Acute Pain
Conditions
Keywords
Wisdom tooth removal, Dental pain
Brief summary
This study evaluated a new drug fixed-dose combination tablet (FDC) called tramadol/diclofenac at two different strengths (fixed doses of 25 milligrams \[mg\] of tramadol and of diclofenac or of 50 mg each). Tramadol and diclofenac each relieve pain, but they do so by different mechanisms. They were used alone as comparator drug in this study. Both are marketed drugs and are standard treatment for acute pain, including wisdom tooth removal.
Detailed description
The purpose of this study was to demonstrate that the FDC of Tramadol and Diclofenac 50/50 has superior analgesic effect than the monotherapies and that the FDC of Tramadol and Diclofenac 25/25 has non-inferior analgesic effect than the monotherapies. There was an Enrollment Period, a blinded Treatment Period, and a Follow-up Period. Previously used analgesic medication was washed out for at least 24 hours before surgery. The Treatment Period starts on Day 1 with dental surgery and treatment allocation. Treatment was started within 4 hours after the end of surgery if the participant's pain intensity had reached at least 5 points on the 11-point numerical rating scale (NRS). Each participant received 3 doses of one of the four treatments within 24 hours. One fourth of the participants received the fixed-dose combination tablet at a low dose, one fourth at the higher dose, one fourth received 50 mg of the comparator tramadol alone, and one fourth 50 mg of the comparator diclofenac alone. The first 2 doses of the investigational medicinal product (IMP) were taken at the site, the last dose in an out-patient setting. Participants returned to the site at 24 hours after the first dose. A Follow-up Period included a final visit at the site or a phone call on Day 14 to assess the participant's safety.
Interventions
DRUGTramadol/Diclofenac 50/50
Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
DRUGTramadol/Diclofenac 25/25
Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
DRUGTramadol 50
Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were taken 8 hours apart.
DRUGDiclofenac 50
Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart.
Sponsors
Grünenthal, S.A.
Grünenthal GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This study used double-blind and double-dummy methods to guarantee the blinding of all personnel involved in the study. Participants, investigators, and all persons involved in the conduct, data management, and analysis of the study were fully blinded to the participant's treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. The participant has read the informed consent form, has understood the relevant aspects of the clinical study, and grants his/her authorization to participate by signing the informed consent form prior to the inclusion in the clinical study and the performance of any procedure. 2. Male and female participants above 18 years up to 60 years. 3. Female participants of childbearing potential must be practicing an acceptable method of birth control and must have a negative urine pregnancy test at enrollment with confirmation at the Allocation Visit. 4. Participants are in good health, i.e., the medical record, vital signs, physical examination, and laboratory parameter assessments do not show any abnormal deviations impeding the participation in the clinical study. 5. Participants requiring extraction of 3 or more third molars with 2 mandibular impacted third molars. 6. Clinical and radiological diagnosis of impacted lower third molars. 7. Class I and Class II molars according to Pell and Gregory's classification (Gay Escoda et al. 2004). 8. Participants must be able to swallow the IMPs.
