidural opioids or neuraxial local anesthetics ( Table 14.2 ). Equianalgesic doses of IT opioids are typically a small fraction of those used for IV or epidural use. The resultant serum levels, especially with morphine, are barely detectable, thus limiting certain systemic effects while maximizing the analgesic properties. The duration of analgesia for a hydrophilic opioid such as morphine is greater compared with IV or epidural administration. A single IT injection of morphine 0.1–0.5 mg will provide up to 15–24 hours of analgesia. IT morphine may be of benefit in certain clinical situations. For instance, IT opioids may provide an advantage over epidural catheters in operations where anticoagulation will be started immediately postoperatively, necessitating the removal of the epidural catheter at the conclusion of surgery.

Unlike neuraxially administered local anesthetics, opioids do not cause adverse hemodynamic changes when administered intrathecally. In addition, opioids do not cause motor blockade or sensory loss, potentially allowing earlier ambulation. IT opioids do provide a sparing effect for local anesthetics, allowing lower doses to be used intrathecally or epidurally while still maintaining adequate analgesia.

Side Effects of Intrathecal Opioids

IT opioid use does come with a number of adverse effects ( Table 14.3 ). Most of these side effects are dose dependent and may be more common for agents administered intrathecally than by other routes. A majority of the side effects are mediated via interactions with opioid receptors.

The most feared complication is respiratory depression. The clinical use of IT morphine began in the 1980s and was accompanied with a high incidence of respiratory depression. Large IT doses of morphine (up to 20 mg) were administered and associated with an alarmingly high rate of respiratory depression. Correlations between dose and respiratory depression were noted as larger doses resulted in higher incidence of respiratory depression. Clinically significant respiratory depression is typically not seen with doses less than 0.4 mg of IT morphine. However, there have been isolated cases in which respiratory depression has occurred with smaller doses than those specified.

The incidence of respiratory depression is difficult to quantify; however, from the available literature it appears to be less than 1% for IT opioids. Indeed, the incidence of respiratory depression is less than 1% for opioids regardless of the route of administration. A meta-analysis of IT morphine in spinal anesthesia noted that IT morphine did not increase the overall risk of respiratory compromise; however, higher doses of IT morphine were associated with more episodes of respiratory depression when compared with lower doses. Furthermore, when added to a general anesthetic, IT morphine appears to be associated with an increased risk of respiratory depression (odds ratio = 7.86; 95% confidence interval [CI]: 1.54–40.3).

Respiratory depression typically occurs within minutes to hours for the lipophilic opioids. Early respiratory depression (defined in minutes) is not reported with hydrophilic opioids such as morphine. For morphine, delayed respiratory depression characteristically occurs 6–12 hours after administration but has been reported up to 19 hours after IT injection. Considerable hypoventilation may occur following IT morphine even in the presence of “normal” pulse oximetry and respiratory rate. Sedation may be another indicator of impending respiratory depression; however, only arterial blood gas analysis reliably identifies hypercarbia. Supplemental oxygen may prevent hypoxemia but may not correct the underlying etiology or even worsen hypoventilation and hypercarbia due to the elimination of hypoxic respiratory drive, especially when obstruction of the airway (e.g., obstructive sleep apnea) is implicated.

The risk of respiratory depression increases with the addition of systemic opioids and sedatives, increases with age of patient, increases with lack of opioid tolerance (i.e., opioid-naïve state), increases with obesity, and increases with sleep apnea. Respiratory depression occurs when hydrophilic opioids within the CSF migrate and react with opioid receptors in the ventral medulla. Naloxone has been used effectively to treat respiratory depression. Naloxone will need to be readministered or used as a continuous infusion due to its short half-life. Long-acting opioid antagonists have also been used for treatment and prevention of respiratory depression.

The risk of postoperative respiratory depression after the use of IT opioids has created some debate about whether intensive care unit monitoring is required after patients leave the postanesthesia care unit. Lipid soluble opioids have a low likelihood of delayed respiratory depression. However, hydrophilic opioids have a higher incidence and have prompted some institutions to require admission to a monitored unit for all patients receiving IT morphine. In addition, the requirement for monitored beds may in itself be reason enough to discourage the administration of IT opioids to patients who would otherwise benefit from such therapeutics. Patients with comorbidities such as sleep apnea, sedation, pulmonary disease, and mental status changes should be monitored closely after receiving IT opioids. IT morphine should not be used for ambulatory surgery. A higher dose of IT opioid may be acceptable for opioid-tolerant patients. Practice guidelines for the prevention, detection, and management for respiratory depression associated with neuraxial opioid administration have been published.

