A Comparison of Targinact vs. Oxycodone on Gut Function After Colorectal Surgery

Study Overview
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Brief Summary
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Two key requirements for discharge from hospital after major abdominal surgery are adequate oral analgesia and resumption of oral nutrition. Up to 40% of patients suffer delayed discharge after abdominal surgery due to delayed return of gut function, manifesting as nausea, vomiting, constipation and abdominal distension. Opiates and their derivatives are the mainstay of postoperative analgesic regimens after abdominal surgery and are highly effective in achieving adequate pain control. However, opioids cause impaired gut function by reducing normal forward propulsion and increasing gut spasm. Opioid receptor blockers such as Alvimopan counteract these effects and can accelerate postoperative gut recovery but are expensive and cause cardiac complications; alternative painkillers such as non-steroidal anti-inflammatories are less effective than opioids and have been linked with increased risk of anastomotic leaks. Targinact is a combination of prolonged release opioid analgesic (oxycodone hydrochloride) and naloxone hydrochloride (an opioid receptor blocker). The formulation of the product confines the naloxone action to the gut to reduce the unwanted side-effects on gut function. Targinact has been shown in patients with chronic severe pain to provide comparable analgesia to other opioid analgesics whilst reducing the unwanted side-effect of constipation. The Investigators wish to test the hypothesis that Targinact will provide adequate analgesia after colonic resection with reduced postoperative gastrointestinal dysfunction. The surgical procedure chosen to test this hypothesis is laparoscopic segmental colectomy, a consistently reproducible intervention with a postoperative gut dysfunction rate of up to 40% (prospective data from the Edinburgh Colorectal Unit). The main outcome of the study will be return of normal gut function at the time of planned discharge (Day 3).

Detailed Description
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Study hypothesis: Targinact is effective as oral analgesia after major colorectal surgery and is associated with less gut dysfunction than Oxycodone. Up to 40% of patients suffer delayed return of gut function after elective colorectal surgery, leading to prolonged hospital stay and higher inpatient costs. For the patient, this is characterised by a variety of symptoms including nausea and vomiting, delayed ability to regain normal oral intake, abdominal discomfort/distension and constipation. Although post-operative gut dysfunction tends to resolve spontaneously in 3-7 days, both symptoms and supportive treatment (nasogastric tube insertion, repeated venous cannulation for intravenous fluid administration etc) are unpleasant. Elective colorectal surgery is a common hospital intervention hence a reduction in the prevalence of post-operative gut dysfunction would be expected to benefit a large number of patients with attendant reduction in health service costs. The objective aligns well with the current national dissemination of Enhanced Recovery after Surgery programmes by the UK Department of Health and Scottish Government. Post-operative gut dysfunction is multifactorial. Opioid analgesics are contributory and all Enhanced Recovery after Surgery (ERAS) programmes emphasise strategies to minimise systemic opioid use (eg using regional or local anaesthetic techniques). Targinact has not been evaluated in the setting of short-term post operative analgesia in colorectal surgery but offers the potential to achieve effective analgesia with a lower incidence of gut dysfunction and therefore an important role within the ERAS program after colorectal surgery. Oxycodone is currently the oral opioid analgesic of choice in our unit and most patients are prescribed a combination of oxycodone and oxynorm as step-down analgesia following cessation of systemic or epidural analgesia, often in combination with fentanyl patches. Data will be collected from patient hospital records and questionnaires administered by the principal investigator and research study nurse. Multiple measures will be employed to record both presence of good function and absence of dysfunction. Time to first flatus Time to first bowel movement Time from surgery to cessation of iv fluids Total dose of rescue antiemetic (protocol ondansetron not included) Reinstitution of iv fluids (Y/N) Quantity of laxative used Measurement of oral nutritional intake: Preoperative intake will be recorded by means of a recall diary. Postoperative oral intake will be recorded by the participant using a food diary for 7 days from the date of surgery. Energy intake will then be estimated using CompEat Pro® forWindows® (Nutrition Systems, Banbury, UK). Time to attain and maintain 80% of normal solid food intake and the percentage Recommended Nutritional Intake (RNI) achieved on days 1-3 and days 5-7 after surgery will be used in comparisons between study groups. Validated nausea and vomiting score (Miles and Wengritzky) Presence of abdominal distension (Y/N) 13C Stable Isotope Gastric Empyting Breath Test to measure gastric motility on the second postoperative morning. The technique has been previously used in the Edinburgh Department of Surgery and validated to be a reproducible and accurate measurement of upper GI motility. Additional data to be recorded: Patient demographics, co morbidity, regular medications Pre op bowel function questionnaire Postoperative nausea and vomiting prediction data (Apfel score) Day 3 achievement of discharge criteria (pain controlled by oral analgesia, tolerating adequate oral diet and fluids, independently mobile and willing to go home) Y/N 30-day/Inpatient mortality Duration of hospital admission Complications (recorded by organ system and severity as assessed by Clavien/Dindo scale) Unscheduled readmissions to hospital within 30 days of discharge Patient-reported outcome questionnaire

