Drug Interactions Between Morphine and Orally or IV Administered Acetaminophen

Study Overview
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Brief Summary
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Morphine is the opioid used to treat pain after surgery. Acetaminophen (called APAP) can reduce the amount of opioids needed for this. The problem is that morphine slows down digestion. That can delay pain relief from APAP pills. It can even change what the body does to the drug [pharmacokinetics (PK)]. Some doctors have started using intravenous (IV) APAP with morphine, instead of the pills. This study will measure the PK of APAP pills and IV when used with morphine in healthy volunteers. IV APAP will likely be more effective and cause fewer side effects when used with morphine to treat pain after surgery.

Detailed Description
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Acetaminophen can significantly reduce the use of opioid analgesics when both are used concomitantly for treating moderate to severe pain. The use of IV acetaminophen used concomitantly with opioids has increased in practice for postsurgical pain relief over orally administered acetaminophen because it provides an immediate peak plasma concentration and is believed to provide a faster analgesic effect. Opioids used to treat pain inhibit gastrointestinal motility, including delaying gastric emptying. In patients receiving opioids the absorption of orally administered acetaminophen may be delayed and could result in gastric accumulation of acetaminophen thereby markedly changing the pharmacokinetic profile. The opioid-induced inhibition of gastrointestinal motility would not be expected to affect IV acetaminophen pharmacokinetics. Thus coadministered IV acetaminophen with opioid would yield better outcome in efficacy and reduced risk of side effects comparing with coadministration of oral acetaminophen and opioids.

Official Title
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A Randomized, 2-Way, Parallel, Single-Blind Pharmacokinetic Study to Evaluate the Interaction Between Intravenous Morphine and Orally or Intravenously Administered Acetaminophen in Healthy Subjects

Conditions
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Pain

Intervention / Treatment
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* Drug: Oral Acetaminophen
* Drug: IV Acetaminophen
* Drug: IV Morphine
* Drug: Placebo Tablets
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have a health status of healthy assessed by the investigator and defined as no clinically significant deviation from normal medical history, physical examination, vital signs, and clinical laboratory determinations. Subject must have a body mass index ≥ 19.0 and ≤ 32.0 kg/m² with a minimum weight of 110 pounds (50 kg) at Screening. Exclusion Criteria: Subject has a positive test result for human immunodeficiency virus (HIV), hepatitis B (surface antigen), or hepatitis C virus antibody at screening. Subject has a history of any drug allergy, hypersensitivity, or intolerance to acetaminophen or morphine/opioids or to any of the excipients in the IV or oral formulations used. Subject has an oxygen saturation of less than 95% while awake at screening and check-in. Subject has a positive test result for drugs of abuse (minimum: opioids, barbiturates, cannabinoids, benzodiazepines, cocaine, amphetamine) or alcohol at the screening and check-in. Subject has donated or had significant loss of whole blood (480 mL or more) within 30 days, or plasma within 14 days prior to dosing. Subject has any other medical, psychiatric and/or social reason for exclusion as determined by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A: Oral Acetaminophen<br>Treatment A = 4 repeat doses of 1,000 mg oral acetaminophen (2 x 500 mg tablets) and an IV infusion of saline every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of intravenous (IV) morphine (0.125 mg/kg) at Hours 0 and 6 | Drug: Oral Acetaminophen<br>* Acetaminophen for oral administration (2 tablets, 500 mg/tablet)<br>* Other names: APAP Oral;Drug: IV Morphine<br>* Morphine for IV administration (0.125 mg/kg)<br>Drug: Saline<br>* Saline placebo matching IV acetaminophen<br>|
| Experimental: Treatment B: IV Acetaminophen<br>Treatment B = 4 repeat doses of IV acetaminophen (1,000 mg/100 mL) and 2 placebo tablets every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6. | Drug: IV Acetaminophen<br>* Acetaminophen for intravenous (IV) administration (1,000 mg/100 mL)<br>* Other names: APAP IV;Drug: IV Morphine<br>* Morphine for IV administration (0.125 mg/kg)<br>Drug: Placebo Tablets<br>* Placebo tablets matching oral acetaminophen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | The area under the plasma drug concentration-time curve (AUC) is an estimate of how much drug remains available for the body to use, within a certain amount of time after the drug is administered. AUC6 is reported for each of the 6-hour dosing periods of acetaminophen before (hours -6 to 0), during (hours 0-6 and 6-12) and after (hours 12-18) morphine co-administration for each route of acetaminophen administration | hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration | 
| Area Under the Plasma Concentration-time Curve Over 18 Hours (AUC18) for Acetaminophen After First Morphine Co-administration | AUC18 is reported for the 18-hour treatment period after first morphine co-administration, for each route of acetaminophen administration | hours 0-18 during treatment with each mode of acetaminophen administration | 
| Maximum Concentration (Cmax) of Acetaminophen | Following the administration of drugs, the plasma concentration generally reaches a single, well-defined peak which is the most drug that is available for the body to use (Cmax). Cmax is reported for the 6-hour dosing periods before (hours -6 to 0), during (hours 0-6 and 6-12), and after (hours 12-18) morphine co-administration for each route of acetaminophen administration. | hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration | 
| Time to Maximum Concentration (Tmax) of Acetaminophen | Following the administration of drugs, the time at which the plasma concentration reaches Cmax is called Tmax. Tmax is reported for the 6-hour dosing periods before (hours -6 to 0), during (hours 0-6 and 6-12) and after (hours 12-18) morphine co-administration for each route of acetaminophen administration. | hours -6 to 0, 0-6, 6-12 and 12-18 during treatment with each mode of acetaminophen administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-surgical pain, Pharmacokinetics