The most common side effect of IT opioids is pruritus. Compared with placebo, IT morphine is associated with an increased risk of pruritus, with higher doses being associated with a greater risk than are lower doses (relative risk [RR] = 1.8, 95% CI: 1.4–2.2 for <0.3 mg morphine; and RR = 5.0, 95% CI: 2.9–8.6 for >0.3 mg morphine). Pruritus is usually noted in the facial areas innervated by the trigeminal nerve; however, itching may also be generalized. Although IT opioid-induced pruritus is likely due to cephalad migration of the drug and interaction with opioid receptors in the trigeminal nucleus located superficially in the medulla, the exact etiology is unclear. The incidence has been reported anywhere from 20% to 100% in various studies and may be dose dependent. It is difficult to determine differences in the incidence of pruritus among the different opioids due to methodologic issues; however, it appears the patients who receive morphine have a higher incidence of pruritus than those who receive fentanyl. The obstetric patient population appears to have one of the highest incidences of pruritus. Despite the relatively high incidence of pruritus, very few patients actually request treatment, because the pruritus anecdotally is often noted as a problematic side effect only after clinician prompting. Itching does not appear to be histamine mediated nor is it related to systemic absorption of drug. Antihistamines are minimally effective as treatment; however, their sedating properties may relieve symptoms in some patients. Opioid receptor antagonists, such as naloxone, and opioid agonist-antagonists are effective in the treatment of pruritus. Low-dose IV naloxone may be effective in attenuating pruritus but does not generally decrease the analgesic efficacy of IT opioids. Ondansetron may be an effective agent for treating spinal or epidural morphine-induced pruritus. Prophylactic ondansetron 0.1 mg/kg IV has been shown to reduce the incidence of pruritus after IT morphine.

Nausea and vomiting are also common and troublesome side effects after IT opioid injection. Although the incidence is lower than that seen with pruritus, these patients more often require treatment. Nausea occurs in approximately 20%–40% of patients receiving IT opioids. Although the underlying mechanism is not related to systemic absorption, the incidence is comparable with IV and epidural administration. Nausea usually occurs within 4 hours of injection and may be more likely when IT morphine is used. Numerous studies have shown a slight correlation between dose and nausea and vomiting, whereas others have failed to show a connection. The presumed mechanism is the cephalad migration of drug and subsequent interaction with opioid receptors in the area postrema. A meta-analysis suggests that nausea and vomiting induced by IT morphine is not dose dependent. Compared with placebo, low doses of IT morphine (<0.3) were associated with an increased risk of nausea (RR = 1.4; 95% CI: 1.1–1.7) and vomiting (RR = 3.1; 95% CI: 1.5–6.4); however, doses of IT morphine >0.3 mg did not result in an increased risk of either nausea (RR = 1.2; 95% CI: 0.9–1.6) or vomiting (RR = 1.3; 95% CI: 0.9–1.9) compared with lower doses. Naloxone is generally effective in the treatment of nausea and vomiting induced by IT opioids. Long-acting opioid antagonists may not be as effective in treating nausea, but there may be a benefit if given prophylactically.

Urinary retention following IT opioids appears to be much more common than after equivalent doses given intravenously. The incidence of urinary retention varies considerably but occurs most frequently in males. Urinary retention induced by IT opioids does not appear to be dose related, may be more frequent when IT morphine is administered, and is likely related to opioid receptor–induced inhibition of sacral parasympathetic nervous system outflow, resulting in detrusor relaxation and an increase in bladder capacity. Naloxone may be effective in treatment, although bladder catheterization may be required.

Sedation is a dose-dependent side effect of IT opioids that occurs with all opioids. Respiratory depression should be suspected when sedation occurs with other opioids. The difference in the incidence of sedation from IT, IV, and epidural routes is not well documented but appears to be common regardless of the route of delivery. Opioid receptor antagonists are effective in decreasing the level of sedation. Chronic opioid use and subsequent tolerance may decrease the incidence of sedation.

Numerous, although rare, side effects of IT opioids are present in the literature. Generalized muscle rigidity in a neonate was reported following fentanyl during cesarean delivery. Muscle rigidity and myoclonic movements, not mediated by opioid receptors, are also reported in adults. Nystagmus, double vision, and convulsive movements of the eyelids have been described. Epileptic seizure has also been reported following an IT morphine bolus. Large doses of IT morphine have been linked to hyperalgesia in laboratory animals.