Exclusion criteria
at Enrollment: 1. Findings in the medical record, vital signs, and/or physical examination demonstrating abnormal conditions of participant's general state of health preventing his/her participation in the clinical study according to the investigator's opinion. 2. Participant unable to speak, read, or write in Spanish language. 3. Clinical laboratory parameters exceed the pre-defined alert ranges (i.e., 1 standard deviation above or below the upper/lower limit of the normal ranges). 4. Known hypersensitivity to the IMPs, the anesthetic to be used during surgery, or to the rescue medication (ibuprofen, ketorolac). 5. Known alcohol or drug abuse in the last 6 months or any history of seizures. Alcohol abuse is defined as the consumption of more than 3 ounces (about 90 milliliters) of liquor or spirits or 18 ounces (about 530 milliliters) of beer per day, for 5 consecutive days during the 6-month period. Drug abuse is defined as the use of any recreational drug for 5 consecutive days during the 6 month period. 6. Participants who take analgesic medication for chronic pain, monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or other drugs that reduce the seizure threshold within 4 weeks of enrollment. 7. Pregnant or lactating women. 8. Participants who received systemic corticosteroids or opioid analgesics less than 2 weeks before surgery. 9. Participants with molars linked to the mandibular canal. 10. Participants requiring immediate dental procedures other than third and fourth molars extraction,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4) | Up to 4 hours after first dose | Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point verbal rating scale (VRS) with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR4) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 4 hours after IMP intake. Minimum and maximum values for TOTPAR4 were 0=worst score and 16=best score, a higher score indicates more pain relief. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Pain Relief at 8 Hours Post-dose (TOTPAR8) | Up to 8 hours after first dose | Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point VRS with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR8) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 8 hours after IMP intake. Minimum and maximum values for TOTPAR8 were 0=worst score and 32=best score, a higher score indicates more pain relief. |
| Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | Baseline; up to 24 hours after first dose | Pain intensity was assessed by the participant before and at defined time points after the first IMP dose using an 11-point NRS with anchors at 0 for no pain and 10 for pain as bad as you can imagine. Pain Intensity Difference (PIDt) was defined as the difference between baseline pain intensity and pain intensity at time point t, and SPID defined as summed PIDt x \[time (hours) elapsed since previous observation\]. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain \[maximum=10 at each time point\], and negative numbers indicate an increase in pain \[minimum=-10 at each time point\]. The overall minimum and maximum are -10 and 10 times the number of hours specified (SPID-4=\[-40 to 40\], SPID-6=\[-60 to 60\], SPID-8=\[-80 to 80\], and SPID-24=\[-240 to 240\]). |
| Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone) | Up to 24 hours after first dose | Time (hours) when the participant achieved a 50 percent reduction of baseline (starting) pain. It was assessed at defined time points after the first IMP dose using a YES or NO question for pain half gone. |
| Time to Onset of First Perceptible Pain Relief | Up to 8 hours after first dose | Participants used one stopwatch to document the time between first IMP dose and when they begin to feel any pain-relieving effect from the IMP. |
| Total Pain Relief at 6 Hours Post-dose (TOTPAR6) | Up to 6 hours after first dose | Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point VRS with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR6) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 6 hours after IMP intake. Minimum and maximum values for TOTPAR6 were 0=worst score and 24=best score, a higher score indicates more pain relief. |
| Time to Intake of First Rescue Medication Dose | First dose to 24 hours after first dose | The time from first IMP dose to first dose of rescue medication (ibuprofen or ketorolac), if needed, within 24 hours post-dose was calculated. |
| Subject's Global Evaluation of the Treatment | 8 hours after the first dose of IMP or before first intake of rescue medication (whatever the first) and 24 hours after the first dose of IMPs | Participants documented their overall impression of the analgesic efficacy of the IMPs on a 5-point Likert scale from Excellent (4) to Poor (0). |
| Incidence and Type of Adverse Events | Day 1 to Day 14 | The incidence of treatment emergent adverse events (TEAE) reported from first dose (Day 1) to last scheduled contact with the participant on Day 14 was descriptively summarized. Selected TEAEs were events with preferred terms of nausea, vomiting, abdominal pain, gastrointestinal bleeding, dizziness, or hypotension. |
| Time to Onset of Meaningful Pain Relief | Up to 8 hours after first dose | Participants used a second stopwatch to document the time between first IMP dose and when they felt their pain relief was meaningful to them. |
Countries
Mexico
Participant flow
Recruitment details
The first participant was enrolled on 26 August 2017.
Pre-assignment details
A total of 1151 participants signed an informed consent form, 829 participants were allocated to treatment. Of the 829 allocated participants, 3 were not treated (1 each in the Diclofenac 50, Tramadol 50, and Tramadol/Diclofenac 25/25 treatment arms) and were not included in the Safety Set (N=826).
Participants by arm
| Arm | Count |
|---|---|
| Tramadol/Diclofenac 50/50 Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.
Tramadol/Diclofenac 50/50: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart. | 208 |
| Tramadol/Diclofenac 25/25 Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.
Tramadol/Diclofenac 25/25: Each dose comprised 1 fixed-dose combination tablet and 3 placebo tablets or capsules matching the other active treatment groups. Doses were taken 8 hours apart. | 205 |
| Tramadol 50 Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.
