Drug Interactions Between Morphine and Orally or IV Administered Acetaminophen
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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 Design
Arms and Interventions
| 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:
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 Acetaminophen
Acetaminophen for intravenous (IV) administration (1,000 mg/100 mL)
Other Names:
Drug: IV Morphine
Morphine for IV administration (0.125 mg/kg)
Drug: Placebo Tablets
Placebo tablets matching oral acetaminophen
|
Outcome Measures
Primary Outcome Measures
- Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen [hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration]
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
- Area Under the Plasma Concentration-time Curve Over 18 Hours (AUC18) for Acetaminophen After First Morphine Co-administration [hours 0-18 during treatment with each mode of acetaminophen administration]
AUC18 is reported for the 18-hour treatment period after first morphine co-administration, for each route of acetaminophen administration
- Maximum Concentration (Cmax) of Acetaminophen [hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration]
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.
- Time to Maximum Concentration (Tmax) of Acetaminophen [hours -6 to 0, 0-6, 6-12 and 12-18 during treatment with each mode of acetaminophen administration]
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.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Arizona College of Pharmacy | Tucson | Arizona | United States | 85718 |
| 2 | NEMA Research, Inc. | Naples | Florida | United States | 34108 |
| 3 | The University of Rhode Island College of Pharmacy | Kingston | Rhode Island | United States | 02881 |
Sponsors and Collaborators
- Mallinckrodt
Investigators
- Study Director: Global Clinical Leader, Mallinckrodt
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MNK14564059
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Oral Acetaminophen | IV Acetaminophen |
|---|---|---|
| Arm/Group Description | Treatment A = 4 repeat doses of 1,000 mg oral acetaminophen (2 x 500 mg tablets) and an intravenous (IV) infusion of saline every 6 hours (Hours -6, 0, 6, and 12), and 2 infusions of IV morphine (0.125 mg/kg) at Hours 0 and 6. | 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. |
| Period Title: Overall Study | ||
| STARTED | 27 | 23 |
| Per Protocol Population | 11 | 11 |
| Safety Population | 27 | 23 |
| COMPLETED | 11 | 12 |
| NOT COMPLETED | 16 | 11 |
Baseline Characteristics
| Arm/Group Title | Oral Acetaminophen | IV Acetaminophen | Total |
|---|---|---|---|
| Arm/Group Description | 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 IV morphine (0.125 mg/kg) at Hours 0 and 6. | 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. | Total of all reporting groups |
| Overall Participants | 11 | 11 | 22 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
33.1
(9.82)
|
32.5
(11.25)
|
32.8
(10.31)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
0%
|
1
9.1%
|
1
4.5%
|
| Male |
11
100%
|
10
90.9%
|
21
95.5%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| White |
7
63.6%
|
9
81.8%
|
16
72.7%
|
| Black or African American |
2
18.2%
|
2
18.2%
|
4
18.2%
|
| Hispanic or Latino Ethnicity |
4
36.4%
|
6
54.5%
|
10
45.5%
|
| Not Hispanic or Latino |
7
63.6%
|
5
45.5%
|
12
54.5%
|
Outcome Measures
| Title | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen |
|---|---|
| Description | 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 |
| Time Frame | hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per-protocol population, which is defined as the participants who received all study medication, provided all 33 blood samples within required time points and completed the study with no major protocol deviations. |
| Arm/Group Title | First Dose - Before Morphine Co-administration | Second Dose - During Morphine Co-administration | Third Dose - During Morphine Co-administration | Fourth Dose - After Morphine Co-administration |
|---|---|---|---|---|
| Arm/Group Description | AUC6 for acetaminophen before morphine co-administration (hours -6 to -1) | AUC6 for acetaminophen during morphine co-administration (hours 0 to 6) | AUC6 for acetaminophen during morphine co-administration (hours 6 to 12) | AUC6 for acetaminophen after morphine co-administration (hours 12 to 18) |
| Measure Participants | 11 | 11 | 11 | 11 |
| Treatment A: Oral Acetaminophen |
31.00
(5.11)
|
28.51
(5.96)
|
25.31
(11.59)
|
52.38
(13.48)
|
| Treatment B: IV Acetaminophen |
42.56
(3.94)
|
44.37
(4.46)
|
43.59
(4.21)
|
49.05
(3.95)
|
| Title | Area Under the Plasma Concentration-time Curve Over 18 Hours (AUC18) for Acetaminophen After First Morphine Co-administration |
|---|---|
| Description | AUC18 is reported for the 18-hour treatment period after first morphine co-administration, for each route of acetaminophen administration |
| Time Frame | hours 0-18 during treatment with each mode of acetaminophen administration |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per-protocol population, which is defined as the participants who received all study medication, provided all 33 blood samples within required time points and completed the study with no major protocol deviations. |
