Tapentadol IR vs Oxycodone IR vs Placebo in Acute Pain From Vertebral Compression Fracture Associated With Osteoporosis

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness and safety of tapentadol immediate release (IR) as compared with placebo and oxycodone IR in patients with acute pain caused by vertebral compression fractures (VCF) associated with assumed osteoporosis for whom treatment with oral opioid analgesics is appropriate.

Detailed Description
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This is a randomized (study drug assigned by chance), multicenter, double-blind (neither the patient nor the physician know the study drug administered) study to determine the efficacy and safety of tapentadol immediate release (IR) as compared with placebo and oxycodone IR in approximately 625 patients with acute pain caused by vertebral compression fractures (VCFs) associated with assumed osteoporosis for whom treatment with oral opioid analgesics is appropriate. Patients will be randomized to receive multiple doses of tapentadol IR 50 or 75 milligrams (mg) or oxycodone IR 5 or 10 mg or placebo for up to 10 days. Screening/Randomization Visit (Visit 1): Potential patients with acute thoracolumbar pain with either new onset of pain or acute exacerbation of previous pain associated with a VCF will be identified. The acute pain episode must have started within 14 days of Visit 1. The study will be explained and informed consent will be obtained. Patients will either have had a radiographic procedure to confirm diagnosis of a VCF within 3 months prior to Visit 1 or will have a radiographic procedure (e.g., lateral vertebral x-ray or magnetic resonance imaging, etc) performed at Visit 1 as standard of care. Patients must have moderate to severe acute vertebral pain and must be appropriate candidates for pain management with an oral opioid analgesic. At Visit 1, patients must report both a qualifying average back pain intensity score in the last 24 hours related to the current episode and a qualifying current back pain intensity on an 11-point numerical rating scale (NRS) where 0=no pain and 10=pain as bad as you can imagine. Patients must also have a qualifying score on the Mini-Mental State Examination (MMSE) to be eligible for study participation. At Visit 1, patients will have laboratory assessments (including a urine drug screen), physical and back examinations and an electrocardiogram (ECG). Patients will also complete paper copies of the sleep quality, functionality and vomiting assessments (i.e., morning (AM) and evening (PM) Interactive Voice Response [IVR] system questions except satisfaction with treatment). In addition, patients will have physical performance assessed. Patients who have taken long-acting or controlled-release opioid therapy or immediate release CII opioid formulations (e.g., Opana IR, Percocet, Percodan, oxycodone IR, Dilaudid) within the 1 month prior to Visit 1 are not eligible for the study. Patients taking a CIII opioid formulation (e.g., Tylenol with Codeine) or any other analgesic medication (e.g., Non-steroidal anti-inflammatory drugs (NSAIDs) not previously described above will be eligible for study participation if they meet all study criteria (e.g., pain intensity score), unless they take the CIII > 5 days/week in the 1 month prior to Visit 1. After randomization all analgesic medications other than the study drug are prohibited except for NSAIDs taken for a condition other than chronic back pain, provided the patient has been taking a stable regimen for at least one month before screening and plans to continue throughout the study. Patients may take up to 2 pills (any form) of acetaminophen (e.g., Tylenol Extra-Strength) for pain other than back pain (e.g., headache, joint pain) once per day only. Subjects who take up to 325 mg/day aspirin for cardiovascular prevention will be permitted to enter the study provided they are on a stable dose for at least 1 month prior to study entry and plan to continue the same dose during the study. Double-Blind Treatment: Patients may be enrolled and randomized with laboratory and ECG results pending. If the results of any of these tests suggest the patient is not in good health, the patient will immediately be discontinued from the study. Patients meeting study entry criteria will be randomized in a double-blind fashion in a 2:2:1 ratio to receive tapentadol IR, oxycodone IR, or matching placebo every 4-6 hours during waking hours as needed for pain. The first dose of study drug will be one capsule of tapentadol IR 50 mg, oxycodone IR 5 mg or placebo. Most patients will take the first dose of study drug in the office at Visit 1. All patients will be instructed to call the IVR system to complete another assessment of current back pain intensity immediately before taking the first dose of study drug. This call will be