Intrathecal Hydromorphone vs Intrathecal Morphine to Treat Post Cesarean Pain in Patients With Opioid Use Disorder Taking Buprenorphine

Background:

Opioid use disorder (OUD) and neonatal abstinence syndrome (NAS) has increased significantly in pregnancy during the last decade. Lui et al found the rate of OUD in patients undergoing cesarean delivery increased 4 fold from 2007 to 2014. Untreated addiction can lead to increased risk of preterm birth, low birth weight and fetal death. Women with OUD were at higher risk for inpatient mortality and readmission following delivery, particularly those who had a cesarean delivery. Pregnancy outcomes are improved if women with OUD are treated with opioid agonist therapy during pregnancy. The American College of Obstetricians and Gynecologists recommends universal screening for substance use during pregnancy, and initiation of medication assisted treatment (MAT) with opioid agonist therapy. The most commonly used MATs are methadone and buprenorphine. Methadone, a full opioid agonist, is only dispensed via federally regulated opioid treatment programs and requires patients to present daily for their methadone treatment. Buprenorphine, a partial opioid agonist, can be prescribed by a physician and patients are able to treat themselves at home. Because buprenorphine is more easily dispensed, more patients are treated with buprenorphine for OUD.

Continuation of MAT is recommended during the peripartum period to help prevent relapse post-partum. Managing pain for parturients on MAT for OUD can be challenging, particularly for patients taking buprenorphine because of its ability to compete with other opioids at the mu receptor. Women delivering via cesarean who are taking buprenorphine for MAT generally have higher postop opioid use compared to women without OUD. This was particularly true for the immediate 24 hour postop period. A recent collaboration publication between the Society for Obstetric Anesthesiology and Perinatology and Society for Maternal Fetal Medicine highlights the lack of quality research on peripartum pain management in the OUD population.

Various strategies to improve postop pain management in this patient population have been used. Use of continuous epidural infusions postop does improve pain control but has the disadvantage of resulting in weakness that can limit mobility. Others have used low dose ketamine for management of post-cesarean pain. Use of intrathecal (IT) clonidine showed some benefit, however they have higher risk for intra- and postoperative hypotension. Continuous epidural or IV infusions tend to limit patients' functionality postop due to need to be physically connected to a device to receive these treatments.

Buprenorphine is a partial agonist at the mu opioid receptor and therefore has low activity. However, it has very high binding affinity for the mu opioid receptor making it very competitive with other opioid agonists. Hydromorphone also has high binding affinity for the mu opioid receptor, allowing it to more effectively compete for binding in the presence of buprenorphine. Morphine has lower binding affinity at the mu opioid receptor making it less able to compete with buprenorphine.

A multisociety expert panel recommends continuation of buprenorphine therapy in the perioperative period, noting that studies have shown that adequate analgesia can be achieved and relapse potential is higher when buprenorphine is discontinued. They recommend nonopioid strategies for pain management, including use of regional anesthesia, NSAIDs and acetaminophen.

Inclusion of IT long-acting opioid with spinal anesthesia is considered standard of care for post-cesarean pain management. Traditionally IT morphine has been used but more recent studies have looked at use of IT hydromorphone instead of IT morphine. A retrospective study comparing 0.1mg IT morphine to 0.04mg IT hydromorphone found no difference in 24 hour pain scores or 24 hour total opioid consumption. While Marroquin et al found a shorter interval to first opioid use and higher total opioid consumption in the IT hydromorphone group compared to the IT morphine group, they still concluded that hydromorphone was a reasonable alternative to morphine. Sharpe et al showed no difference in pain scores or postop opioid consumption in patients receiving IT hydromorphone compared to morphine. This study excluded patients with history of chronic pain syndromes. These studies demonstrate IT hydromorphone is a safe and effective alternative to IT morphine. Because of the pharmacological properties of buprenorphine, hydromorphone and morphine the investigators hypothesize that the use of IT hydromorphone will provide superior pain control to IT morphine in the presence of buprenorphine.

Methods:

This will be a single center, double-blind, randomized trial to compare the effects of IT hydromorphone vs morphine to treat post cesarean pain in patients with OUD taking buprenorphine. Inclusion criteria include American Society of Anesthesiologists (ASA) Physical Status II or III presenting for cesarean delivery to be done under spinal anesthesia, who have a diagnosis of OUD and are taking buprenorphine. Exclusion criteria include contraindication to spinal anesthesia, allergy/intolerance to acetaminophen or ibuprofen and laboring patients who have an epidural that will be used for anesthesia for cesarean delivery.

Potential subjects will be approached about participating in the study at either their preop anesthesia visit or on the day of surgery after surgical and anesthesia consent has been obtained. Only licensed physician investigators will recruit patients and written informed consent will be obtained. No remuneration will be provided.