Tramadol 50: Each dose comprised 1 capsule containing 50 mg tramadol hydrochloride and 3 placebo tablets matching the other active treatment groups. Doses were be taken 8 hours apart. | 206 |
| Diclofenac 50 Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction
Diclofenac 50: Each dose comprised 1 tablet containing 50 mg diclofenac sodium and 3 placebo tablets or capsules matching the other active treatment groups. Doses were be taken 8 hours apart. | 207 |
| Total | 826 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 3 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 | 0 |
| Overall Study | Other Reason | 1 | 2 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Tramadol/Diclofenac 50/50 | Tramadol/Diclofenac 25/25 | Tramadol 50 | Diclofenac 50 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 208 Participants | 205 Participants | 206 Participants | 207 Participants | 826 Participants |
| Age, Continuous | 22.9 years | 24.0 years | 23.8 years | 23.6 years | 23.6 years |
| Baseline pain intensity 11-point NRS | 7.0 units on a scale STANDARD_DEVIATION 1.51 | 7.0 units on a scale STANDARD_DEVIATION 1.45 | 7.0 units on a scale STANDARD_DEVIATION 1.45 | 7.0 units on a scale STANDARD_DEVIATION 1.4 | 7.0 units on a scale STANDARD_DEVIATION 1.45 |
| Baseline pain intensity categorized Mild | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline pain intensity categorized Missing | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Baseline pain intensity categorized Moderate | 88 Participants | 87 Participants | 86 Participants | 81 Participants | 342 Participants |
| Baseline pain intensity categorized None | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline pain intensity categorized Severe | 120 Participants | 117 Participants | 120 Participants | 126 Participants | 483 Participants |
| Body mass index (BMI) | 24.5 kg/m^2 STANDARD_DEVIATION 4.08 | 25.0 kg/m^2 STANDARD_DEVIATION 4.39 | 25.1 kg/m^2 STANDARD_DEVIATION 4.25 | 24.5 kg/m^2 STANDARD_DEVIATION 4.51 | 24.8 kg/m^2 STANDARD_DEVIATION 4.31 |
| Duration of surgery, minutes | 33.0 minutes STANDARD_DEVIATION 21.9 | 35.0 minutes STANDARD_DEVIATION 21.56 | 34.2 minutes STANDARD_DEVIATION 20.25 | 32.9 minutes STANDARD_DEVIATION 19.21 | 33.8 minutes STANDARD_DEVIATION 20.74 |
| End of surgery to first dose of IMP, hours | 2.2 hours STANDARD_DEVIATION 0.89 | 2.2 hours STANDARD_DEVIATION 0.83 | 2.1 hours STANDARD_DEVIATION 0.9 | 2.1 hours STANDARD_DEVIATION 0.85 | 2.2 hours STANDARD_DEVIATION 0.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 208 Participants | 204 Participants | 206 Participants | 206 Participants | 824 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Lidocaine used during surgery, mg | 211.1 mg STANDARD_DEVIATION 44.18 | 211.4 mg STANDARD_DEVIATION 41.13 | 211.3 mg STANDARD_DEVIATION 43.36 | 207.7 mg STANDARD_DEVIATION 42.13 | 210.4 mg STANDARD_DEVIATION 42.67 |
| Number of molars extracted Number of molars extracted 3 | 37 Participants | 41 Participants | 42 Participants | 43 Participants | 163 Participants |
| Number of molars extracted Number of molars extracted 4 | 171 Participants | 164 Participants | 164 Participants | 164 Participants | 663 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 202 Participants | 198 Participants | 200 Participants | 203 Participants | 803 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 2 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) White | 0 Participants | 4 Participants | 4 Participants | 2 Participants | 10 Participants |
| Region of Enrollment Mexico | 208 participants | 205 participants | 206 participants | 207 participants | 826 participants |
| Sex: Female, Male Female | 126 Participants | 136 Participants | 132 Participants | 135 Participants | 529 Participants |
| Sex: Female, Male Male | 82 Participants | 69 Participants | 74 Participants | 72 Participants | 297 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 208 | 0 / 205 | 0 / 206 | 0 / 207 |
| other Total, other adverse events | 96 / 208 | 62 / 205 | 105 / 206 | 48 / 207 |
| serious Total, serious adverse events | 0 / 208 | 1 / 205 | 0 / 206 | 0 / 207 |
Outcome results
Primary
Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4)
Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point verbal rating scale (VRS) with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR4) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 4 hours after IMP intake. Minimum and maximum values for TOTPAR4 were 0=worst score and 16=best score, a higher score indicates more pain relief.
