Intrathecal Opioids for Colorectal Resection

Intrathecal Opioids for Pain Control After Colorectal Resection: Determining the Optimal Dose

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.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative; Colorectal Surgery; Analgesic, Opioid
• Intervention / Treatment: Drug: Morphine; Drug: Hydromorphone

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.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Morphine; Subjected to sequential up and down dose titration using biased coin method in parallel with the hydromorphone arm	Drug: 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.
Experimental: Hydromorphone; Subjected to sequential up and down dose titration using biased coin method in parallel with the morphine arm	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative Pain Control	Failure was reported as a pain score of over 4/10 on a Numeric Rating Scale (NRS), scale range 0-10, 0 being no pain and 10 being the worst pain imaginable	12 hours after intrathecal (IT) drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Recovery (QoR) 15 Score	QoR 15 score is a multidimensional, valid, reliable, responsive, and easy-to-use method of measuring quality in patients' postoperative recovery. The scale ranges from 0 to 150, with higher the score, the better the recovery is.	24 hours after IT drug administration
Postoperative Pain Control	Reported as Numeric Rating Scale (NRS), scale range 0-10, 0 being no pain and 10 being the worst pain imaginable.	24 hours after IT drug administration
Presence and Severity of Opioid-related Side Effects at Their Highest Doses	Nausea and vomiting, pruritus, sedation, respiratory depression. The ordinal subjective scale of mild, moderate, and severe will be used.	12 and 24 hours after IT drug administration
Overall Benefits of Analgesia Score (OBAS)	OBAS is a validated measure incorporating both effectiveness of pain control and unwanted effects related to analgesic treatment. The scale ranges from 0 to 24, with higher the score, worse the pain control.	12 and 24 hours after highest IT drug administration

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Adam W Amundson, MD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2021
• Primary Completion (Actual): February 17, 2023
• Study Completion (Actual): February 17, 2023

Study Registration Dates

• First Submitted: January 28, 2021
• First Submitted That Met QC Criteria: February 8, 2021
• First Posted (Actual): February 12, 2021

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Morphine; Dose Finding; Hydromorphone; Intrathecal
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Morphine; Hydromorphone
• Other Study ID Numbers: 20-009205

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No