made by the patient from the study site unless the first dose cannot be taken in the office, in which case the patient will make the call from home. Patients will be instructed to call the IVR system every morning and each evening to complete assessments related to back pain intensity and pain relief. Patients will also respond to IVR system questions related to sleep quality, patient satisfaction with treatment and functionality (AM only) and vomiting (PM only). Patients who discontinue prematurely for any reason will be instructed to contact the study site to complete final assessments, prior to taking supplemental pain medication if applicable, and to schedule a final study visit. During this call, site personnel will obtain current pain intensity and pain relief scores from the patient; these scores will be documented. Patients will begin treatment on Day 1 with one lower dose capsule of study drug (tapentadol IR 50 mg, oxycodone IR 5 mg, or matching placebo). For subsequent doses, patients may remain at the lower dose capsule (tapentadol IR 50 mg, oxycodone IR 5 mg, or matching placebo) or may choose to take the higher dose (tapentadol IR 75 mg, oxycodone IR 10 mg, or matching placebo) every 4 to 6 hours during waking hours as needed depending on their level of pain and tolerability of the study drug. The duration of treatment with study drug will be up to 10 days. Tapentadol IR 450 mg or oxycodone IR 60 mg is the maximum daily dose allowed. Patients who require supplemental medication for insufficient analgesia will be discontinued from the study and will be treated at the investigator's discretion. All patients will receive a telephone call from the study staff on Day 3. During this telephone call, site personnel will inquire about the patient's overall status. Patients will return to the study site on Day 10/End of Study for the final visit (Visit 2). Patients who have not discontinued from the study prior to the final visit will complete a final assessment of current pain intensity and pain relief (on paper). In addition, all patients will have physical functionality assessed. Patients and investigators will each complete a global assessment of study drug. The investigator will also respond to two ease-of-care questions. Vital signs will be obtained, safety assessments will be completed and study drug will be collected. All patients will have their post-study analgesia prescribed at the investigator's discretion. Tapentadol IR 50 or 75 mg, oxycodone IR 5 or 10 mg, or placebo for up to 10 days. The dose is every 4-6 hours, as needed for pain. Maximum dosage is 450 mg tapentadol or 60 mg oxycodone per day.

Official Title
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A Randomized, Double-Blind, Placebo- and Oxycodone Immediate Release (IR)-Controlled Study of Tapentadol IR for the Treatment of Acute Pain Caused by Vertebral Compression Fractures Associated With Osteoporosis

Conditions
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Back Pain

Intervention / Treatment
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* Drug: oxycodone IR
* Drug: placebo
* Drug: tapentadol IR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female (non-pregnant, non-lactating) and male new onset of pain or acute exacerbation of previous pain associated with a VCF within 14 days prior to Visit 1 Radiographic confirmation of a VCF within 3 months prior to Visit 1 or a radiographic procedure performed at Visit 1 Average back pain intensity score in the last 24 hours related to the current episode and a qualifying current back pain intensity score Qualifying score on the Mini-Mental Status Exam Able to verbalize and differentiate with regard to location and intensity of pain Medically stable Sexually active women must be postmenopausal for at least 1 year, surgically sterile, or practicing an effective method of birth control at study entry and throughout the trial Women of childbearing potential must have a negative urine pregnancy test at Visit 1 Physically and mentally willing and able to adhere to the protocol requirements and its prohibitions and restrictions Sign an informed consent document Exclusion Criteria: Neurological symptoms or deficits, or radiculopathy related to the VCF Taken any of the following in the month before Visit 1: long-acting or controlled-release opioid, immediate release Class II opioid formulations or Class III opioid formulation (e.g., Tylenol with Codeine) > 5 days/week Systemic steroid therapy within 3 months before Visit 1 Anticonvulsants, monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or serotonin norepinephrine reuptake inhibitor within 2 weeks before randomization Major trauma to or infection in the fractured vertebrae in the 6 months preceding study Pain due to herniated nucleus pulposus, high energy trauma, severe spinal stenosis, bone tumor at the level(s) of pathology or known canal compromise causing clinical manifestations of cord, neural foramen, or nerve root compression with an ongoing pain level of >= 5 Severe cardiopulmonary deficiencies Active systemic or local infection History of alcohol or drug abuse in the investigator's judgment based on medical history and physical examination Malignancy within the past 2 years, with the exception of basal cell carcinoma Concomitant autoimmune inflammatory conditions History of laboratory values reflecting severe renal insufficiency History of moderately or severely impaired hepatic function or alanine aminotransaminase or aspartate aminotransferase greater than 3 times the upper limit of normal.