Time frame: Up to 4 hours after first dose
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tramadol/Diclofenac 50/50 | Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4) | 9.9 units on a scale |
| Tramadol/Diclofenac 25/25 | Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4) | 8.6 units on a scale |
| Tramadol 50 | Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4) | 5.4 units on a scale |
| Diclofenac 50 | Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4) | 5.8 units on a scale |
Comparison: Bonferroni-Holm procedure used for determining the statistical significance of the results.p-value: <0.000195% CI: [-4.8, -3.4]ANCOVA
Comparison: Bonferroni-Holm procedure used for determining the statistical significance of the results.p-value: <0.000195% CI: [-5.2, -3.8]ANCOVA
Comparison: Bonferroni-Holm procedure used for determining the statistical significance of the results. The planned test was a test for non-inferiority.p-value: <0.000195% CI: [-3.9, -2.5]ANCOVA
Comparison: Bonferroni-Holm procedure used for determining the statistical significance of the results. The planned test was a test for non-inferiority.p-value: <0.000195% CI: [-3.5, -2.1]ANCOVA
Secondary
Incidence and Type of Adverse Events
The incidence of treatment emergent adverse events (TEAE) reported from first dose (Day 1) to last scheduled contact with the participant on Day 14 was descriptively summarized. Selected TEAEs were events with preferred terms of nausea, vomiting, abdominal pain, gastrointestinal bleeding, dizziness, or hypotension.
Time frame: Day 1 to Day 14
Population: Safety Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | TEAE leading to dose interruption | 1 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | Severe TEAE | 6 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | TEAE with outcome of death | 0 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | Serious TEAE | 0 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | TEAE leading to dose reduction | 0 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | TEAE | 96 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | TEAE related to IMP or rescue medication | 49 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | Dose reduction, interruption, or withdrawal | 3 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | Selected TEAE | 68 participants |
| Tramadol/Diclofenac 50/50 | Incidence and Type of Adverse Events | TEAE leading to IMP withdrawal | 2 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | TEAE leading to dose interruption | 2 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | TEAE | 62 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | TEAE leading to IMP withdrawal | 1 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | Dose reduction, interruption, or withdrawal | 3 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | TEAE related to IMP or rescue medication | 23 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | Serious TEAE | 1 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | TEAE with outcome of death | 0 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | Selected TEAE | 26 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | Severe TEAE | 1 participants |
| Tramadol/Diclofenac 25/25 | Incidence and Type of Adverse Events | TEAE leading to dose reduction | 0 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | TEAE related to IMP or rescue medication | 64 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | Dose reduction, interruption, or withdrawal | 2 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | TEAE leading to dose reduction | 0 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | Selected TEAE | 77 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | Severe TEAE | 3 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | TEAE leading to IMP withdrawal | 1 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | Serious TEAE | 0 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | TEAE | 105 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | TEAE leading to dose interruption | 1 participants |
| Tramadol 50 | Incidence and Type of Adverse Events | TEAE with outcome of death | 0 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | Dose reduction, interruption, or withdrawal | 0 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | TEAE | 48 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | Severe TEAE | 2 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | TEAE related to IMP or rescue medication | 10 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | Serious TEAE | 0 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | TEAE with outcome of death | 0 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | Selected TEAE | 13 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | TEAE leading to dose reduction | 0 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | TEAE leading to dose interruption | 0 participants |
| Diclofenac 50 | Incidence and Type of Adverse Events | TEAE leading to IMP withdrawal | 0 participants |
Secondary
Subject's Global Evaluation of the Treatment
Participants documented their overall impression of the analgesic efficacy of the IMPs on a 5-point Likert scale from Excellent (4) to Poor (0).
