Intrathecal Hydromorphone for Cesarean Section

SpecificAims Cesarean section (C/S) is usually performed under spinal anesthesia with
preservative free morphine added for pain relief, but currently the investigators have a
severe shortage of this formulation of morphine. Hydromorphone is a narcotic which has been
used in spinals for acute postoperative pain relief and in pain pumps for relief of chronic
pain. The investigators hypothesize that a dose between 25 and 200 mcg of IT hydromorphone
will provide pain relief for at least 16 hours following C/S, with the need for minimal
rescue medication, and therefore may be a reasonable alternative to IT morphine.

Background and Significance Cesarean section is usually performed under spinal anesthesia
using bupivacaine. Intrathecal preservative free morphine is often added to decrease
postoperative pain for 12-24 hours with only the need for minor rescue medication (a
significant intravenous and oral opioid sparing effect). This allows earlier mobilization and
interaction with family/infant of these hypercoagulable patients. With the critical shortage
of this formulation of morphine, we must find an alternative medication. Hydromorphone is a
narcotic which acts peripherally and centrally to decrease pain. It has been used in spinal
anesthetics for acute postoperative pain relief and in pain pumps for relief of chronic pain.
Currently hydromorphone is not approved for intrathecal administration by the FDA, but pain
practitioners commonly prescribe hydromorphone for intrathecal pumps and have so for years.
The most recent Poly Analgesic Consensus Conference (PACC) of 2012 included IT hydromorphone
as an acceptable opioid for chronic use. Its inclusion for the management of neuropathic and
nociceptive pain infers hydromorphone's relative neurologic safety, as it is used in much
higher doses than for cesarean section. The investigators reviewed the literature to learn if
IT hydromorphone has been used for post C/S pain relief, and if so, at what dose. A
retrospective chart review comparing IT hydromorphone to fentanyl after C/S and a case report
of IT hydromorphone for a repeat C/S were all the investigators found.3,4 No randomized
controlled studies exist.

Our study will find the optimal dose of IT hydromorphone for pain relief following cesarean
section as well as delineate the incidence and severity of side effects and how long the drug
lasts. This information is critical as no other viable alternatives currently exist to
replace IT morphine in this capacity.

Preliminary Studies/Progress Report

The spinal anesthetic including the IT hydromorphone will be performed by a competent
anesthesia resident or attending (residents on the obstetric anesthesia service, the
principal investigator, or one of the co-investigators). Our C/S rate is about 31% of 2100
deliveries per year and most (>80%) are done under spinal.

Research Design and Methods

This is a randomized double-blind controlled trial utilizing the up-down sequential
allocation method (continual reassessment)1,2 to find the best dose of IT hydromorphone that
provides pain relief following C/S. Spinal anesthetic containing the specified dose of IT
hydromorphone will be administered in the OR by the anesthesia resident or attending.

After consent is obtained, the first patient will be assigned to a dose of 200 mcg of IT
hydromorphone. Although the dose of IT hydromorphone equivalent to that of IT morphine for
post cesarean section pain is not known, some sources suggest that 50 - 100 mcg of IT
hydromorphone may be similar to 100 - 200 mcg of IT morphine5-8. After preliminary
observations using varying doses of IT hydromorphone for post C/S analgesia, the
investigators observed that average and median morphine consumption in the following 16 hours
was not markedly decreased until a dose of 200 mcg IT hydromorphone was reached (40
observational patients to date, no increased side effects). The investigators now use this
dose routinely on labor and delivery so the investigators have chosen this as a starting
dose. The spinal anesthetic will also include 15mg of hyperbaric bupivacaine. All patients
will be provided with a morphine patient controlled analgesia (PCA) pump in the
post-anesthesia care unit (PACU) for additional pain relief. At 4, 8, 12 and 24 hours
following the C/S, the patient will rate her pain, degree of nausea, and itching with verbal
numeric rating scales, (pain: 0 - 10, nausea and itching: 0 - 5) and the investigators will
record the incidence of vomiting. These verbal numeric rating scales are commonly used at
Thomas Jefferson for any patient using IV PCA pumps for postoperative pain. The investigators
will also obtain a (validated) "quality of recovery scale" from each patient. Standard
nursing orders include monitoring respiratory rate every 1 hour for 6 hours, then every 2
hours for 6 hours, for signs of respiratory depression, use of pulse oximetry, and
administration of naloxone if needed. These orders are currently standard for all patients
receiving IT preservative free morphine and are in an order set in Jeff Chart. The PCA pump
will be queried the next day to evaluate the number of attempts and actual use of morphine in
the first 16 hours postoperatively. The data will be compiled and analyzed by our
statistician. Success will be defined as a median dose of less than or equal to 1mg/hour of
morphine usage in the following 16 postoperative hours. If a patient is determined to be a
success, the next patient will be assigned to a dose of IT hydromorphone that is 10 mcg less
than the previous patient. (If the first patient is a success, the second patient will
receive 190 mcg of IT hydromorphone). If a patient is deemed a failure, the next patient will
receive a dose of IT hydromorphone that is 10 mcg higher than the previous patient. (If the
first patient is a failure, the second patient will receive 210 mcg of IT hydromorphone). Our
goal is to stop the study when the investigators get 5 points of success using the lowest
concentration of IT hydromorphone resulting in a median dose of less than or equal to 1mg/hr
of morphine consumption in the 16 hours post-operatively.

