A Study of Serial Magnetic Resonance Cholangiopancreatography (MRCP) Following Morphine-neostigmine and Secretin Provocation in Healthy Volunteers

A Randomised, Double Blind Cross-over Study of Serial MRCP Following Morphine-neostigmine and Secretin Provocation in Healthy Volunteers

The sphincter of Oddi is a circular band of muscle which controls the flow of pancreatic juices and bile into the small intestine. Abnormal function of the Sphincter of Oddi, known as Sphincter of Oddi dysfunction (SOD), can lead to recurrent episodes of abdominal pain. Making a diagnosis of SOD is difficult and is currently achieved using an invasive pressure test. This pressure test is associated with some adverse effects including inflammation of the pancreas gland. We are investigating an alternative test in which medication is given to provoke spasm of the sphincter. Following provocation, blood can be sampled to detect changes in blood composition and changes in sphincter anatomy can be evaluated using specialized imaging techniques.

Our aim is to study and compare the effects of two provocation medications (morphine-prostigmine and secretin) on biliary and pancreatic ductal anatomy, using dynamic serial MRCP in healthy volunteers.

Our hypothesis is that morphine-neostigmine provocation results in greater changes in biliary and pancreatic ductal anatomy when assessed using dynamic serial MRCP.

Study Overview

• Status: Completed
• Conditions: Sphincter of Oddi Dysfunction
• Intervention / Treatment: Drug: Morphine; Drug: Neostigmine; Drug: 0.9% saline; Drug: 0.9% saline; Drug: Secretin

Detailed Description

The sphincter of Oddi (SO), which encases the distal common bile duct (CBD) and pancreatic duct (PD), comprises a fibromuscular complex to control the flow of biliary and pancreatic secretions into the duodenum. Aberrant function of the SO, known as Sphincter of Oddi dysfunction (SOD), can lead to recurrent episodes of biliary or pancreatic type pain. Both surgical sphincteroplasty and endoscopic sphincterotomy can improve symptoms in some patients who are suspected to have SOD. However, poor results are obtained in a significant proportion reflecting the difficulties in achieving an accurate diagnosis and also in selecting those patients likely to benefit from these procedures. A number of investigative modalities have been employed in the assessment of SOD. Of the available diagnostic tests sphincter of Oddi manometry (SOM) is considered the gold standard, but is associated with a high rate of post procedure morbidity including pancreatitis and biliary sepsis.

It is therefore unsurprising that attention has focussed on non-invasive diagnostic tests. Developments in magnetic resonance cholangiopancreatography (MRCP) have allowed for the detailed non-invasive assessment of biliary and pancreatic ductal morphology and can be used in conjunction with intravenous secretin provocation (ss-MRCP). Evaluations of this technique have so far been disappointing, demonstrating only a modest concordance with SOM in patients suspected with SOD.

The morphine-prostigmine provocation test (Nardi test) has previously been utilised as a screening test in patients with symptoms suggestive of SOD. It is performed by giving an intramuscular injection of morphine 10mg and prostigmine 1mg, with a positive test indicated by the reproduction of pain or a fourfold increase in either serum amylase or lipase levels. As enzymatic changes have been shown to occur in healthy subjects and in those with irritable bowel syndrome, the test has largely fallen out of favour. However, a recent publication has suggested morphine used as a pharmacological provocation agent can improve ductal distension and aid the differentiation of pancreaticobiliary variants on MRCP. To date this has not been investigated in a randomised or blinded study and we have therefore proposed to examine the effects of morphine-neostigmine and secretin provocation on gallbladder volume and biliary and pancreatic ductal morphology in healthy volunteers using serial MRCP.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
      • University of Nottingham

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Healthy age matched and sex matched volunteers
• No history of chronic abdominal pain
• No previous abdominal surgery
• No history suggestive of gastrointestinal motility disorders
• No history of regular medication or substance abuse

Exclusion Criteria:

• Acute illness within preceding 6 weeks
• Participation in another study within 3 months
• Allergy to morphine or neostigmine
• Pregnancy
• Refusal to consent to the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Morphine-neostigmine	Drug: Morphine; 10mg IM; Drug: Neostigmine; 1mg IM; Drug: 0.9% saline; 0.1 ml/kg; Drug: 0.9% saline; 1ml IM
Active Comparator: Secretin	Drug: 0.9% saline; 0.1 ml/kg; Drug: 0.9% saline; 1ml IM; Drug: Secretin; 1 unit/kg IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Serum amylase (U/L)	0, 60, 120, 180 and 240 minutes
Serum lipase (U/L)	0, 60, 120, 180 and 240 minutes
Liver function tests	0, 60, 120, 180 and 240 minutes

Secondary Outcome Measures

Outcome Measure	Time Frame
Pancreatic duct diameter (mm)	0, 5, 30, 60, 90, 120, 150 and 180 minutes
Pancreatic duct length (mm)	0, 5, 30, 60, 90, 120, 150 and 180 minutes
Common bile duct diameter (mm)	0, 5, 30, 60, 90, 120, 150 and 180 minutes
Gallbladder volume (mm3)	0, 5, 30, 60, 90, 120, 150 and 180 minutes

Collaborators and Investigators

• Sponsor: University of Nottingham
• Investigators: Principal Investigator: Dileep Lobo, MBBS DM FRCS, University of Nottingham; Study Director: Abeed Chowdhury, MB ChB BSc MRCS, University of Nottingham

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: May 28, 2010
• First Submitted That Met QC Criteria: June 1, 2010
• First Posted (Estimate): June 2, 2010

Study Record Updates

• Last Update Posted (Estimate): June 2, 2010
• Last Update Submitted That Met QC Criteria: June 1, 2010
• Last Verified: May 1, 2010

More Information

Terms related to this study

• Keywords: Bile ducts; Sphincter of Oddi; Pancreatic ducts
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Biliary Dyskinesia; Common Bile Duct Diseases; Sphincter of Oddi Dysfunction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Analgesics, Opioid; Narcotics; Cholinesterase Inhibitors; Parasympathomimetics; Morphine; Neostigmine; Secretin
• Other Study ID Numbers: C/10/2007

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No