Time frame: 8 hours after the first dose of IMP or before first intake of rescue medication (whatever the first) and 24 hours after the first dose of IMPs
Population: Full Analysis Set
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 24-Hours | Excellent | 132 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 24-Hours | Poor | 3 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 8-Hours | Excellent | 103 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 8-Hours | Very Good | 73 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 24-Hours | Very Good | 57 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 8-Hours | Fair | 10 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 8-Hours | Poor | 4 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 24-Hours | Good | 12 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 24-Hours | Fair | 4 Participants |
| Tramadol/Diclofenac 50/50 | Subject's Global Evaluation of the Treatment | 8-Hours | Good | 17 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 8-Hours | Excellent | 83 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 8-Hours | Poor | 7 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 8-Hours | Fair | 12 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 8-Hours | Good | 33 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 8-Hours | Very Good | 64 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 24-Hours | Poor | 4 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 24-Hours | Fair | 5 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 24-Hours | Good | 18 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 24-Hours | Very Good | 65 Participants |
| Tramadol/Diclofenac 25/25 | Subject's Global Evaluation of the Treatment | 24-Hours | Excellent | 109 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Good | 36 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Poor | 7 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Poor | 28 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Fair | 23 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Fair | 30 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Good | 34 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Excellent | 82 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Very Good | 59 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Very Good | 52 Participants |
| Tramadol 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Excellent | 51 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Excellent | 51 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Very Good | 67 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Good | 39 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Poor | 7 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Fair | 25 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Poor | 23 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Very Good | 67 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Fair | 13 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 8-Hours | Good | 35 Participants |
| Diclofenac 50 | Subject's Global Evaluation of the Treatment | 24-Hours | Excellent | 80 Participants |
Secondary
Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose
Pain intensity was assessed by the participant before and at defined time points after the first IMP dose using an 11-point NRS with anchors at 0 for no pain and 10 for pain as bad as you can imagine. Pain Intensity Difference (PIDt) was defined as the difference between baseline pain intensity and pain intensity at time point t, and SPID defined as summed PIDt x \[time (hours) elapsed since previous observation\]. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain \[maximum=10 at each time point\], and negative numbers indicate an increase in pain \[minimum=-10 at each time point\]. The overall minimum and maximum are -10 and 10 times the number of hours specified (SPID-4=\[-40 to 40\], SPID-6=\[-60 to 60\], SPID-8=\[-80 to 80\], and SPID-24=\[-240 to 240\]).
Time frame: Baseline; up to 24 hours after first dose
Population: Full Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol/Diclofenac 50/50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 8 Hours | 33.70 units on a scale | Standard Error 1.121 |
| Tramadol/Diclofenac 50/50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 4 Hours | 16.24 units on a scale | Standard Error 0.564 |
| Tramadol/Diclofenac 50/50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 6 Hours | 25.54 units on a scale | Standard Error 0.836 |
| Tramadol/Diclofenac 50/50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 24 Hours | 107.15 units on a scale | Standard Error 3.787 |
| Tramadol/Diclofenac 25/25 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 24 Hours | 91.99 units on a scale | Standard Error 3.873 |
| Tramadol/Diclofenac 25/25 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 8 Hours | 28.90 units on a scale | Standard Error 1.146 |
| Tramadol/Diclofenac 25/25 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 4 Hours | 13.67 units on a scale | Standard Error 0.576 |
| Tramadol/Diclofenac 25/25 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 6 Hours | 21.86 units on a scale | Standard Error 0.855 |
| Tramadol 50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 6 Hours | 12.89 units on a scale | Standard Error 0.845 |
| Tramadol 50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 4 Hours | 6.43 units on a scale | Standard Error 0.57 |
| Tramadol 50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 8 Hours | 19.10 units on a scale | Standard Error 1.133 |
| Tramadol 50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 24 Hours | 71.41 units on a scale | Standard Error 3.828 |
| Diclofenac 50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 6 Hours | 14.36 units on a scale | Standard Error 0.843 |
| Diclofenac 50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 4 Hours | 7.72 units on a scale | Standard Error 0.568 |
| Diclofenac 50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 24 Hours | 72.08 units on a scale | Standard Error 3.816 |
| Diclofenac 50 | Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose | 8 Hours | 20.54 units on a scale | Standard Error 1.129 |
Secondary
Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone)
Time (hours) when the participant achieved a 50 percent reduction of baseline (starting) pain. It was assessed at defined time points after the first IMP dose using a YES or NO question for pain half gone.
