Introduction

Cesarean delivery is a surgical procedure typically provided when it is not indicated for a pregnant patient to deliver vaginally. Notably, higher cesarean delivery rates have been associated with lower maternal and neonatal mortality [1]. Globally, it is estimated that about 21.1% of all births occur through cesarean delivery [2]. Proper pain control post-cesarean delivery is vital as it can lead to poor mobility, increased thromboembolic events, and an decreased ability to care for the neonate during the postpartum period [3, 4]. The type of anesthesia used during the cesarean delivery can affect the pain intensity and analgesic requirements [5]. General anesthesia is only used in an estimated 6% of births in the United States, due to its maternal complications, such as increased risk of infection and thromboembolic events [6].

Currently, a multimodal analgesic approach is considered the gold standard for post-cesarean care [7]. This approach typically involves a combination of neuraxial morphine, non-steroidal anti-inflammatory drugs, and acetaminophen while minimizing opioid use [8]. Neuraxial morphine has been traditionally used, as it is cost-effective, easy to administer, and has greater analgesic effects [8]. Neuraxial morphine can be administered into either the intrathecal or epidural space to provide analgesia [9]. The aim of this review is to review the efficacy and safety of the use of intrathecal morphine (ITM) for cesarean delivery including the risks and side effects and the additional use of ITM in other surgical procedures.

Methods

Inclusion and Exclusion Criteria

Inclusion criteria were the following 1. Peer-reviewed studies in English with partcipants ≥ 18 years of age 2. Studies evaluating the use of ITM and other analgesic forms during cesarean delivery and other surgical procedures. Exclusion criteria were the following: 1. Non-peer reviewed studies 2. Studies not in English 3. Studies with participant < 18 years of age 4. Case reports or case series with < 10 participants. A total of 8 studies were reviewed in this narrative review.

Efficacy

Currently, ITM is the most common form of post-cesarean delivery analgesia. Our literature search found 7 studies that directly compare the effectiveness of ITM to alternative forms of pain management. Generally, ITM was found to be as effective or better than other analgesic options (Table 1). A study by Pangthipampai et al. found that ITM had a significantly higher pain-free period, compared to a bilateral quadratus lumborum block (QLB) [10]. QLB also had an increased morphine usage in the first 24 h compared to ITM alone. QLB had an initial, beneficial impact, but this was limited to the first 6–12 h post-cesarean delivery. When patients were provided intrathecal fentanyl post-cesarean section, patients experienced significantly higher visual analog scale (VAS) pain scores and required more intravenous morphine during the first 24 h compared to ITM [11]. Additionally, these patients had a higher rate of nausea and vomiting compared to ITM. ITM also provided better analgesia compared to opioid-free epidural analgesia (CSEA-EDA) [12]. Patients using ITM experienced a significantly lower frequency of rescue analgesic use in the first 24 h after the cesarean delivery. However, analgesia effects were found in both pain management options. Pruritus only occurred in patients using ITM, and patients using CSEA-EDA had more adverse effects that impact early ambulation, such as lower extremity numbness and weakness.

Table 1 Efficacy of intrathecal morphine compared to alternative forms of pain management
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Several pain management options should be considered if ITM is contraindicated. One study found that a transversus abdominis plane (TAP) block used a significantly greater morphine equivalent dose between 10 and 24 h post-delivery and caused significantly greater pain at rest and on movement at 10 h post-delivery compared to ITM [13]. However, the TAP block had a significantly lower rate of side effects, such as nausea and vomiting, compared to ITM. ITM had a significant decrease in pain scores at 18 h compared to intrathecal hydromorphone (ITH), but there was not a significant difference between the two pain management options 24 h after the delivery [14]. There was also no significant difference in opioid use within the first 24 h, median opioid consumption, and side effects between the two options. ITH was a suitable alternative to ITM. ITM and oral analgesia were effective options for post-cesarean section pain [15]. ITM caused significantly fewer breakthrough pain events compared to oral analgesia, but ITM did have a longer duration and a greater rate of side effects.

Since ITM has previously been shown to be an effective pain management option after a cesarean delivery, several studies have studied the effect of a combination of ITM and another pain management option on post-cesarean delivery analgesia. Our literature review found 3 studies (one described in the aforementioned section, Pangthipampai et al. [10]) that directly compare the effectiveness of ITM alone to a combination of ITM with other forms of pain management (Table 2). Overall, these studies found that a combination of analgesic options provided better analgesia than ITM alone. A combination of ITM with continuous patient-controlled epidural anesthesia (PCEA) provided better analgesia than ITM alone during the first 24 h with mobilization and at rest during the first 12 hours [16]. The number of patients requiring rescue analgesics and the number of requests per patient was also significantly higher for patients being treated with ITM compared to patients using PCEA with ITM. ITM with PCEA was also found to have a significantly higher interval time before the first request for rescue analgesics. The efficacy of ITM alone compared to TAP with ITM in patients with pre-eclampsia was evaluated [17]. VAS scores in patients at rest and with movement were significantly lower in patients with the combination of TAP and ITM compared to ITM alone in the first 12 h and 8 h, respectively. Although there were no significant differences in opioid consumption or side effects between the two groups, patient satisfaction was significantly greater in patients with TAP and ITM compared to those with only ITM.

