Pain
Conditions
Keywords
Postsurgical Dental Pain
Brief summary
With this study researchers want to collect information on how long the pain relief lasts after a fixed dose of naproxen sodium or hydrocodone/acetaminophen or placebo (contains no medication) over 12 hours in subjects experiencing moderate to severe pain after having their wisdom teeth removed. Naproxen Sodium (Aleve®) is a drug that is used for the temporary relief of minor aches and pains. Hydrocodone/Acetaminophen is a combination drug used to relieve moderate to severe pain. It contains an opioid (narcotic) pain reliever (hydrocodone) and a non-opioid pain reliever (acetaminophen).
Interventions
220 mg per tablet, two tablets (440 mg), intake a single dose orally.
5/325 mg per tablet, two tablets (10/650 mg), intake a single dose orally.
DRUGPlacebo
two tablets, intake a single dose orally.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* Healthy, ambulatory, male or female volunteers 18 to 40 years of age; * Subjects will undergo surgical extraction of three or four third molars, two of which must be mandibular molars. Maxillary third molars may be removed regardless of impaction level. The mandibular extractions must have a trauma rating of mild or moderate and meet one of the following scenarios: * two full bony impactions * two partial bony impactions * one full bony impaction in combination with one partial bony impaction Supernumerary teeth present may also be removed at the discretion of the oral surgeon; * Have not consumed alcoholic beverages, or foods and beverages containing caffeine (examples; coffee, tea, chocolate, and colas) after midnight prior to surgery and agree not to consume any of these foods or beverages throughout their stay at the study site; * Use of only short-acting local anesthetic (e.g., mepivacaine or lidocaine) preoperatively, with or without a vasoconstrictor and nitrous oxide at the discretion of the Investigator; * Have moderate to severe postoperative pain on the Categorical Pain Intensity Scale (a score of at least 2 on a 4 point scale) and a score of ≥ 5 on the 0-10 pain intensity NRS within 4.5 hours postsurgery; * Ability to understand and follow study-related instructions; * Be willing and able to participate in all scheduled visits, treatment plan, and trial procedures according to the clinical protocol;
Exclusion criteria
* History of hypersensitivity to naproxen sodium, hydrocodone/acetaminophen, ibuprofen, NSAIDS, aspirin, similar pharmacological agents, local anesthetics, rescue medication or components of the investigational products; * Evidence or history of clinically significant (in the judgment of the investigator) hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular (including hypertension), hepatic, psychiatric, neurologic diseases, or malignancies within the last 5 years; * Subjects with the following medical conditions may be eligible at the discretion of the investigator: ADHD on a stable dose regimen of methylphenidate/(dextro)amphetamine for at least 6 months; subjects with hypothyroidism on a stable dose of synthetic thyroid hormone for at least 6 months; * Have received any form of treatment in the form of medication for depression in the past 6 months or any form of psychotropic agent (including selective serotonin uptake inhibitors \[SSRI\] but excluding ADHD medications described above) within the last 6 months; * Use of any OTC or prescription medications with which the administration of naproxen, hydrocodone/acetaminophen, acetaminophen, ibuprofen, any other NSAID, (e.g., tramadol) or if a medication is contraindicated; * Females who are planning to become pregnant, pregnant or lactating; * Habituation to analgesic drugs including opioids (i.e., routine use of oral analgesics 5 or more times per week for greater than 3 weeks within the past 2 years); * Alcoholism or drug abuse within 2 years prior to the Screening Visit or routine consumption of 3 or more alcohol containing beverages per day; Alcohol containing beverages are defined as one beer (5%), one glass of wine (11%) and one shot (40%) hard liquor; * Surgeon's trauma rating of severe following surgery; * Unwilling or unable to comply with all requirements outlined in the protocol;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sum of Pain Intensity Difference Over 12 Hours (SPID 0-12) | Up to 12 hours postdose | Pain intensity is measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). For each post dose time point, pain intensity difference (PID) is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. Sum of Pain Intensity Differences (SPIDs) was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 12 hours ranges from -120 to 120. A higher value indicates a better pain reduction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Pain Relief Over 6 Hours (TOTPAR 0-6) | Up to 6 hours postdose | Pain relief is measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = A little relief, 2 = Some relief, 3 = A lot of relief, 4 = Complete relief). Total Pain Relief is calculated as the area under the curve of pain relief score over time for the given time period by multiplying the pain relief score at each time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. TOTPAR over 6 hours ranges from 0 to 24, a higher value indicates more pain relief. |