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>tapentadol IR 50 or 75 mg capsule every 4 - 6 hr as needed for up to 10 days maximum daily dose 450 mg | Drug: tapentadol IR<br>* 50 or 75 mg capsule every 4 - 6 hr as needed for up to 10 days<br>|
| Experimental: 002<br>oxycodone IR 5 or 10 mg capsule every 4 - 6 hr as needed for up to 10 days maximum daily dose 60 mg | Drug: oxycodone IR<br>* maximum daily dose 450 mg<br>|
| Placebo Comparator: 003<br>placebo 1 capsule every 4 - 6 hr as needed for up to 10 days | Drug: placebo<br>* 5 or 10 mg capsule every 4 - 6 hr as needed for up to 10 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of Pain Intensity Difference Over 3 Days (SPID72) | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0=no pain to 10=pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between baseline PI (prior to the first dose) and current PI at assessment. SPID72 was calculated as the time-weighted Sum of PID scores over 72 hours. The range of SPID72 is from -720 to 720. The higher value in SPID indicates greater pain relief. The study was terminated prematurely due to slow enrollment after 108 of 600 subjects enrolled. Valid statistical conclusions cannot be made due to the low number of subjects. | 3 Days (72 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30% Responder Rate on Day 3. | The 30% responder rate was defined as the proportion of participants with a value of percentage change greater than or equal to the 30% from baseline in pain intensity at Day 3 (average of Day 3 PM and Day 4 AM). | Day 3 | 
| 50% Responder Rate on Day 3. | The 50% responder rate was defined as the proportion of participants with a value of percentage change greater than or equal to the 50% from baseline in pain intensity at Day 3 (average of Day 3 PM and Day 4 AM). | Day 3 | 
| 30% Responder Rate on Day 5. | The 30% responder rate was defined as the proportion of participants with a value of percentage change greater than or equal to the 30% from baseline in pain intensity at Day 5 (average of Day 5 PM and Day 6 AM). | Day 5 | 
| 50% Responder Rate on Day 5. | The 50% responder rate was defined as the proportion of participants with a value of percentage change greater than or equal to the 50% from baseline in pain intensity at Day 5 (average of Day 5 PM and Day 6 AM). | Day 5 | 
| 30% Responder Rate on Day 10. | The 30% responder rate was defined as the proportion of participants with a value of percentage change greater than or equal to the 30% from baseline in pain intensity at Day 10 (average of Day 9 PM and Day 10 AM). | Day 10 | 
| 50% Responder Rate on Day 10. | The 50% responder rate was defined as the proportion of participants with a value of percentage change greater than or equal to the 50% from baseline in pain intensity at Day 10 (average of Day 9 PM and Day 10 AM). | Day 10 | 
| Sum of Pain Intensity Difference Over 2 Days (SPID48) | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0=no pain to 10=pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between baseline PI (prior to the first dose) and current PI at assessment. SPID48 was calculated as the time-weighted Sum of PID scores over 48 hours. The range of SPID48 is from -480 to 480. The higher value in SPID indicates greater pain relief. | 2 Days (48 hours) | 
| Sum of Pain Intensity Difference Over 5 Days (SPID120) | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0=no pain to 10=pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between baseline PI (prior to the first dose) and current PI at assessment. SPID120 was calculated as the time-weighted Sum of PID scores over 120 hours. The range of SPID120 is from -1200 to 1200. The higher value in SPID indicates greater pain relief. | 5 Days (120 hours) | 
| Sum of Pain Intensity Difference Over 10 Days | Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0=no pain to 10=pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between baseline PI (prior to the first dose) and current PI at assessment. Sum of Pain Intensity Difference Over 10 Days was calculated as the time-weighted Sum of PID scores up to Day 10, 8 AM. The range is from -2160 to 2160. The higher value in Sum of Pain Intensity Difference indicates greater pain relief. | 10 Days (216 Hours) | 
