Intrathecal Opioids for Colorectal Resection

NCT ID: NCT04752033

Last Updated: 2024-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-03-10
• Study Completion Date: 2023-02-17

Brief Summary

This research study is being done to determine the optimal dose of spinal morphine and hydromorphone in patients undergoing minimally-invasive (i.e., surgery performed through small entry sites and using cameras) colorectal surgery.

Detailed Description

Intrathecal (IT) opioids have been established as a safe and efficacious modality to treat postoperative pain. In the setting of colorectal surgery, studies have shown that intrathecal opioids together with multimodal analgesic regimens provide pain relief superior to multimodal analgesia alone. Furthermore, in the setting of multimodal analgesia, IT opioids also appear to be equianalgesic to epidural analgesia while conferring an improved safety profile. As a result, many institutions have incorporated intrathecal opioids into their Enhanced Recovery after Surgery (ERAS) pathways.

While morphine has traditionally been considered the "gold standard" in IT opioid therapy for postsurgical pain, hydromorphone has been gaining popularity as an alternative. The doses ranging between 0.005 mg to 0.25 mg for hydromorphone12-15 and 0.05 mg to 0.625 mg (with doses as high as 10 mcg/kg in the setting of cardiac surgery) for morphine has been found to be efficacious in this patient population. However, increasing opioid doses are associated with increased incidence of adverse effects. A meta-analysis reviewing twenty-eight studies which investigated intrathecal morphine versus placebo demonstrated moderate increases in the incidences of pruritus, nausea and vomiting. In fact, the incidence of nausea with IT morphine has been reported to be 33%. While hydromorphone is similar chemically to morphine, it is metabolized differently. Differences in pharmacokinetics may allow for differences in side effect profiles. Hydromorphone is more lipid soluble than morphine. This decreases its spread within the intrathecal space and enhances its penetration into the dorsal horn of the spinal cord where interactions with opioid receptors occur. Some studies (performed in the women undergoing cesarean delivery) have also found that hydromorphone causes less nausea and pruritus than morphine, while others have not.

Despite the widespread use of IT hydromorphone and morphine for pain after colorectal surgery, the optimal dose for neither drug has been established in prospective trials. The investigators have previously performed a dose-finding study of IT hydromorphone and morphine in women undergoing cesarean delivery. Briefly, 80 parturients scheduled for elective cesarean delivery were randomized to receive IT morphine or IT hydromorphone at a dose determined using up-down sequential allocation with a biased-coin design to determine ED90, which was found to be 75 mcg for IT hydromorphone and 150 mcg for IT morphine. The follow-up study performed by the investigators also found no differences in adverse effects or efficacy between the drugs. The results from the obstetric population, however, cannot be directly translated to the colorectal surgery population due to pharmacodynamic and pharmacokinetics differences related to the pregnancy, age, presence of comorbidities, differences in surgical techniques, and co-administration of IT local anesthetic.

This study applies the methodology the investigators have previously used in the obstetric population to the patients undergoing colorectal resection and aims to identify the optimal dose of IT hydromorphone and morphine that provides good pain relief without causing significant side effects. Secondarily, the investigators will compare each drug at its optimal dose in terms of opioid consumption and side effects. Based on their prior findings, the investigators hypothesize that the optimal dose of intrathecal hydromorphone will be 75 mcg and the optimal dose of intrathecal morphine will be 150 mcg. Additionally, the investigators hypothesize that exploratory findings comparing the two drugs at their optimal doses will show no difference in the incidence of adverse effects.

Conditions

Colorectal Surgery; Pain, Postoperative; Analgesic, Opioid

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Morphine

Subjected to sequential up and down dose titration using biased coin method in parallel with the hydromorphone arm

Group Type: EXPERIMENTAL

Morphine

Intervention Type: DRUG

Dose titration utilizing will be done using sequential up and down design using biased coin method. All participant will receive a morphine dose that is within the range of doses currently utilized clinically and no participant will receive placebo only.

Hydromorphone

Subjected to sequential up and down dose titration using biased coin method in parallel with the morphine arm

Group Type: EXPERIMENTAL

Hydromorphone

Intervention Type: DRUG

Dose titration utilizing will be done using sequential up and down design using biased coin method. All participant will receive a hydromorphone dose that is within the range of doses currently utilized clinically and no participant will receive placebo only.

Interventions

Morphine

Dose titration utilizing will be done using sequential up and down design using biased coin method. All participant will receive a morphine dose that is within the range of doses currently utilized clinically and no participant will receive placebo only.

Intervention Type: DRUG

Hydromorphone

Dose titration utilizing will be done using sequential up and down design using biased coin method. All participant will receive a hydromorphone dose that is within the range of doses currently utilized clinically and no participant will receive placebo only.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Adult patients with an American Society of Anesthesiologists (ASA) physiological status I-III.
• Undergoing colorectal minimally invasive surgery (MIS).
• Age between 18 and 75 years of age.
• Body mass index (BMI) between 18.5 and 40.
• Ability to understand and read English.

Exclusion Criteria

• Not able or unwilling to sign consent.
• Patients undergoing ileostomy closure.
• Patients undergoing ambulatory surgery or anticipated to be discharged sooner than 24 hours after surgery
• Patients with chronic pain, requiring daily opioid use at the time of surgery.
• Patient intolerant or allergic to opioids, NSAIDs, or acetaminophen.
• Patients requiring emergent surgery.
• Any contraindication to neuraxial anesthesia (coagulopathy, localized infection at the site of injection, pre-existing spinal pathology, or peripheral neuropathy).
• Any patients currently receiving any anticoagulation medication other than aspirin and who have not discontinued the medication per American Society of Regional Anesthesia anticoagulation guidelines22, and/or an abnormal INR.
• Patients with hepatic or renal insufficiency in as much as the patient is not a candidate for acetaminophen or NSAIDs, respectively.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

Adam Amundson MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Adam W Amundson, MD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Countries

United States

References

Vinsard PA, Pleticha J, Sharpe EE, Panchamia JK, Olsen DA, Sviggum HP, Shawki SF, Behm KT, Larson DW, LeMahieu AM, Niesen AD, Amundson AW. A Prospective Randomized Dose-Finding Study of Intrathecal Opioids for Postoperative Analgesia After Minimally Invasive Colorectal Operation. Mayo Clin Proc Innov Qual Outcomes. 2025 Mar 3;9(2):100600. doi: 10.1016/j.mayocpiqo.2025.100600. eCollection 2025 Apr.

Reference Type: DERIVED

PMID: 40114986 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.mayo.edu/research/clinical-trials

Mayo Clinic Clinical Trials

Other Identifiers

20-009205

Identifier Type: -

Identifier Source: org_study_id