Drug Interactions Between Morphine and Orally or IV Administered Acetaminophen

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

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.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: Oral Acetaminophen; Drug: IV Morphine; Drug: Saline; Drug: IV Acetaminophen; Drug: Placebo Tablets

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85718
      • University of Arizona College of Pharmacy
  • Florida
    • Naples, Florida, United States, 34108
      • NEMA Research, Inc.
  • Rhode Island
    • Kingston, Rhode Island, United States, 02881
      • The University of Rhode Island College of Pharmacy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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.
2. 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:

1. Subject has a positive test result for human immunodeficiency virus (HIV), hepatitis B (surface antigen), or hepatitis C virus antibody at screening.
2. 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.
3. Subject has an oxygen saturation of less than 95% while awake at screening and check-in.
4. 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.
5. 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.
6. Subject has any other medical, psychiatric and/or social reason for exclusion as determined by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment A: Oral Acetaminophen; 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; Acetaminophen for oral administration (2 tablets, 500 mg/tablet); Other Names: APAP Oral; Drug: IV Morphine; Morphine for IV administration (0.125 mg/kg); Drug: Saline; Saline placebo matching IV acetaminophen
EXPERIMENTAL: Treatment B: IV Acetaminophen; 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 Morphine; Morphine for IV administration (0.125 mg/kg); Drug: IV Acetaminophen; Acetaminophen for intravenous (IV) administration (1,000 mg/100 mL); Other Names: APAP IV; Drug: Placebo Tablets; Placebo tablets matching oral acetaminophen

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mallinckrodt

Publications and helpful links

General Publications

• Raffa RB, Pawasauskas J, Pergolizzi JV Jr, Lu L, Chen Y, Wu S, Jarrett B, Fain R, Hill L, Devarakonda K. Pharmacokinetics of Oral and Intravenous Paracetamol (Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult Subjects. Clin Drug Investig. 2018 Mar;38(3):259-268. doi: 10.1007/s40261-017-0610-4.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2016
• Primary Completion (ACTUAL): March 1, 2016
• Study Completion (ACTUAL): March 1, 2016

Study Registration Dates

• First Submitted: July 26, 2016
• First Submitted That Met QC Criteria: July 26, 2016
• First Posted (ESTIMATE): July 28, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 5, 2020
• Last Update Submitted That Met QC Criteria: January 30, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Post-surgical pain
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Analgesics, Opioid; Narcotics; Acetaminophen; Morphine
• Other Study ID Numbers: MNK14564059

Plan for Individual participant data (IPD)

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