| Sum of Pain Intensity Difference Over 6 Hours (SPID 0-6) | Up to 6 hours postdose | Pain intensity is measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). For each post dose time point, pain intensity difference (PID) is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. Sum of Pain Intensity Differences (SPIDs) was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 6 hours ranges from -60 to 60. A higher value indicates a better pain reduction. |
| Number of Participants Required or Did Not Reqiure Rescue Pain Medication | Up to 12 hours postdose | — |
| Total Pain Relief Over 12 Hours (TOTPAR 0-12) | Up to 12 hours postdose | Pain relief is measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = A little relief, 2 = Some relief, 3 = A lot of relief, 4 = Complete relief). Total Pain Relief is calculated as the area under the curve of pain relief score over time for the given time period by multiplying the pain relief score at each time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. TOTPAR over 12 hours ranges from 0 to 48, a higher value indicates more pain relief. |
| Time to First Use of Rescue Medication | Up to 12 hours postdose | If a subject did not take the rescue medication during the treatment period, (s)he was censored at the time of last assessment. |
| Duration of Pain at Least Half Gone Over 12 Hours | Up to 12 hours postdose | — |
| Duration of Pain at Least Half Gone Over 6 Hours | Up to 6 hours postdose | — |
| Amount of Rescue Medication | Up to 12 hours postdose | To quantify the use of opioid analgesics in treatment of post-operative dental pain, the amount of rescue medications (opioids) was converted to a standard unit, which was Morphine Milligram Equivalent (MME) using below formula: MME/Day = Strength per Unit × (Number of units / Days supply) × MME conversion factor |
Countries
United States
Participant flow
Recruitment details
Study was conducted at one center in the US between 12-MAR-2020 (first participant first visit) and 05-OCT-2020 (last participant last visit).
Pre-assignment details
Overall, 221 participants were randomized into this post-operative dental pain study; 90 participants received naproxen sodium treatment, 87 participants received hydrocodone/APAP (acetaminophen) treatment, and 44 participants received placebo.
Participants by arm
| Arm | Count |
|---|---|
| Naproxen Sodium Participants received a single dose of naproxen sodium tablets 440 mg (220 mg × 2 tablets) after surgical teeth extractions | 90 |
| Hydrocodone / APAP Participants received a single dose of hydrocodone/acetaminophen tablets 10/650 mg (5/325 mg × 2 tablets) after surgical teeth extractions | 87 |
| Placebo Participants received a single dose of matching placebo tablets (2 tablets) after surgical teeth extractions | 44 |
| Total | 221 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 1 |
Baseline characteristics
| Characteristic | Naproxen Sodium | Hydrocodone / APAP | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 19.3 Years STANDARD_DEVIATION 1.62 | 19.3 Years STANDARD_DEVIATION 1.69 | 19.3 Years STANDARD_DEVIATION 2 | 19.3 Years STANDARD_DEVIATION 1.72 |
| Baseline pain intensity Moderate | 34 Participants | 36 Participants | 17 Participants | 87 Participants |
| Baseline pain intensity Severe | 56 Participants | 51 Participants | 27 Participants | 134 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 18 Participants | 6 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants | 69 Participants | 38 Participants | 179 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 50 Participants | 42 Participants | 20 Participants | 112 Participants |
| Sex: Female, Male Male | 40 Participants | 45 Participants | 24 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 90 | 0 / 87 | 0 / 44 |
| other Total, other adverse events | 2 / 90 | 33 / 87 | 11 / 44 |
| serious Total, serious adverse events | 0 / 90 | 0 / 87 | 0 / 44 |
Outcome results
Primary
Sum of Pain Intensity Difference Over 12 Hours (SPID 0-12)
Pain intensity is measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). For each post dose time point, pain intensity difference (PID) is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. Sum of Pain Intensity Differences (SPIDs) was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 12 hours ranges from -120 to 120. A higher value indicates a better pain reduction.