The randomization process will occur through use of a computer generated randomization scheme with allocation concealment in numbered opaque envelopes carried out by a blinded observer. Enrolled patients will be randomly allocated to receive either 200 mcg of IT morphine or 100 mcg of IT hydromorphone. Following randomization, opioid medications will be prepared by an anesthesia provider who is not involved in the clinical care of the patient. The opioid medications will be prepared so that the volume will be the same for both medications to ensure adequate blinding. Opioid medications will be either 200mcg of preservative free morphine (0.4mL) or 100mcg of preservative free hydromorphone (0.1mL) with 0.3mL of saline added for a total volume of 0.4mL. The opioid medication will be labeled "intrathecal opioid" and given to the anesthesia provider that will be taking care of the patient.

Patients will be brought to the operating room on labor and delivery where standard ASA monitors will be applied and an IV fluid co-load with lactated ringers will be started. With the patient in a sitting position a spinal block will be performed with administration of 0.75% bupivacaine in 8.25% dextrose, 15 mcg fentanyl and the study opioid medication. The patient will then be placed in the supine position and an infusion of phenylephrine will be started and titrated to maintain baseline blood pressure, as is our standard protocol. All patients will receive ondansetron and dexamethasone for antiemetic prophylaxis. Additional antiemetics will be administered as needed to treat intraoperative nausea. After delivery, oxytocin will be administered per institutional protocol. Supplemental intraoperative analgesia/anxiolysis will be administered at the discretion of the anesthesia care team. Ultrasound-guided transversus abdominis plane blocks will be performed bilaterally at the end of the procedure with 10mL liposomal bupivacaine mixed with 10mL 0.25% bupivacaine injected on each side. Respiratory rate and sedation will be assessed every 2 hours for 12 hours by nursing staff. Naloxone 0.4 mg will be administered for respiratory rate <6 or if patient is unarousable. All post-cesarean pain needs are managed by the anesthesia team at UNC. Post-cesarean multimodal pain regimen will include scheduled acetaminophen 650mg every 6 hours and scheduled ibuprofen 600mg every 6 hours. Oxycodone will be ordered for breakthrough pain, starting at 5mg every 6 hours as needed. Escalation of as needed pain medication will be at the discretion of the anesthesia team. Ondansetron and promethazine will be ordered to treat nausea as needed. Treatment of opioid induced pruritus with nalbuphine or naloxone will be at the discretion of the anesthesia care team in collaboration with the patient.

Early end points: Change in fetal or maternal health mandating the use of other anesthetic techniques, inability to perform the spinal technique, withdrawal of subject consent at any time

Surgical complications resulting in the need for additional surgical procedures: There will be no additional costs to the patient as a result of participation in this study. The costs of routine labor and delivery analgesia and anesthetic care will be the responsibility of the patient and their insurance provider.

Risks and Discomforts:

Hypotension is one of the most common sequelae from spinal anesthesia techniques. Intravascular volume expansion and standardized vasopressor treatment will be immediately available and utilized as needed. The risk of hypotension will not be increased due to the randomization of study medications.

Approximately 10-40% of the time, nausea may occur during a cesarean delivery. If nausea occurs, it will be treated and managed according to usual measures. Approximately 10% of the time pruritus may occur, which will be treated and managed according to usual measures.

The risk of a post dural puncture headache (PDPH) exists for spinal techniques. The risk is approximately 1% in an obstetric population with a 25 gauge Whitacre needle, and will not be increased by the administration of study medications. If a PDPH occurs, various methods are available for treatment and will be discussed with the patient.

Uncommon (less than 1%) sequelae include failure to obtain anesthesia, incomplete anesthesia, and need to repeat the spinal anesthetic. There is less than 0.1% risk of infection, epidural or spinal hematomas, and nerve injury. The use of the study medications will not increase these risks.

Potential Benefits: Patients may experience improved pain control with fewer opioid related side effects. Information from this study may benefit other patients undergoing neuraxial anesthesia for cesarean delivery.

Assurance of safety and tolerability:

Following continuous care during the cesarean delivery, all patients will have a scheduled visit with study personnel at 6, 12 and 24 hours after IT injection to evaluate the efficacy of analgesia. As noted, numerical rating scale pain scores, satisfaction, and opioid side effects will be recorded. Patients will also be evaluated for pain by nursing staff per unit protocol.

A patient may withdraw from the study at any time.

Serious Adverse Experiences: Any serious or unexpected adverse experiences, whether or not considered to be related to the study, shall be reported immediately via the UNC patient safety reporting system. These events are reviewed by the Director of Obstetric Anesthesia. Anyone involved in the patients' care will be able to report adverse experiences.