Epidural opioids are widely used in combination with local anaesthetics to provide analgesia both during labour and following caesarean section and other procedures. Spinal opioids have also been used to enhance surgical anaesthesia and to provide postoperative analgesia, and more recently to provide analgesia for labour (in combined spinal-epidural techniques). Spinal and epidural opioids alone do not provide adequate pain relief for the late first stage and second stage of labour.
All opioids have significant maternal side effects, ranging from mild nausea to lifethreatening respiratory depression. These side effects may occur following administration of opioids by any route, although the published literature has tended to focus on adverse effects associated with neuraxial administration. In the UK, fentanyl is the opioid most commonly used to provide labour analgesia, with diamorphine or fentanyl used for intra- and postoperative analgesia. Epidural morphine is less commonly used because of the greater risk of late respiratory depression, although spinal morphine appears to be safe in low-risk parturients.
Sufentanil is widely used in the rest of Europe and in North America, but is not available in the UK. Other drugs such as pethidine and hydromorphone have also been used for obstetric neuraxial blocks.
Site of action
Opioids act at the opioid receptors in the substantia gelatinosa of the spinal cord. Drugs injected into the epidural space have to penetrate the dura to reach the site of action. Ease of dural penetration will depend on lipid solubility and molecular weight, with highly lipid- soluble molecules (such as fentanyl) entering the subarachnoid space most readily. Once the opioid has reached the cerebrospinal fluid (CSF), the more lipid-soluble drugs will fix readily in the spinal cord, whereas less lipid-soluble drugs (such as morphine) remain in the CSF and are carried in a cranial direction with CSF flow, reaching the lateral ventricles in around 6 hours or longer. This accounts for the slow onset of action, higher incidence of nausea, vomiting and pruritus, and late respiratory depression seen with morphine.
The epidural space is highly vascular in the pregnant woman, and there is significant systemic uptake of epidurally administered opioids (with similar blood concentration curves to those seen after parenteral administration). In addition, some opioid is bound to fat in the epidural space and does not reach the spinal cord. The ratio of epidural to spinal dose of opioid is thus in the order of 5-10:1.
Commonly used epidural and spinal bolus doses are:
• Fentanyl: epidural 50-100 µg, spinal 15-25 µg
• Diamorphine: epidural 2-3 mg, spinal 200-500 µg
• Morphine: epidural 3-4 mg, spinal 75-100 µg
Benefits
Several studies have confirmed that epidural administration of opioids alone provides analgesia for early labour but is inadequate for the later stages of labour. However, the combination of local anaesthetic and opioid is synergistic, allowing improved quality of analgesia, reduced consumption of local anaesthetic, reduced motor block and reduction in opioid side effects. Typical combinations used consist of 0.1-0.125% bupivacaine with 2-2.5 µg/ml fentanyl.
Improved maternal mobility increases maternal satisfaction with labour analgesia, and improvement in rates of spontaneous vaginal delivery compared with the traditional, higher-dose and opioid-free techniques (e.g. 0.25-5% bupivacaine alone). The mechanism of local anaesthetic-opioid synergy is unclear.
Epidural and intrathecal opioids are claimed to provide superior postoperative analgesia, although there are so many variables involved, and different measures of analgesic outcome, that it is difficult to assess this reliably.
Side effects
Side effects of both epidural and intrathecal opioids are dose-dependent and are more severe for less lipophilic drugs such as morphine. With the exception of urinary retention (which is not dose-related), all the side effects seen after neuraxial administration of opioids may occur following parenteral administration (although itching is only common when opioids are given epidurally or intrathecally). A unique side effect is the potential for reactivation of herpes simplex labialis 2-5 days after the epidural administration of morphine. Several theories have been proposed, but the exact mechanism is uncertain.
Use of an opioid receptor antagonist such as naloxone reliably reverses the side effects of epidural and intrathecal opioids, but reversal of analgesia may occur. This has encouraged symptomatic treatment of individual side effects, for example using antihistamines such as chlorphenamine 4 mg orally or 10 mg parenterally for itching. Low doses of propofol (10 mg) and ondansetron have been reported to reduce opioid-induced itching, but the evidence for benefit is inconclusive.
Respiratory depression
The incidence of respiratory depression with neuraxial opioids in obstetric patients is reported to be less than 1%, although methods of detection and definitions vary. Fentanyl has the shortest duration of action following epidural or subarachnoid administration (approximately 4 hours) and the lowest potential to cause respiratory depression, although cases have been reported. Epidural morphine is well recognised as being associated with a small risk of respiratory depression for up to 12-24 hours after administration, but will also provide analgesia for a similar period of time. Diamorphine has an intermediate duration of action, and there have been no reported cases of delayed respiratory depression, although early cases have occurred - usually in combination with other sedatives.
The potential for this life-threatening side effect of centrally administered opioids has led to a general prohibition on the concomitant use of strong opioid and sedative drugs by any other route. It has also caused considerable controversy about the intensity and duration of monitoring and nursing care required for patients who have received epidural or spinal opioids. Respiratory depression manifests itself as increasing sedation (due to carbon dioxide retention) rather than reduced respiratory rate; therefore, in the absence of facilities for prolonged high-dependency nursing (which few obstetric units possess), it is sensible to nurse the mother in a postnatal bed that can be readily observed from the central nursing station, and in the company of other mothers, rather than in a side room. This is particularly recommended in women with additional risk factors such as obesity, and in those who have received or will receive additional parenteral opioids or other drugs with depressant effects, e.g. magnesium. Many obstetric anaesthetists consider that the small but real risks of late respiratory depression associated with neuraxial morphine outweigh the benefits of using it in preference to diamorphine or fentanyl, although there are many studies confirming the safety of spinal morphine.
If naloxone is required to reverse respiratory depression, it is important to use either repeated doses or an infusion, because of the prolonged action of the opioid compared with its antagonist.
Gastric emptying
This is delayed after epidural or intrathecal boluses of opioids, although there is some evidence that low-dose infusions of fentanyl do not impair gastric emptying.
Placental transfer
Although centrally administered opioids cross the placenta, this occurs in a dose-dependent manner. Administration of an epidural bolus of fentanyl 100 µg 20 minutes before delivery results in umbilical artery concentrations well below those needed to cause neonatal respiratory depression. Similarly, although opioids can be found in breast milk after maternal epidural administration, the amounts are negligible.
Key points
• There is synergy between neuraxial opioids and local anaesthetics.
• Side effects occur following all routes of administration.
• Side effects are dose-dependent, with the exception of urinary retention.
• Morphine has a slower onset, longer duration of action and increased incidence of side effects compared with fentanyl. The action of diamorphine is intermediate.
Further reading
American Society of Anesthesiologists Task Force on Neuraxial Opioids. Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration. An updated report by the American Society of Anesthesiologists Task Force on Neuraxial Opioids and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology 2016; 124: 535-52.
Armstrong S, Fernando R. Side effects and efficacy of neuraxial opioids in pregnant patients at delivery: a comprehensive review. Drug Saf 2016; 39: 381-99.
Kwok S, Wang H, Sng BL. Post-caesarean analgesia. Trends Anaesth Crit Care 2014; 4: 189-94.
Marroquin B, Feng C, Balofsky A, et al Neuraxial opioids for post-cesarean delivery analgesia: can hydromorphone replace morphine? A retrospective study. Int J Obstet Anesth 2017; 30: 16-22.
Sultan P, Halpern SH, Pushpanathan E, Patel S, Carvalho B. The effect of intrathecal morphine dose on outcomes after elective cesarean delivery: a meta-analysis. Anesth Analg 2016; 123: 154-64.