Post Operative Pain
Conditions
Keywords
Oxycodone, Naloxone, Postoperative pain, Arthroplasty, Efficacy
Brief summary
The purpose of this study is to demonstrate that treatment with OXN PR tablets is non inferior to treatment with OXY PR tablets in terms of analgesic efficacy in patients with postoperative pain after knee arthroplasty based on average pain intensity scores.
Interventions
DRUGOxycodone/Naloxone PR 20/10mg or 10/5mg tablets
Oxycodone/Naloxone prolonged release 20/10mg or 10/5mg tabs twice a day (BID) for 2.5 days (total 5 dosages)or Oxycodone 20mg
DRUGOxycodone
Oxycodone 20mg or 10mg BID for 2.5 days (total 5 dosages)
Sponsors
Mundipharma Oy
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Males and females 18 - 75 years of age. * Body mass index (BMI) 18 - 35 kg/m2. * If female and less than one year post-menopausal: * negative serum or urine pregnancy test (positive beta-human chorionic gonadotrophin test) at screening. * using an adequate and highly effective method of contraception throughout the study. A highly effective method of contraception is defined as one with a failure rate of less than 1% per year when used consistently and correctly. Examples include sterilisation, implants, injectables, combined oral contraceptives, hormonal intra uterine devices, sexual abstinence or vasectomised partner. * Confirmed diagnosis of osteoarthritis of the knee. * Planned surgical arthroplasty on one knee. * Planned postoperative epidural analgesia for approximately 48 hours. * Anticipated requirement for daily opioid treatment after epidural analgesia for 2.5 days. * Able to participate in the study and have given written informed consent.
Exclusion criteria
* Females who are pregnant or lactating. * Opioid use within 3 months before the start of the screening period. Stable treatment with analgesics in World Health Organisation (WHO) Step I (non-opioid analgesics) is allowed. * History of laxative use to treat constipation within 3 months before the start of the screening period. * History of chronic constipation. * Concurrent rheumatoid arthritis. * Planned bilateral arthroplasty or revision knee arthroplasty. * History of moderate to severe hepatic impairment. * History of moderate to severe respiratory depression with hypoxia or hypercapnia, chronic obstructive pulmonary disease, cor pulmonale, bronchial asthma, or any severe impairment of pulmonary function. * History of uncontrolled hypothyroidism, Addison's disease (adrenal cortical insufficiency), psychosis, cholelithiasis, prostatic hypertrophy(with documented residual of over 100 ml after voiding), delirium tremens, pancreatitis, hypotension, uncontrolled hypertension, uncontrolled cardiovascular diseases, head injury, epileptic disorder or predisposition to convulsions, or treatment with monoamine oxidase inhibitors (concurrent or within 2 weeks of discontinuation). * Contraindication to treatment with opioids. * History of hypersensitivity to oxycodone, naloxone, or to any of the excipients of OXN PR tablets. * History of non-opioid induced paralytic ileus. * Previous or current history of drug abuse, including alcohol abuse or opioid abuse. * Evidence of clinically unstable disease * Receipt of an investigational medicinal product within 30 days before the start of the screening period. * Galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. * Delayed gastric emptying. * Severe renal impairment (i.e. creatinine clearance \<10 mL/minute). * Weight \<50 kg.Inclusion Criteria:
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean of 4 NRS Scores for 24 Hour Pain Intensity at Rest, Shown as Absolute Change From Baseline (i.e. a Decrease From the Baseline Value) | Mean of 24 hour pain intensity (absolute change from baseline) | The primary efficacy variable was the 24hr pain intensity score at rest, on a Numerical Rating Scale (NRS), with 0 = no pain and 10 = worst possible pain. This was assessed 1 hour after dosing on Day 1 (evening only), Day 2(morning and evening) and Day 3 (morning only). The primary efficacy end point (absolute change from baseline) was analysed on the per protocol (PP) data. The mean of these scores is shown as a value that is a mean change (a decrease in pain score) from the baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Dose (mg) of Rescue Analgesia for the Treatment Phase for Subjects Taking 20/10mg OXN PR Tablets or 20mg OXY PR Tablets | Mean dose during the whole double blind treatment phase (2.5 days) | To compare the use of rescue analgesia for the 2 groups (OXN 20/10mg tablets and OXY 20mg tablets) during the double blind treatment phase. Rescue medication was given (OXY Immediate Release, 5mg capsules) if the subjects pain score on the (Numeric Rating Scale (NRS), 0 (no pain) to 10 (worst possible pain)), was greater than or equal to 4. The value presented is the mean dose over the double blind phase. |