| Total Pain Relief (TOTPAR) Over 2 Days | Pain Relief was defined as a 5-point categorical scale of 0-4 (0=none, 1=A little, 2=Some, 3=A lot, 4=Complete). Total Pain Relief (TOTPAR) was calculated as the time-weighted sum over all pain relief up to hour 48. The range of TOTPAR over 2 days is from 0 to 192. A higher value in TOTPAR indicated greater pain relief. | 2 Days (48 Hours) | 
| Total Pain Relief (TOTPAR) Over 3 Days | Pain Relief was defined as a 5-point categorical scale of 0-4 (0=none, 1=A little, 2=Some, 3=A lot, 4=Complete). Total Pain Relief (TOTPAR) was calculated as the time-weighted sum over all pain relief up to hour 72. The range of TOTPAR over 3 days is from 0 to 288. A higher value in TOTPAR indicated greater pain relief. | 3 Days (72 Hours) | 
| Total Pain Relief (TOTPAR) Over 5 Days | Pain Relief was defined as a 5-point categorical scale of 0-4 (0=none, 1=A little, 2=Some, 3=A lot, 4=Complete). Total Pain Relief (TOTPAR) was calculated as the time-weighted sum over all pain relief up to hour 120. The range of TOTPAR over 5 days is from 0 to 480. A higher value in TOTPAR indicated greater pain relief. | 5 Days (120 Hours) | 
| Total Pain Relief (TOTPAR) Over 10 Days | Pain Relief was defined as a 5-point categorical scale of 0-4 (0=none, 1=A little, 2=Some, 3=A lot, 4=Complete). Total Pain Relief (TOTPAR) was calculated as the time-weighted sum over all pain relief up to Day 10, 8 AM. The range of TOTPAR over 10 days is from 0 to 864. A higher value in TOTPAR indicated greater pain relief. | 10 Days (216 Hours) | 
| Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID) Over 2 Days | The Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID) was derived from Sum of TOTPAR and SPID. The range of SPRID over 2 days is from -480 to 672. A higher value in SPRID indicated greater pain relief. | 2 Days | 
| Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID) Over 3 Days | The Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID) was derived from Sum of TOTPAR and SPID. The range of SPRID over 3 days is from -720 to 1008. A higher value in SPRID indicated greater pain relief. | 3 Days | 
| Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID) Over 5 Days | The Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID) was derived from Sum of TOTPAR and SPID. The range of SPRID over 5 days is from -1200 to 1680. A higher value in SPRID indicated greater pain relief. | 5 Days | 
| Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID) Over 10 Days | The Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID) was derived from Sum of TOTPAR and SPID. The range of SPRID over 10 days is from -2160 to 3024. A higher value in SPRID indicated greater pain relief. | 10 Days | 
| Change From Baseline in Physical Performance: Measured Walk - Change in Distance Walked in the End of Study | The participants were assessed whether were able to walk for 4 meters at each visit. For those subjects who were unable to walk 4 meters, the distance walked would be recorded. For those completed the walk, 4 meters were recorded. The change in distance walked at the end of study was derived using the distance walked at baseline minus the distance walked at the end of study (Day 10). The range of change in distance walked is from -4 to 4. A negative value indicated better performance. | Day 10 | 
| Change From Baseline in Physical Performance: Measured Walk - Change in Time Taken Per Meter to Take Walk in the End of Study | The time for the subject to walk for 4 meters was measured at baseline and the end of study. Change = baseline - end of study. For the change in each treatment group, only subjects who were assessed at both baseline and end of study were summarized. A positive value of Change indicated performance improved. | Day 10 | 
| Change From Baseline in Physical Performance: Chair Stand - Change in Number of Chair Stands Completed in the End of Study | The participants were assessed whether were able to rise from a chair 5 times at each visit. For those subjects who were unable to complete all 5 rises, the number of rises would be recorded. For those completed the 5 rises, 5 were recorded. The change in number of chair stands at the end of study was derived using the number of chair stands at baseline minus the number of chair stands at the end of study (Day 10). The range of change in number of chair stands is from -5 to 5. A negative value indicated better performance. | Day 10 | 
| Change From Baseline in Physical Performance: Chair Stand - Change in Time Taken to Complete Chair Stands in the End of Study | The time for the subject to rise from a chair 5 times was measured at baseline and the end of study. Change = baseline - end of study. For the change in each treatment group, only subjects who were assessed at both baseline and end of study were summarized. A positive value of Change indicated performance improved. | Day 10 | 
