Evaluate Analgesic/Sedative Efficacy of Naproxen Sodium and Diphenhydramine

Study Overview
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Brief Summary
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The objectives of the study are to evaluate the analgesic and hypnotic efficacy of naproxen sodium and diphenhydramine combination when compared to naproxen sodium, diphenhydramine, and an ibuprofen and diphenhydramine combination

Official Title
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A Double-Blind, Randomized, Pilot Study Assessing the Analgesic and Hypnotic Effect of Naproxen Sodium and Diphenhydramine Combination in Dental Pain

Conditions
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Sleep

Intervention / Treatment
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* Drug: Naproxen Sodium 440 mg (BAYH6689) / DPH 50mg
* Drug: Naproxen Sodium 440 mg (BAYH6689)
* Drug: Naproxen Sodium 220 mg (BAYH6689) / DPH 50mg
* Drug: Naproxen Sodium 220 mg (BAYH6689)
* Drug: DPH 50mg
* Drug: Ibuprofen 400 mg / Diphenhydramine citrate 76 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, ambulatory, male and female volunteers between 16-45 years of age; Scheduled to undergo surgical removal of 1 to 3 impacted third molars, one of which must be at least a partial bony mandibular impaction; Have moderate to severe postoperative pain on the Categorical Pain Rating Scale and a score of >/= 50 mm on the 100-mm visual analog Pain Severity Rating Scale by 2030 h +/- 15 minutes on the day of surgery; Female subjects of childbearing potential must be using a medically acceptable form of birth control for at least 1 month prior to screening (3 months on oral contraceptives), e.g. oral or patch contraceptives, intrauterine device, Depo-Provera, or double-barrier and have a negative pregnancy test at Screening and prior to surgery. Female subjects of nonchildbearing potential must be amenorrheic for at least 2 years or had a hysterectomy and/or bilateral oophorectomy; Provide a personally signed and dated informed consent indicating that the subject has been informed of all pertinent aspects of the trial, (subjects <18 years of age must sign a written assent and have parental or guardian consent). Exclusion Criteria: History of hypersensitivity to naproxen, diphenhydramine, nonsteroidal antiinflammatory drugs (NSAIDS), tramadol, aspirin or any other antihistamine and similar pharmacological agents or components of the products; Evidence or history of clinically significant (in the judgment of the investigator) hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic diseases, or malignancies within the last 5 years; Relevant concomitant disease such as asthma (exercise induced asthma is permitted), chronic sinusitis or nasal structural abnormalities causing greater than 50 percent obstruction (polyposis nasi, marked septal deviation) that can interfere with the conduct of the study in the judgment of the investigator; Current or past history of bleeding disorder(s); Acute illness or local infection prior to surgery that can interfere with the conduct of the study in the judgment of the investigator; Chronic use of antihistamines defined as using 5 or more times a week for 2 or more consecutive weeks during the past 3 months; Positive alcohol breathalyzer test and negative urine drug test prior to surgery; Females who are pregnant or lactating; Chronic or severe sleep problems that do not respond to Over the counter (OTC) medication and requires a prescription hypnotic or sedative;