Time frame: Up to 24 hours after first dose
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol/Diclofenac 50/50 | Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone) | 1.27 hours | Standard Deviation 1.216 |
| Tramadol/Diclofenac 25/25 | Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone) | 1.73 hours | Standard Deviation 2.778 |
| Tramadol 50 | Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone) | 3.01 hours | Standard Deviation 3.731 |
| Diclofenac 50 | Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone) | 2.53 hours | Standard Deviation 2.865 |
Secondary
Time to Intake of First Rescue Medication Dose
The time from first IMP dose to first dose of rescue medication (ibuprofen or ketorolac), if needed, within 24 hours post-dose was calculated.
Time frame: First dose to 24 hours after first dose
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol/Diclofenac 50/50 | Time to Intake of First Rescue Medication Dose | 21.84 hours | Standard Deviation 6.222 |
| Tramadol/Diclofenac 25/25 | Time to Intake of First Rescue Medication Dose | 20.99 hours | Standard Deviation 7.45 |
| Tramadol 50 | Time to Intake of First Rescue Medication Dose | 17.37 hours | Standard Deviation 9.745 |
| Diclofenac 50 | Time to Intake of First Rescue Medication Dose | 17.38 hours | Standard Deviation 9.646 |
Secondary
Time to Onset of First Perceptible Pain Relief
Participants used one stopwatch to document the time between first IMP dose and when they begin to feel any pain-relieving effect from the IMP.
Time frame: Up to 8 hours after first dose
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol/Diclofenac 50/50 | Time to Onset of First Perceptible Pain Relief | 0.57 hours | Standard Deviation 0.483 |
| Tramadol/Diclofenac 25/25 | Time to Onset of First Perceptible Pain Relief | 0.67 hours | Standard Deviation 0.875 |
| Tramadol 50 | Time to Onset of First Perceptible Pain Relief | 1.07 hours | Standard Deviation 1 |
| Diclofenac 50 | Time to Onset of First Perceptible Pain Relief | 1.12 hours | Standard Deviation 1.151 |
Secondary
Time to Onset of Meaningful Pain Relief
Participants used a second stopwatch to document the time between first IMP dose and when they felt their pain relief was meaningful to them.
Time frame: Up to 8 hours after first dose
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol/Diclofenac 50/50 | Time to Onset of Meaningful Pain Relief | 1.47 hours | Standard Deviation 1.149 |
| Tramadol/Diclofenac 25/25 | Time to Onset of Meaningful Pain Relief | 2.04 hours | Standard Deviation 1.81 |
| Tramadol 50 | Time to Onset of Meaningful Pain Relief | 2.93 hours | Standard Deviation 1.895 |
| Diclofenac 50 | Time to Onset of Meaningful Pain Relief | 2.75 hours | Standard Deviation 1.882 |
Secondary
Total Pain Relief at 6 Hours Post-dose (TOTPAR6)
Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point VRS with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR6) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 6 hours after IMP intake. Minimum and maximum values for TOTPAR6 were 0=worst score and 24=best score, a higher score indicates more pain relief.
Time frame: Up to 6 hours after first dose
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tramadol/Diclofenac 50/50 | Total Pain Relief at 6 Hours Post-dose (TOTPAR6) | 15.2 units on a scale |
| Tramadol/Diclofenac 25/25 | Total Pain Relief at 6 Hours Post-dose (TOTPAR6) | 13.3 units on a scale |
| Tramadol 50 | Total Pain Relief at 6 Hours Post-dose (TOTPAR6) | 9.3 units on a scale |
| Diclofenac 50 | Total Pain Relief at 6 Hours Post-dose (TOTPAR6) | 9.8 units on a scale |
Secondary
Total Pain Relief at 8 Hours Post-dose (TOTPAR8)
Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point VRS with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR8) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 8 hours after IMP intake. Minimum and maximum values for TOTPAR8 were 0=worst score and 32=best score, a higher score indicates more pain relief.
Time frame: Up to 8 hours after first dose
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tramadol/Diclofenac 50/50 | Total Pain Relief at 8 Hours Post-dose (TOTPAR8) | 20.1 units on a scale |
| Tramadol/Diclofenac 25/25 | Total Pain Relief at 8 Hours Post-dose (TOTPAR8) | 17.8 units on a scale |
| Tramadol 50 | Total Pain Relief at 8 Hours Post-dose (TOTPAR8) | 13.1 units on a scale |
| Diclofenac 50 | Total Pain Relief at 8 Hours Post-dose (TOTPAR8) | 13.7 units on a scale |