| Summary of Subject Satisfaction With Treatment on Day 2 | Treatment satisfaction was measured using a 7-point scale where 1 = very satisfied and 7 = very dissatisfied. | Day 2 | 
| Summary of Subject Satisfaction With Treatment on Day 3 | Treatment satisfaction was measured using a 7-point scale where 1 = very satisfied and 7 = very dissatisfied. | Day 3 | 
| Summary of Subject Satisfaction With Treatment on Day 5 | Treatment satisfaction was measured using a 7-point scale where 1 = very satisfied and 7 = very dissatisfied. | Day 5 | 
| Summary of Subject Satisfaction With Treatment on Day 10 | Treatment satisfaction was measured using a 7-point scale where 1 = very satisfied and 7 = very dissatisfied. | Day 10 | 
| Sleep Quality - Shift From Baseline to End of Study (Tapentadol IR) | Sleep Quality was assessed by a 4-point numeric scale (1=excellent, 2=good, 3=fair, and 4=poor). The sleep question was Please rate the overall quality of your sleep last night., which was administered via Interactive Voice Response (IVR) system in the morning. | 10 days | 
| Sleep Quality - Shift From Baseline to End of Study (Oxycodone IR) | Sleep Quality was assessed by a 4-point numeric scale (1=excellent, 2=good, 3=fair, and 4=poor). The sleep question was Please rate the overall quality of your sleep last night., which was administered via IVR system in the morning. | 10 days | 
| Sleep Quality - Shift From Baseline to End of Study (Placebo) | Sleep Quality was assessed by a 4-point numeric scale (1=excellent, 2=good, 3=fair, and 4=poor). The sleep question was Please rate the overall quality of your sleep last night., which was administered via IVR system in the morning. | 10 days | 
| Summary of Functionality: Dressing - Proportion With at Least 2 Points of Improvement From Baseline to Day 2 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 2 | 
| Summary of Functionality: Dressing - Proportion With at Least 2 Points of Improvement From Baseline to Day 3 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 3 | 
| Summary of Functionality: Dressing - Proportion With at Least 2 Points of Improvement From Baseline to Day 5 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 5 | 
| Summary of Functionality: Dressing - Proportion With at Least 2 Points of Improvement From Baseline to Day 10 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 10 | 
| Summary of Functionality: Bath/Shower - Proportion With at Least 2 Points of Improvement From Baseline to Day 2 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 2 | 
| Summary of Functionality: Bath/Shower - Proportion With at Least 2 Points of Improvement From Baseline to Day 3 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 3 | 
| Summary of Functionality: Bath/Shower - Proportion With at Least 2 Points of Improvement From Baseline to Day 5 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 5 | 
| Summary of Functionality: Bath/Shower - Proportion With at Least 2 Points of Improvement From Baseline to Day 10 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 10 | 
| Summary of Functionality: Chair - Proportion With at Least 2 Points of Improvement From Baseline to Day 2 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 2 | 
| Summary of Functionality: Chair - Proportion With at Least 2 Point of Improvement From Baseline to Day 3 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 3 | 
| Summary of Functionality: Chair - Proportion With at Least 2 Points of Improvement From Baseline to Day 5 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 5 | 
| Summary of Functionality: Chair - Proportion With at Least 2 Points of Improvement From Baseline to Day 10 | Level of functionality assessed using a 5-point scale where 0=no difficulty and 4=impossible without help. | Day 10 | 
| Patient Global Impression of Change (PGIC) at End of Study | Patient Global Impression of Change (PGIC) was defined as the 7-point numeric scale, where 1=very much improved to 7=very much worse. | Day 10 | 
| Clinician Global Impression of Change (CGIC) at End of Study | Clinician Global Impression of Change (CGIC) was defined as the 7-point numeric scale, where 1=very much improved to 7=very much worse. | Day 10 | 
| Summary of Clinician Ease-of-Care at the End of Study: Time Comsuming | The Clinician Ease-of-Care was defined on a 6-point scale, where 0 = not at all to 5=a very great deal. | Day 10 | 
| Summary of Clinician Ease-of-Care at the End of Study: Bothersome | The Clinician Ease-of-Care was defined on a 6-point scale, where 0 = not at all to 5=a very great deal. | Day 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vertebral compression fracture, Osteoporosis, Acute pain, Analgesic, Oxycodone, Tapentadol