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naproxen Sodium 440 mg (BAYH6689) / DPH 50mg<br> | Drug: Naproxen Sodium 440 mg (BAYH6689) / DPH 50mg<br>* Participants received 2 tablets of Naproxen Sodium 220 mg and 2 tablets of Diphenhydramine hydrochloride (DPH) 25 mg, single dose, orally.<br>|
| Active Comparator: Naproxen Sodium 440 mg (BAYH6689)<br> | Drug: Naproxen Sodium 440 mg (BAYH6689)<br>* Participants received 2 tablets of Naproxen Sodium 220mg and 2 tablets of placebo, single dose, orally.<br>|
| Experimental: Naproxen Sodium 220 mg (BAYH6689) / DPH 50mg<br> | Drug: Naproxen Sodium 220 mg (BAYH6689) / DPH 50mg<br>* One dose of naproxen sodium 220 mg plus diphenhydramine 50 mg<br>|
| Active Comparator: Naproxen Sodium 220 mg (BAYH6689)<br> | Drug: Naproxen Sodium 220 mg (BAYH6689)<br>* Participants received 1 tablet of Naproxen Sodium 220 mg and 3 tablets of placebo, single dose, orally.<br>|
| Active Comparator: DPH 50mg<br> | Drug: DPH 50mg<br>* Participants received 2 tablets of Diphenhydramine hydrochloride (DPH) 25 mg and 2 tablets of placebo, single dose, orally.<br>|
| Active Comparator: Ibuprofen 400 mg / Diphenhydramine citrate 76 mg<br> | Drug: Ibuprofen 400 mg / Diphenhydramine citrate 76 mg<br>* Participants received 2 tablets of Advil PM (ibuprofen 200 mg and diphenhydramine citrate 38 mg) and 2 tablets of Placebo, single dose, orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Sleep Time Measured by Actigraphy | Actigraphy is a non-intrusive tool that measures an individual's movement during sleep. Actigraphy was used to obtain data in discriminating between sleep and wake states in the subjects. In calculating the total sleep time, subjects who took rescue medication were treated as awake from the time the rescue medication was given until the end of the sleep period. In addition, if subjects rescued before sleep onset, their total sleep time was set to zero. | Up to 10 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wake After Sleep Onset (WASO) Measured by Actigraphy | Actigraphy is a non-intrusive tool that measures an individual's movement during sleep. Actigraphy was used to obtain data in discriminating between sleep and wake states in the subjects. WASO was defined as minutes of awake during the period of sleep onset and offset, where sleep onset is the first 20-minute block with 19 minutes of sleep. | Up to 10 hours | 
| Sleep Latency Measured by Actigraphy | Actigraphy is a non-intrusive tool that measures an individual's movement during sleep. Actigraphy was used to obtain data in discriminating between sleep and wake states in the subjects. Sleep latency was defined as minutes to sleep onset since dosing, where sleep onset was the first 20-minute block with 19 minutes of sleep. For subjects who had not achieved sleep onset (e.g., due to taking rescue medication before achieving sleep onset), sleep latency was considered as censored at the time of wakening. | Up to 10 hours | 
| Global Assessment of Study Medication as a Sleep-aid | Subject rating of following question with 0 being poor to 4 being excellent: How would you rate the study medication you received as a sleep aid? | Up to 10 hours | 
| Karolinska Sleep Diary - Sleep Quality | Subject rating of following question with 1 being very poor and 5 being very good: How was your sleep? | Up to 10 hours | 
| Karolinska Sleep Diary - Calmness of Sleep | Subject rating of following question with 1 being very restless and 5 being very calm: How calm was your sleep? | Up to 10 hours | 
| Karolinska Sleep Diary - Easiness to Fall Asleep | Subject rating of following question with 1 being very difficult to 5 being very easy: How easy was it to fall asleep? | Up to 10 hours | 
| Karolinska Sleep Diary - Premature Awakening | Subject rating of following question with 1 being woke up much too early to 3 being no: Premature awakening? | Up to 10 hours | 
| Karolinska Sleep Diary - Ease of Awakening | Subject rating of following question with 1 being very difficult to 5 being very easy: Ease of awakening? | Up to 10 hours | 
| Karolinska Sleep Diary - Well Rested | Subject rating of following question with 1 being not rested at all to 3 being completely rested: Well-rested? | Up to 10 hours | 
| Karolinska Sleep Diary - Sufficient Sleep | Subject rating of following question with 1 being no, definitely too little to 5 being yes, definitely enough: Did you get enough (sufficient) sleep? | Up to 10 hours | 