| Arm/Group Title | After First Dose of Morphine Co-administration |
|---|---|
| Arm/Group Description | AUC18 after first dose of morphine co-administration (hours 0-18) |
| Measure Participants | 11 |
| Treatment A: Oral Acetaminophen |
82.50
(23.28)
|
| Treatment B: IV Acetaminophen |
63.58
(6.74)
|
| Title | Maximum Concentration (Cmax) of Acetaminophen |
|---|---|
| Description | 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. |
| Time Frame | hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per-protocol population |
| Arm/Group Title | First Dose - Before Morphine Co-administration | Second Dose - During Morphine Co-administration | Third Dose - During Morphine Co-administration | Fourth Dose - After Morphine Co-administration |
|---|---|---|---|---|
| Arm/Group Description | Pharmacokinetics of oral acetaminophen before morphine co-administration (hours -6 to -1) | Pharmacokinetics of oral acetaminophen during morphine co-administration (hours 0 to 6) | Pharmacokinetics of oral acetaminophen during morphine co-administration (hours 6 to 12) | Pharmacokinetics of oral acetaminophen during morphine co-administration (hours 12 to 18) |
| Measure Participants | 11 | 11 | 11 | 11 |
| Treatment A: Oral Acetaminophen |
11.6
(4.11)
|
7.29
(1.82)
|
7.25
(3.95)
|
13.5
(3.31)
|
| Treatment B: IV Acetaminophen |
22.6
(3.83)
|
17.0
(1.48)
|
17.5
(1.93)
|
28.5
(4.31)
|
| Title | Time to Maximum Concentration (Tmax) of Acetaminophen |
|---|---|
| Description | 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. |
| Time Frame | hours -6 to 0, 0-6, 6-12 and 12-18 during treatment with each mode of acetaminophen administration |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per-protocol population |
| Arm/Group Title | First Dose - Before Morphine Co-administration | Second Dose - During Morphine Co-administration | Third Dose - During Morphine Co-administration | Fourth Dose - After Morphine Co-administration |
|---|---|---|---|---|
| Arm/Group Description | Pharmacokinetics of oral acetaminophen before morphine co-administration (hours -6 to -1) | Pharmacokinetics of oral acetaminophen during morphine co-administration (hours 0 to 6) | Pharmacokinetics of oral acetaminophen during morphine co-administration (hours 6 to 12) | Pharmacokinetics of oral acetaminophen during morphine co-administration (hours 12 to 18) |
| Measure Participants | 11 | 11 | 11 | 11 |
| Oral Acetaminophen |
1.48
|
1.64
|
3.26
|
2.84
|
| IV Acetaminophen |
0.25
|
0.50
|
0.51
|
0.25
|
Adverse Events
| Time Frame | From start of the study to the end of study (approximately 2 weeks, including wash-out period) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | The safety analysis set, defined as all participants who received study drug, was used for the adverse events module. | |||
| Arm/Group Title | Oral Acetaminophen | IV Acetaminophen | ||
| Arm/Group Description | 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 IV morphine (0.125 mg/kg) at Hours 0 and 6. | 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. | ||
All Cause Mortality |
||||
| Oral Acetaminophen | IV Acetaminophen | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/27 (0%) | 0/23 (0%) | ||
Serious Adverse Events |
||||
| Oral Acetaminophen | IV Acetaminophen | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/27 (0%) | 0/23 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Oral Acetaminophen | IV Acetaminophen | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 22/27 (81.5%) | 17/23 (73.9%) | ||
| Gastrointestinal disorders | ||||
| Vomiting | 15/27 (55.6%) | 11/23 (47.8%) | ||
| Nausea | 12/27 (44.4%) | 10/23 (43.5%) | ||
| Abdominal discomfort | 1/27 (3.7%) | 0/23 (0%) | ||
| Abdominal pain | 1/27 (3.7%) | 0/23 (0%) | ||
| Salivary hypersecretion | 0/27 (0%) | 1/23 (4.3%) | ||
| General disorders | ||||
| Asthenia | 2/27 (7.4%) | 0/23 (0%) | ||
| Catheter site pain | 2/27 (7.4%) | 0/23 (0%) | ||
| Chills | 0/27 (0%) | 1/23 (4.3%) | ||
| Fatigue | 1/27 (3.7%) | 0/23 (0%) | ||
| Feeling abnormal | 1/27 (3.7%) | 0/23 (0%) | ||
| Feeling hot | 1/27 (3.7%) | 0/23 (0%) | ||
| Feeling of relaxation | 1/27 (3.7%) | 0/23 (0%) | ||
| Infusion site pruritus | 0/27 (0%) | 1/23 (4.3%) | ||
| Nervous system disorders | ||||
| Dizziness | 4/27 (14.8%) | 4/23 (17.4%) | ||
| Somnolence | 4/27 (14.8%) | 1/23 (4.3%) | ||
| Headache | 2/27 (7.4%) | 2/23 (8.7%) | ||
| Paraesthesia | 1/27 (3.7%) | 2/23 (8.7%) | ||
| Psychiatric disorders | ||||
| Euphoric mood | 1/27 (3.7%) | 3/23 (13%) | ||
| Irritability | 1/27 (3.7%) | 0/23 (0%) | ||
| Renal and urinary disorders | ||||
| Micturition disorder | 1/27 (3.7%) | 0/23 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Pruritus | 2/27 (7.4%) | 2/23 (8.7%) | ||
| Pruritus generalised | 0/27 (0%) | 1/23 (4.3%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Medical Information Call Center |
|---|---|
| Organization | Mallinckrodt Pharmaceuticals |
| Phone | 800-556-3314 |
| clinicaltrials@mnk.com |
- MNK14564059