Countries
Finland
Participant flow
Recruitment details
First patient first visit 25 March 2010 and last patient last visit 17 Oct 2010. Five Hospital Investigator Centres
Pre-assignment details
14 day screening period before planned surgery. Run-in period 48 hours, 2.5 day double-blind period after surgery
Participants by arm
| Arm | Count |
|---|---|
| OXN Tablets Oxycodone/Naloxone prolonged release (PR) 20/10mg or 10/5mg tablets twice a day (BID) for 2.5 days (total = 5 doses) | 70 |
| OXY Tablets Oxycodone prolonged release (PR) 20mg or 10mg tablets twice a day (BID) for 2.5 days (total = 5 doses) | 67 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | OXY Tablets | OXN Tablets | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 34 Participants | 34 Participants | 68 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 36 Participants | 69 Participants |
| Age Continuous | 64 years STANDARD_DEVIATION 6.7 | 64 years STANDARD_DEVIATION 6.7 | 64 years STANDARD_DEVIATION 6.7 |
| Region of Enrollment Finland | 67 participants | 70 participants | 137 participants |
| Sex: Female, Male Female | 39 Participants | 44 Participants | 83 Participants |
| Sex: Female, Male Male | 28 Participants | 26 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 43 / 70 | 39 / 67 |
| serious Total, serious adverse events | 2 / 70 | 0 / 67 |
Outcome results
Primary
Mean of 4 NRS Scores for 24 Hour Pain Intensity at Rest, Shown as Absolute Change From Baseline (i.e. a Decrease From the Baseline Value)
The primary efficacy variable was the 24hr pain intensity score at rest, on a Numerical Rating Scale (NRS), with 0 = no pain and 10 = worst possible pain. This was assessed 1 hour after dosing on Day 1 (evening only), Day 2(morning and evening) and Day 3 (morning only). The primary efficacy end point (absolute change from baseline) was analysed on the per protocol (PP) data. The mean of these scores is shown as a value that is a mean change (a decrease in pain score) from the baseline value.
Time frame: Mean of 24 hour pain intensity (absolute change from baseline)
Population: The primary efficacy end point (absolute change from baseline) was analysed on the PP data using a mixed model repeated measures of analysis of covariance (RMANCOVA).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OXN Tablets | Mean of 4 NRS Scores for 24 Hour Pain Intensity at Rest, Shown as Absolute Change From Baseline (i.e. a Decrease From the Baseline Value) | -1.2 Units on a scale |
| OXY Tablets | Mean of 4 NRS Scores for 24 Hour Pain Intensity at Rest, Shown as Absolute Change From Baseline (i.e. a Decrease From the Baseline Value) | -1.1 Units on a scale |
Comparison: The sample size was calculated for a significance level of 2.5% (1 sided) with 90% power. A within SD 1.7, and expected treatment difference of 0 and a non-inferiority margin of 1.0 were assumed.95% CI: [-0.5, 0.3]ANCOVA
Secondary
Mean Dose (mg) of Rescue Analgesia for the Treatment Phase for Subjects Taking 20/10mg OXN PR Tablets or 20mg OXY PR Tablets
To compare the use of rescue analgesia for the 2 groups (OXN 20/10mg tablets and OXY 20mg tablets) during the double blind treatment phase. Rescue medication was given (OXY Immediate Release, 5mg capsules) if the subjects pain score on the (Numeric Rating Scale (NRS), 0 (no pain) to 10 (worst possible pain)), was greater than or equal to 4. The value presented is the mean dose over the double blind phase.
Time frame: Mean dose during the whole double blind treatment phase (2.5 days)
Population: This is the per protocol population (PP), which is a subset of the full analysis population. The data presented is only for those subjects taking the higher dose (20/10 mg OXN or 20 mg OXY) in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OXN Tablets | Mean Dose (mg) of Rescue Analgesia for the Treatment Phase for Subjects Taking 20/10mg OXN PR Tablets or 20mg OXY PR Tablets | 24 mg of rescue analgesia | Standard Deviation 28.7 |
| OXY Tablets | Mean Dose (mg) of Rescue Analgesia for the Treatment Phase for Subjects Taking 20/10mg OXN PR Tablets or 20mg OXY PR Tablets | 17 mg of rescue analgesia | Standard Deviation 25.4 |