Table 2 Efficacy of intrathecal morphine alone compared to a combination of intrathecal morphine and an alternative form of pain management
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Safety

A common concern is the safety profile of ITM compared to other standards of care. In general, common side effects of oral opioids include sedation, dizziness, nausea, vomiting, constipation, physical dependence and tolerance, and respiratory depression [18]. However, it is thought that intrathecal administration of opioids has adverse effects that are more short-lived [19]. Commonly observed side effects of intrathecal opioids includes nausea, vomiting, pruritus, and urinary retention [20].

Low dose intrathecal morphine at 60 µg had a lower incidence of pruritus compared to high dose intrathecal morphine at 100 micrograms [21]. There was no difference between low and high dose morphine in regards to nausea, vomiting, and respiratory distress [21]. No chills or agitation were seen in either group.

ITM was compared with ITH in terms of the side effect profile [14]. One hundred and fifty micrograms of ITM were used compared to 75 µg of ITH. Overall, nausea significant enough to call for medication intervention was not statistically significant between the two groups, with 33% need for intervention in the ITH group and 32% in the ITM group (p > 0.99). Additionally, there was no statistically significant difference in reported pruritus requiring medication intervention, 11% in hydromorphone group and 19% in morphine group required medications (p = 0.226). In both groups, there was no observed respiratory depression with respiratory rate below 8 and no oxygen saturation below 92%.

With regard to urinary retention and delay in micturition post-spinal anesthesia, by Gautier et al. compared the addition of ITM to spinal anesthesia with prilocaine and sufentanil versus no ITM [22]. The study indicated a statistically significant effect in delay time to micturition with addition of intrathecal morphine to spinal anesthesia (p < 0.001), with 8 h to micturition in the ITM group versus 6 h in the control group. Lastly, the recovery time of spinal-epidural anesthesia with ITM was compared to those who received opioid-free epidural anesthesia (CSEA-EDA). A common precaution post-cesarean delivery is development of deep vein thrombosis and coagulation. ITM may reduce the risk of thromboembolic disease and facilitate ambulation as it has been shown to decrease lower extremity weakness and numbness. This allows for patients to ambulate sooner and decrease risk of stagnant blood flow [12]. Reduced rescue analgesia use was also shown in the ITM group, which will ultimately decrease side effects associated with these additional medications. Postoperative nausea and vomiting were similar between ITM and CSEA-EDA groups.

Conclusion

Our narrative review examined the efficacy of ITM both alone and in combination with other forms of pain management and the safety of using ITM in the post-partum period. Consistent with our findings, studies revealed ITM to be the superior analgesic in the post-cesarean delivery period when compared to QLB alone, 25 µg of fentanyl, CSEA-EDA, TAP alone, and oral analgesics [10,11,12,13, 15]. There was no superiority of ITM when compared to ITH or epidural though it is important to note that both of these studies found no difference in pain relief or side effects between the two pain relief modalities, indicating that either may be used depending on the circumstances relative to individual patients [14, 15]. Additionally, there were three studies supporting the benefit of ITM in combination with PCEA, QLB, or TAP [10, 16, 17]. It is important to note that ITM with TAP did not reduce opioid consumption but did reduce pain at certain time markers post-operatively and led to a higher maternal satisfaction when compared to ITM alone [17]. A prospective cohort study has also shown that ITM might be effective and safe in the treatment of refractory pain for patients with cancer at or above the middle thoracic vertebrae. The study compares two delivery sites of ITM: the cisterna magna or the lower thoracic region, and details an improvement in pain relief, depression, as well as quality of life in patients who received ITM delivered to the cisterna magna [25].

Our narrative review found one article comparing the side effect profile of ITM at different doses and three articles comparing the side effect profile of ITM to other analgesic control modalities including intrathecal hydromorphone, spinal-epidural anesthesia, and CSEA-EDA. There were no differences in side effect profile between 60 µg and 100 µg of ITM with regards to nausea, vomiting, or respiratory distress but there was a decreased incidence of pruritus is in the group receiving 60 µg of ITM [24]. This indicates that the side effect of pruritus may be dose dependent. ITM and intrathecal hydromorphone preformed similarly concerning side effects, with no clinical or statistical significance difference in nausea requiring antiemetics, pruritus, or respiratory depression [14]. There was a statically significant increase in urinary retention when ITM was added to spinal anesthesia of 2 h as opposed to the control group [23]. When ITM was compared to CSEA-EDA, ITM was found to require fewer opioids for breakthrough pain and have a similar side effect profile in regards to post-operative nausea and vomiting. Additionally, it was suggested that ITM use leads to earlier ambulation by reducing the lower extremity weakness in women due to the local anesthetic decreasing the risk of thromboembolic events in the post-partum period. These studies consistently report that ITM has a similar side effect profile as other commonly accepted and practiced analgesic control methods, further supporting the safety of ITM in cesarean delivery cases. Another factor to consider in the use of ITM for cesarean delivery is the racial disparities in anesthetic techniques and obstetric outcomes. According to a retrospective cohort study that includes 8 years of data, Black women face a much higher rate of severe maternal morbidity with significant short- and long-term health consequences postpartum than white women, and are also 44% more likely to receive general anesthesia than regional anesthesia during a cesarean delivery. The increasing evidence of the safety and efficacy of the use of ITM during cesarean delivery may aid in improving these racial disparities if this anesthetic technique is offered to Black women as often as it is offered to White women [26].