Pain
Conditions
Keywords
Post-surgical pain, Pharmacokinetics
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.
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.
Interventions
Acetaminophen for oral administration (2 tablets, 500 mg/tablet)
DRUGIV Acetaminophen
Acetaminophen for intravenous (IV) administration (1,000 mg/100 mL)
DRUGIV Morphine
Morphine for IV administration (0.125 mg/kg)
DRUGPlacebo Tablets
Placebo tablets matching oral acetaminophen
DRUGSaline
Saline placebo matching IV acetaminophen
Sponsors
Mallinckrodt
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 IV morphine (0.125 mg/kg) at Hours 0 and 6. | 11 |
| 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. | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Emesis | 15 | 11 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Oral Acetaminophen | IV Acetaminophen | Total |
|---|---|---|---|
| Age, Continuous | 33.1 years STANDARD_DEVIATION 9.82 | 32.5 years STANDARD_DEVIATION 11.25 | 32.8 years STANDARD_DEVIATION 10.31 |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino Ethnicity | 4 Participants | 6 Participants | 10 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 7 Participants | 5 Participants | 12 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 23 |
| other Total, other adverse events | 22 / 27 | 17 / 23 |
| serious Total, serious adverse events | 0 / 27 | 0 / 23 |
Outcome results
Primary
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
Time frame: hours 0-18 during treatment with each mode of acetaminophen administration
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| First Dose - Before Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 18 Hours (AUC18) for Acetaminophen After First Morphine Co-administration | Treatment A: Oral Acetaminophen | 82.50 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 23.28 |
| First Dose - Before Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 18 Hours (AUC18) for Acetaminophen After First Morphine Co-administration | Treatment B: IV Acetaminophen | 63.58 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 6.74 |
Primary
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
Time frame: hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| First Dose - Before Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | Treatment A: Oral Acetaminophen | 31.00 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 5.11 |
| First Dose - Before Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | Treatment B: IV Acetaminophen | 42.56 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 3.94 |
| Second Dose - During Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | Treatment B: IV Acetaminophen | 44.37 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 4.46 |
| Second Dose - During Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | Treatment A: Oral Acetaminophen | 28.51 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 5.96 |
| Third Dose - During Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | Treatment B: IV Acetaminophen | 43.59 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 4.21 |
| Third Dose - During Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | Treatment A: Oral Acetaminophen | 25.31 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 11.59 |
| Fourth Dose - After Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | Treatment B: IV Acetaminophen | 49.05 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 3.95 |
| Fourth Dose - After Morphine Co-administration | Area Under the Plasma Concentration-time Curve Over 6 Hours (AUC6) for Acetaminophen | Treatment A: Oral Acetaminophen | 52.38 hour*microgram per milliliter (h*mcg/mL) | Standard Deviation 13.48 |
Primary
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.
Time frame: hours -6 to 0, 0-6, 6-12, and 12-18 during treatment with each mode of acetaminophen administration
Population: Per-protocol population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| First Dose - Before Morphine Co-administration | Maximum Concentration (Cmax) of Acetaminophen | Treatment A: Oral Acetaminophen | 11.6 mcg/mL | Standard Deviation 4.11 |
| First Dose - Before Morphine Co-administration | Maximum Concentration (Cmax) of Acetaminophen | Treatment B: IV Acetaminophen | 22.6 mcg/mL | Standard Deviation 3.83 |
| Second Dose - During Morphine Co-administration | Maximum Concentration (Cmax) of Acetaminophen | Treatment A: Oral Acetaminophen | 7.29 mcg/mL | Standard Deviation 1.82 |
| Second Dose - During Morphine Co-administration | Maximum Concentration (Cmax) of Acetaminophen | Treatment B: IV Acetaminophen | 17.0 mcg/mL | Standard Deviation 1.48 |
| Third Dose - During Morphine Co-administration | Maximum Concentration (Cmax) of Acetaminophen | Treatment B: IV Acetaminophen | 17.5 mcg/mL | Standard Deviation 1.93 |
| Third Dose - During Morphine Co-administration | Maximum Concentration (Cmax) of Acetaminophen | Treatment A: Oral Acetaminophen | 7.25 mcg/mL | Standard Deviation 3.95 |
| Fourth Dose - After Morphine Co-administration | Maximum Concentration (Cmax) of Acetaminophen | Treatment B: IV Acetaminophen | 28.5 mcg/mL | Standard Deviation 4.31 |
| Fourth Dose - After Morphine Co-administration | Maximum Concentration (Cmax) of Acetaminophen | Treatment A: Oral Acetaminophen | 13.5 mcg/mL | Standard Deviation 3.31 |
Primary
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.
Time frame: hours -6 to 0, 0-6, 6-12 and 12-18 during treatment with each mode of acetaminophen administration
Population: Per-protocol population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| First Dose - Before Morphine Co-administration | Time to Maximum Concentration (Tmax) of Acetaminophen | Oral Acetaminophen | 1.48 hours |
| First Dose - Before Morphine Co-administration | Time to Maximum Concentration (Tmax) of Acetaminophen | IV Acetaminophen | 0.25 hours |
| Second Dose - During Morphine Co-administration | Time to Maximum Concentration (Tmax) of Acetaminophen | Oral Acetaminophen | 1.64 hours |
| Second Dose - During Morphine Co-administration | Time to Maximum Concentration (Tmax) of Acetaminophen | IV Acetaminophen | 0.50 hours |
| Third Dose - During Morphine Co-administration | Time to Maximum Concentration (Tmax) of Acetaminophen | IV Acetaminophen | 0.51 hours |
| Third Dose - During Morphine Co-administration | Time to Maximum Concentration (Tmax) of Acetaminophen | Oral Acetaminophen | 3.26 hours |
| Fourth Dose - After Morphine Co-administration | Time to Maximum Concentration (Tmax) of Acetaminophen | Oral Acetaminophen | 2.84 hours |
| Fourth Dose - After Morphine Co-administration | Time to Maximum Concentration (Tmax) of Acetaminophen | IV Acetaminophen | 0.25 hours |