Time frame: Up to 12 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naproxen Sodium | Sum of Pain Intensity Difference Over 12 Hours (SPID 0-12) | 53.20 Scores on a scale*hours | Standard Error 3.09 |
| Hydrocodone / APAP | Sum of Pain Intensity Difference Over 12 Hours (SPID 0-12) | 38.39 Scores on a scale*hours | Standard Error 3.14 |
| Placebo | Sum of Pain Intensity Difference Over 12 Hours (SPID 0-12) | 13.57 Scores on a scale*hours | Standard Error 4.35 |
p-value: 0.00195% CI: [6.1, 23.51]ANCOVA
p-value: <0.00195% CI: [29.08, 50.18]ANCOVA
p-value: <0.00195% CI: [14.26, 35.39]ANCOVA
Secondary
Amount of Rescue Medication
To quantify the use of opioid analgesics in treatment of post-operative dental pain, the amount of rescue medications (opioids) was converted to a standard unit, which was Morphine Milligram Equivalent (MME) using below formula: MME/Day = Strength per Unit × (Number of units / Days supply) × MME conversion factor
Time frame: Up to 12 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naproxen Sodium | Amount of Rescue Medication | 7.8 Morphine Milligram Equivalent (MME) | Standard Deviation 3.08 |
| Hydrocodone / APAP | Amount of Rescue Medication | 9.3 Morphine Milligram Equivalent (MME) | Standard Deviation 4.02 |
| Placebo | Amount of Rescue Medication | 10.5 Morphine Milligram Equivalent (MME) | Standard Deviation 4.5 |
Secondary
Duration of Pain at Least Half Gone Over 12 Hours
Time frame: Up to 12 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naproxen Sodium | Duration of Pain at Least Half Gone Over 12 Hours | 8.87 Hours | Standard Error 0.46 |
| Hydrocodone / APAP | Duration of Pain at Least Half Gone Over 12 Hours | 6.57 Hours | Standard Error 0.46 |
| Placebo | Duration of Pain at Least Half Gone Over 12 Hours | 3.31 Hours | Standard Error 0.64 |
Secondary
Duration of Pain at Least Half Gone Over 6 Hours
Time frame: Up to 6 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naproxen Sodium | Duration of Pain at Least Half Gone Over 6 Hours | 4.60 Hours | Standard Error 0.22 |
| Hydrocodone / APAP | Duration of Pain at Least Half Gone Over 6 Hours | 4.08 Hours | Standard Error 0.22 |
| Placebo | Duration of Pain at Least Half Gone Over 6 Hours | 1.49 Hours | Standard Error 0.31 |
Secondary
Number of Participants Required or Did Not Reqiure Rescue Pain Medication
Time frame: Up to 12 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Naproxen Sodium | Number of Participants Required or Did Not Reqiure Rescue Pain Medication | Number of participants required rescue pain medication | 18 Participants |
| Naproxen Sodium | Number of Participants Required or Did Not Reqiure Rescue Pain Medication | Number of participants did not require any rescue pain medication | 68 Participants |
| Hydrocodone / APAP | Number of Participants Required or Did Not Reqiure Rescue Pain Medication | Number of participants required rescue pain medication | 43 Participants |
| Hydrocodone / APAP | Number of Participants Required or Did Not Reqiure Rescue Pain Medication | Number of participants did not require any rescue pain medication | 40 Participants |
| Placebo | Number of Participants Required or Did Not Reqiure Rescue Pain Medication | Number of participants required rescue pain medication | 29 Participants |
| Placebo | Number of Participants Required or Did Not Reqiure Rescue Pain Medication | Number of participants did not require any rescue pain medication | 14 Participants |
Secondary
Sum of Pain Intensity Difference Over 6 Hours (SPID 0-6)
Pain intensity is measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). For each post dose time point, pain intensity difference (PID) is derived by subtracting the pain intensity at the post dose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference is indicative of improvement. Sum of Pain Intensity Differences (SPIDs) was calculated by multiplying the PID score at each post-dose time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. SPID over 6 hours ranges from -60 to 60. A higher value indicates a better pain reduction.