| Total Sleep Time by Subject Assessment | Subject responded to: Please estimate the number of hours and minutes you think that you slept. | Up to 10 hours | 
| Sleep Quality Index | Sleep Quality Index is the mean score of items, 'sleep quality', 'calm sleep', 'ease falling asleep', and 'slept throughout' on the Karolinska Sleep Diary, ranges from 1 (worst possible) to 5 (best possible). | Up to 10 hours | 
| Overall Rating of Severity in Categorical Pain Rating Scale Score | Subject responded to question, 'My pain at this time is' by selecting one of the following choices: no pain (0), mild pain (1), moderate pain (2), or severe pain (3). | Up to 10 hours | 
| Change From Baseline in Categorical Pain Rating Scale Score | Subjects responded to question, 'My pain at this time is' with following choices: no pain (0), mild pain (1), moderate pain (2), or severe pain (3). Subjects completed this question at baseline (post-dental surgery) and after sleep period. The following measure is the change in pain rating from baseline. | Baseline and up to 10 hours | 
| Overall Rating of Severity in Visual Analog Scale (VAS) Score | Subjects marked a line on a 100-mm scale to indicate the severity of pain they are experiencing from 0 being no pain to 100 being worse possible pain. | At 10 hours | 
| Change From Baseline in Visual Analog Scale (VAS) Score | Subjects completed the VAS scale at baseline (post-dental surgery) and after completion of the sleep period. Subjects marked a line on a 100-mm scale to indicate the severity of pain they are experiencing from 0 being no pain to 100 being worse possible pain.This measure indicates the change in pain severity rating on the VAS scale from baseline. | Baseline and up to 10 hours | 
| Overall Rating of Pain Relief | Subjects responded to question, Overall, the relief from my starting pain was by checking one of the following choices: no relief (0), a little relief (1), some relief (2), a lot of relief (3), complete relief (4). | Up to 10 hours | 
| Time to Rescue Medication | Subjects were allowed to rescue and take a non-study pain reliever if the pain was not tolerable. This measure represents for the time to taking rescue medication from the time the subject took study treatment. | Up to 10 hours | 
| Cumulative Proportion of Participants Taking Rescue Medication by Hour | Subjects were allowed to rescue and take a non-study pain reliever if the pain was not tolerable. This measure represents for the proportion of subjects who rescued in the study. | Up to 10 hours | 
| Global Assessment of Study Medication as a Pain Reliever | Subject responded to question, 'How would you rating this study medication you received as a pain-reliever?' with the following choices: Poor (0), Fair(1), Good(2), Very Good(3), Excellent(4) | Up to 10 hours | 
| Number of Times Participants Took Rescue Medication | Subjects were allowed to rescue and take a non-study pain reliever if the pain was not tolerable. This measure represents for the number of times rescue medication was taken by a subject. | Up to 10 hours | 
| Total Wake Time Measured by Actigraphy | Actigraphy is a non-intrusive tool that measures an individual's movement during sleep. Actigraphy was used to obtain data in discriminating between sleep and wake states in the subjects. | Up to 10 hours | 
| Sleep Efficiency Measured by Actigraphy | Sleep efficiency was calculated as (total sleep time/total time in-bed time) × 100; total in-bed time was fixed at 10 hours. Actigraphy is a non-intrusive tool that measures an individual's movement during sleep. Actigraphy was used to obtain data in discriminating between sleep and wake states in the subjects. | Up to 10 hours | 
| Activity Mean Measured by Actigraphy | Actigraphy is a non-intrusive tool that measures an individual's movement during sleep. Actigraphy was used to obtain data in discriminating between sleep and wake states in the subjects. Activity mean - average movement per minute. | Up to 10 hours | 
| Wake Episode Measured by Actigraphy | Actigraphy is a non-intrusive tool that measures an individual's movement during sleep. Actigraphy was used to obtain data in discriminating between sleep and wake states in the subjects. Wake Episodes - # of blocks of continuous wake epochs (defined as 2 or more consecutive epochs scored as wake that ends when there is at least one epoch scored as sleep subsequent to the start of the wake epochs). | Up to 10 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Naproxen sodium, Diphenhydramine, Drugs, Investigational