Intrathecal Opioids for Colorectal Resection
Condition: Colorectal Surgery; Pain, Postoperative; Analgesic, Opioid
MeSH terms: Pain, Postoperative
Study type: Interventional
Phase: Phase 4

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 morphinehas 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.
    

Intervention name(s): Morphine; Hydromorphone
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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 MeSH terms: Morphine; Hydromorphone
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Dose Finding Study Utilizing Sequential Up and Down Method Using Biased Coin Design
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Intrathecal; Morphine; Hydromorphone; Dose Finding