Time frame: Up to 6 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naproxen Sodium | Sum of Pain Intensity Difference Over 6 Hours (SPID 0-6) | 28.41 Scores on a scale*hours | Standard Error 1.46 |
| Hydrocodone / APAP | Sum of Pain Intensity Difference Over 6 Hours (SPID 0-6) | 24.35 Scores on a scale*hours | Standard Error 1.48 |
| Placebo | Sum of Pain Intensity Difference Over 6 Hours (SPID 0-6) | 6.23 Scores on a scale*hours | Standard Error 2.05 |
Secondary
Time to First Use of Rescue Medication
If a subject did not take the rescue medication during the treatment period, (s)he was censored at the time of last assessment.
Time frame: Up to 12 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Naproxen Sodium | Time to First Use of Rescue Medication | NA Hours |
| Hydrocodone / APAP | Time to First Use of Rescue Medication | 10.42 Hours |
| Placebo | Time to First Use of Rescue Medication | 2.57 Hours |
Secondary
Total Pain Relief Over 12 Hours (TOTPAR 0-12)
Pain relief is measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = A little relief, 2 = Some relief, 3 = A lot of relief, 4 = Complete relief). Total Pain Relief is calculated as the area under the curve of pain relief score over time for the given time period by multiplying the pain relief score at each time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. TOTPAR over 12 hours ranges from 0 to 48, a higher value indicates more pain relief.
Time frame: Up to 12 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naproxen Sodium | Total Pain Relief Over 12 Hours (TOTPAR 0-12) | 28.41 Scores on a scale*hours | Standard Error 1.36 |
| Hydrocodone / APAP | Total Pain Relief Over 12 Hours (TOTPAR 0-12) | 21.31 Scores on a scale*hours | Standard Error 1.39 |
| Placebo | Total Pain Relief Over 12 Hours (TOTPAR 0-12) | 10.63 Scores on a scale*hours | Standard Error 1.92 |
Secondary
Total Pain Relief Over 6 Hours (TOTPAR 0-6)
Pain relief is measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = A little relief, 2 = Some relief, 3 = A lot of relief, 4 = Complete relief). Total Pain Relief is calculated as the area under the curve of pain relief score over time for the given time period by multiplying the pain relief score at each time point by the duration (in hours) since the preceding time point and then summing these values over the specific time period. TOTPAR over 6 hours ranges from 0 to 24, a higher value indicates more pain relief.
Time frame: Up to 6 hours postdose
Population: PP Population: all subjects in safety population who provided at least one pain assessment after the first dose of study drug and did not have any major protocol violations and completed the 12-hour assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naproxen Sodium | Total Pain Relief Over 6 Hours (TOTPAR 0-6) | 14.53 Scores on a scale*hours | Standard Error 0.61 |
| Hydrocodone / APAP | Total Pain Relief Over 6 Hours (TOTPAR 0-6) | 12.69 Scores on a scale*hours | Standard Error 0.62 |
| Placebo | Total Pain Relief Over 6 Hours (TOTPAR 0-6) | 5.14 Scores on a scale*hours | Standard Error 0.87 |