Statistical Methods This is a randomized double-blind controlled trial utilizing the up-down
sequential allocation method of Dixon and Massey.1,2 On the basis of previous non-probability
sequential dosing studies with binary outcomes (success vs failure), the investigators
estimate on enrolling 40-50 patients.9-11 Using the referenced studies, the investigators
estimate a minimum of 10 independent negative-positive up-and-down deflections in the study.
Our goal is to stop the study when the investigators get 5 points of success using the lowest
concentration of IT hydromorphone resulting in less than or equal to 1mg/hr of morphine
consumption for 16 hours post-operatively.

All data will be analyzed using the Statistical Package for the Social Sciences (SPSS
software, Version 21.0 (IBM Corporation). The continuous data will be reported as mean ±
standard deviation (SD). Tests of significance include the t test for independent samples,
Wilcoxon rank-sum test for non-parametric data and Chi-square or Fisher's exact test for
frequency count data. Repeated measurements (pain scores, nausea scores) will be analyzed by
repeated measure analysis of variance where normally distributed, with further paired
comparisons at each time interval performed using the t-test. A P value < 0.05 will be
considered significant. A dose response curve will also be created to determine the effective
dose in 95% of patients (ED95) and effective dose in 50% of patients (ED50) for the patient
population.

1. The investigators would like to enroll at least 40 - 50 patients as needed.

2. PCA pump attempts and usage for 16 hours, pain medication adjuncts used, verbal numeric
rating scores for nausea, itching and pain, incidence of vomiting, and respiratory rate
(recorded every one hour) will be obtained.

3. The patient will be approached if she meets inclusion criteria when she is admitted to
the labor floor on the morning of her scheduled C/S. The study will be explained to her,
the possible risks, benefits, and alternatives will be discussed, she will be given the
opportunity to ask questions and if she agrees, the consent will be signed. The dose of
IT hydromorphone will be determined and made up by our statistician physician. The
spinal anesthetic will be administered to the patient in the operating room and the C/S
will proceed as usual. Data will be collected over the next 16 hours according to the
above research design.

4. Risks of any narcotic medication include analgesia, drowsiness, mental clouding, changes
in mood, euphoria or dysphoria, respiratory depression, cough suppression, decreased
gastrointestinal motility, nausea, vomiting, increased cerebrospinal fluid pressure,
increased biliary pressure, pinpoint constriction of the pupils, increased
parasympathetic activity and transient hyperglycemia. There is also the risk that the
study drug is ineffective at controlling post C/S pain.

5. Standard nursing orders will include monitoring respiratory rate every 1 hour for 6
hours, then every 2 hours for 6 hours, for signs of respiratory depression, use of pulse
oximetry, and administration of naloxone if needed. These orders are currently standard
for all patients receiving IT preservative free morphine and are in an order set in Jeff
Chart. They allow early recognition of and/or minimize the risk of respiratory
depression should it occur. Also, the dosages the investigators will use are well below
documented safe doses of this drug for the IT route. All patients will be provided with
a morphine patient controlled analgesia (PCA) pump in the postanesthesia care unit
(PACU) for additional pain relief whether or not the study drug is effective.

6. Potential benefit of the study is pain relief in the postoperative period following C/S
(Our usual medication is currently unavailable or in critically limited supply).

7. The side effect profiles for our standard drug, IT morphine and the study drug IT
hydromorphone are similar. Delayed respiratory depression and itching are more notable
with IT morphine than described with IT hydromorphone so this may be beneficial. The
duration of action of IT hydromorphone may not be as long as that of IT morphine.

This study poses minimal risk. This is a dose finding study. The dosages the investigators
will use are well below documented safe doses of this drug for the IT route.

Inclusion Criteria:

- Females undergoing a primary or repeat elective, scheduled C/S who are not yet in
labor will be approached for inclusion in the study

Exclusion Criteria:

- Patient refusal,

- Age less than 18 years

- Onset of labor

- Current opioid abuse

- Use of methadone maintenance for previous opioid abuse

- Allergy to hydromorphone

- Contraindication to spinal anesthesia

- Inability to obtain a spinal anesthetic

- Language other than English or if unable to understand use of a PCA pump will be
excluded.