Official Title
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A Randomized Blinded Pilot Study to Compare Targinact vs. Oxycodone in Early Return of Gastrointestinal Function After Colorectal Surgery

Conditions
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Postoperative Pain, Postoperative Nausea and Vomiting

Intervention / Treatment
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* Drug: Targinact
* Drug: Oxycodone
* Procedure: Laparoscopic segmental colectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients scheduled for elective laparoscopic segmental colectomy at the Colorectal Surgery Unit, Western General Hospital, Edinburgh. Exclusion Criteria: Pregnancy Age <18 years Patients lacking capacity to give informed consent. Severe liver dysfunction (Child's A or greater) Patients participating in another therapeutic clinical trial Contraindication to oxycodone, naloxone or Targinact Pre-existing dependence on opioid analgesia (current medications will be checked prior to discussing consent) Pre-existing use of opioid analgesia for chronic pain (current medications will be checked prior to discussing consent) Patients with rectal cancer Plan to form any stoma during procedure

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Targinact<br>Oral Targinact 10-20mg bd following laparoscopic segmental colectomy | Drug: Targinact<br>* Post-operative analgesia<br>* Other names: Oxycodone-Naloxone;Procedure: Laparoscopic segmental colectomy<br> <br> |
| Active Comparator: Oxycodone<br>Oral oxycodone 10-20mg bd following laparoscopic segmental colectomy | Drug: Oxycodone<br>* Postoperative analgesia<br>Procedure: Laparoscopic segmental colectomy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Postoperative Gut Dysfunction | The proportion of participants with gut dysfunction, defined as the presence of any of the following sufficient to delay discharge on the 3rd postoperative day: nausea, vomiting, intolerance of oral intake or constipation. | Day 3 post-op | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Opioid Analgesia Consumption | Total dose of systemic and oral Oxycodone or Targinact taken in hospital or at home until discontinued by the participant | Total postoperative period of analgesic consumption, an average of 1 week | 
| Pain Scores | Overall Benefit of Analgesia Score (OBAS): Score range 0-28 with low score=high benefit. Summed from subscales of 0-4 for the following questions: Please rate your current pain at rest on a scale between 0⁄4 minimal pain and 4⁄4 maximum imaginable pain Please grade any distress and bother from vomiting in the past 24 h (0⁄4 not at all to 4⁄4 very much) Please grade any distress and bother from itching in the past 24 h (0⁄4 not at all to 4⁄4 very much) Please grade any distress and bother from sweating in the past 24 h (0⁄4 not at all to 4⁄4 very much) Please grade any distress and bother from freezing in the past 24 h (0⁄4 not at all to 4⁄4 very much) Please grade any distress and bother from dizziness in the past 24 h (0⁄4 not at all to 4⁄4 very much) How satisfied are you with your pain treatment during the past 24 h (0⁄4 not at all to 4⁄4 very much) Lehmann N. British Journal of Anaesthesia 105 (4): 511-18 (2010) | Postoperative day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal, Surgery, Laparoscopic, Analgesia, Enhanced Recovery, Targinact