Evaluate Analgesic/Sedative Efficacy of Naproxen Sodium and Diphenhydramine in Patients With Postsurgical Dental Pain (Morpheus II)

A Multicenter, Randomized, Double-Blind, Parallel Group Trial Assessing the Efficacy of Naproxen Sodium and Diphenhydramine Combination in Postsurgical Dental Pain With Phase Advanced Sleep

The objective of the study is to evaluate the efficacy and safety of a single oral dose of two dose combinations of naproxen sodium and diphenhydramine (DPH) to demonstrate that naproxen sodium/DPH combination provides added clinical benefit to sleep improvement than either single ingredient alone in subjects with post-surgical dental pain and phase advanced sleep.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative
• Intervention / Treatment: Drug: Naproxen sodium 440 mg / DPH 50 mg (BAY98-7111); Drug: Naproxen sodium 220 mg / DPH 50 mg (BAY98-7111); Drug: Naproxen sodium 440 mg (BAYH6689); Drug: DPH 50 mg

• Study Type: Interventional
• Enrollment (Actual): 712
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78744
  • Utah
    • Salt Lake City, Utah, United States, 84124

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy, ambulatory, male and female volunteers ages 12 and older

• Scheduled to undergo surgical removal of a minimum of two third molars of which at least one has to be a mandibular third molar. The mandibular extraction(s) required by each subject must meet one of the following scenarios:

  • one full bony impaction
  • two partial bony impactions
  • one full bony impaction and one partial bony impaction
  • one full bony impaction and one soft tissue impaction
  • one full bony impaction and one erupted third molar. Two full bony mandibular impactions are not allowed. Maxillary third molars may be removed regardless of impaction level.
• 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 between 1600 hour and 1830 hour 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 anti-inflammatory drug (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 positive 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
• Habitually spends less than 6.5 hours in bed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naproxen sodium 440 mg / DPH 50 mg (BAY98-7111)	Drug: Naproxen sodium 440 mg / DPH 50 mg (BAY98-7111); Participants received two Naproxen sodium 220 mg / DPH (Diphenhydramine hydrochloride) 25 mg tablets orally, single dose
Experimental: Naproxen sodium 220 mg / DPH 50 mg (BAY98-7111)	Drug: Naproxen sodium 220 mg / DPH 50 mg (BAY98-7111); Participants received one Naproxen sodium 220 mg / DPH 50 mg tablet and one matching placebo capsule orally, single dose
Active Comparator: Naproxen sodium 440 mg (BAYH6689)	Drug: Naproxen sodium 440 mg (BAYH6689); Participants received two Naproxen sodium 220 mg tablets orally, single dose
Active Comparator: DPH 50 mg	Drug: DPH 50 mg; Participants received two DPH (Diphenhydramine hydrochloride) 25mg tablets orally, single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wake Time After Sleep Onset (WASO) Measured by Actigraphy	WASO was defined as Total wake time (in minutes) after sleep onset during the 10 hours in-bed period as 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 Latency Measured by Actigraphy	Sleep latency was defined as the time to sleep onset from the time of dosing as 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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Sleep Time Measured by Actigraphy	Total time time was measured as total time spent sleeping (not to exceed 600 minutes) during the in-bed period as 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
Global Assessment of Investigational Product as a Sleep Aid	The Global Assessment of Investigational Product as a Sleep-Aid was rated using a 5-point categorical scale for which the potential response was poor (0), fair, (1), good (2), very good (3), or excellent (4).	Up to 10 hours
Karolinska Sleep Diary - Sleep Quality	Subjects responded to the following question: How was your sleep? very poor (1); rather poor (2); neither poor nor good (3); rather good (4); very good (5)	Up to 10 hours
Karolinska Sleep Diary - Calmness of Sleep	Subjects responded to the following question: How calm was your sleep? very restless (1); rather restless (2); neither restless nor calm (3); rather calm (4); very calm (5)	Up to 10 hours
Karolinska Sleep Diary - Easiness to Fall Asleep	Subjects responded to the following question: How easy was it to fall asleep? very difficult (1); rather difficult (2); neither difficult nor easy (3); rather easy (4); very easy (5)	Up to 10 hours
Karolinska Sleep Diary - Premature Awakening	Subjects responded to the following question: Premature awakening? woke up much too early (1); woke up somewhat too early (2); no (3)	Up to 10 hours
Karolinska Sleep Diary - Ease of Awakening	Subjects responded to the following question: Ease of awakening? (1) very difficult; (2) rather difficult; (3) neither difficult nor easy; (4) rather easy; very easy (5)	Up to 10 hours
Karolinska Sleep Diary - Well Rested	Subjects responded to the following question: Well Rested? not rested at all (1); somewhat unrested (2); completely rested (3)	Up to 10 hours
Karolinska Sleep Diary - Sufficient Sleep	Subjects responded to the following question: Did you get enough (sufficient) sleep? no, definitely too little (1); no, much too little (2); no, somewhat too little (3); yes, almost enough (4); yes, definitely enough (5)	Up to 10 hours
Subjective Sleep Questionnaire - Quality of Your Sleep Last Night	Subjects responded to Quality of sleep (10-point scale, where 1 was poor and 10 was excellent)	Up to 10 hours
Subjective Sleep Questionnaire - Refreshing Nature of Your Sleep Last Night	Subjects responded to Refreshing nature of sleep (10-point scale, where 1 was not refreshing and 10 was very refreshing)	Up to 10 hours
Subjective Sleep Questionnaire - Time to Fall Asleep Last Night	Subjects responded to Estimate of how long it took to fall asleep (minutes)	Up to 10 hours
Subjective Sleep Questionnaire - Number of Minutes You Think That You Were Awake From the Time You Fell Asleep Until the Time You Got Out of Bed	Subjects responded to Estimate of the amount of time the subject was awake from the time he or she fell asleep until the time he or she got out of bed (hours and minutes)	Up to 10 hours
Change From Baseline in Pain Intensity	Pain Severity was collected on a 4-point categorical scale: 0=no pain, 1=mild pain, 2=moderate pain, 4=severe pain	Baseline and up to 10 hours
Overall Rating of Pain Relief	The Pain Relief Rating Scale was a 5-point categorical scale which included the following possible responses to the request to finish statement "Overall, the relief from my starting pain was": 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	If rescue medication was taken by a subject for pain, then the time of rescue medication administration was recorded	Up to 10 hours
Cumulative Proportion of Subjects Taking Rescue Medication by Hour	If rescue medication was taken by a subject for pain, then the time of rescue medication administration was recorded	Up to 10 hours
Global Assessment of Investigational Product as a Pain Reliever	The Global Assessment of Investigational Product as a Pain Reliever was a 5- point categorical scale which included the following possible responses: poor (0); fair (1); good (2); very good (3); excellent (4).	Up to 10 hours

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Cooper S, Laurora I, Wang Y, Venkataraman P, An R, Roth T. Efficacy and tolerability studies evaluating a sleep aid and analgesic combination of naproxen sodium and diphenhydramine in the dental impaction pain model in subjects with induced transient insomnia. Int J Clin Pract. 2015 Oct;69(10):1149-58. doi: 10.1111/ijcp.12669. Epub 2015 May 21.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: January 20, 2011
• First Submitted That Met QC Criteria: January 20, 2011
• First Posted (Estimate): January 21, 2011

Study Record Updates

• Last Update Posted (Estimate): June 8, 2015
• Last Update Submitted That Met QC Criteria: May 13, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Naproxen sodium; Diphenhydramine
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Gout Suppressants; Naproxen
• Other Study ID Numbers: 14837

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No