Tapentadol Prolonged Release (PR) Versus Oxycodone/Naloxone Prolonged Release in Severe Chronic Low Back Pain With a Neuropathic Component.

Study Overview
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Brief Summary
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This was a clinical effectiveness trial designed to compare the effectiveness, safety, and tolerability of treatment with tapentadol prolonged release with that of oxycodone/naloxone prolonged release in non-opioid pre-treated subjects with severe chronic low back pain with a neuropathic pain component. Both tapentadol and the opioid oxycodone are effective in chronic severe pain and tapentadol and oxycodone/naloxone have shown advantages in gastrointestinal tolerability versus oxycodone. Therefore, it was of high scientific interest to compare the latter 2 analgesics with respect to gastrointestinal tolerability. Tapentadol may have advantages regarding the neuropathic pain-related symptoms of low back pain due to its 2 mechanisms of action.

Official Title
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Evaluation of the Effectiveness, Safety, and Tolerability of Tapentadol PR Versus Oxycodone/Naloxone PR in Non-opioid Pre-treated Subjects With Uncontrolled Severe Chronic Low Back Pain With a Neuropathic Pain Component.

Conditions
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Back Pain, Low Back Pain, Neuropathic Pain

Intervention / Treatment
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* Drug: Tapentadol Prolonged Release
* Drug: Oxycodone/Naloxone Prolonged Release


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent signed. Male or female 18 years of age or older. Women of childbearing potential must have a negative pregnancy test at the Enrollment Visit. Women of childbearing potential must practice medically acceptable methods of birth control during the trial. Participant must be appropriately communicative and able to differentiate with regard to location and intensity of the pain, and to complete the questionnaires used in this trial. Participants must have a diagnosis of chronic low back pain; chronic pain defined as pain lasting for at least 3 months prior to enrollment. Participant's pain must require a strong analgesic (defined as World Health Organization Step III) as judged by the investigator. Participants who require a washout of co-analgesics at enrolment must have an average pain score (NRS-3) of 5 points or higher. Participants who do not require a washout of co-analgesics at enrollment must have an average pain intensity score (NRS-3) during the last 3 days of 6 points or higher. The painDETECT diagnostic screening questionnaire must be either positive (score of 19 to 38 inclusive) or unclear (score of 13 to 18 inclusive). If the participant is being treated with a stable regimen of centrally acting co-analgesics, a negative painDETECT score (score 9 points or higher). Inclusion criteria prior to allocation to treatment: Participants must have an average pain intensity score (NRS-3) during the last 3 days of 6 points or higher. Participants must score either positive (score of 19 to 38 inclusive) or unclear (score of 13 to 18 inclusive) on the painDETECT diagnostic screening questionnaire. Exclusion Criteria: Presence of a clinically significant disease or clinical laboratory values that in the investigator's opinion may affect effectiveness, quality of life, or safety/tolerability assessments. Presence of active systemic or local infections that may, in the opinion of the investigator, affect the effectiveness, quality of life, or safety/tolerability assessments. Employees of the investigator or trial site, with direct involvement in this trial or other trials under the direction of the investigator or trial site, as well as family members of employees of the investigator. Participation in another trial concurrently, or within 4 weeks prior to the Enrollment Visit. Known to or suspected of not being able to comply with the protocol and/or appropriate use of the Investigational Medicinal Products. Any painful procedures (e.g., major surgery) scheduled during the trial duration (Enrollment Visit until Final Evaluation Visit) that may, in the opinion of the investigator, affect the effectiveness, quality of life, or safety assessments. Pending litigation or application for insurance/governmental benefits due to chronic pain or disability and/or if the granted benefits might be influenced by a successful participation in the trial. Low back pain caused by cancer and/or metastatic diseases. History of alcohol or drug abuse, or suspicion thereof in the investigator's judgment. Presence of concomitant autoimmune inflammatory conditions. Participants with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic active substances. Participants with severe renal impairment, i.e., estimated glomerular filtration rate less than 30 mL/min (according to the National Kidney Foundation 2002). Known history of clinical laboratory values or current clinical laboratory values reflecting moderately or severely impaired hepatic function. History of seizure disorder or epilepsy. Any of the following within 1 year: mild/moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm (including brain metastases if present at the Enrollment Visit). Severe traumatic brain injury within 15 years (consisting of 1 or more of the following: brain contusion, intracranial hematoma, either unconsciousness or post traumatic amnesia lasting more than 24 hours) or residual sequelae suggesting transient changes in consciousness. Pregnant or breast-feeding women. Severe respiratory depression with hypoxia and/or hypercapnia, acute or severe bronchial asthma or severe chronic obstructive pulmonary disease. Presence or suspicion of paralytic ileus. Participants with severe cardiac impairment, e.g., New York Heart Association class >3, myocardial infarction less than 6 months prior to the Enrollment Visit, and/or unstable angina pectoris and/or cor pulmonale. Participant with known history of rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption. History of allergy or hypersensitivity to tapentadol, oxycodone, naloxone, and their formulations. Participants with acute biliary obstruction or acute pancreatitis. Participants with hypothyroidism (including myxedema) or Addison's disease. Participants taking any prohibited concomitant medication.

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tapentadol Prolonged Release (PR)<br> | Drug: Tapentadol Prolonged Release<br>* All participants started with 50 mg tapentadol hydrochloride prolonged release (twice daily). The dose of tapentadol hydrochloride prolonged release will be adjusted in increments of 50 mg to a level that provided adequate analgesia. Titration will be after a minimum of 3 days on a dose. Participants are permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants will remain on the stable dose for 9 weeks.<br>* Other names: Palexia;|
| Active Comparator: Oxycodone/Naloxone Prolonged Release<br> | Drug: Oxycodone/Naloxone Prolonged Release<br>* All participants start with 10 mg/5 mg oxycodone/naloxone (twice daily). The dose of oxycodone/naloxone may be adjusted in increments of 10mg/ 5 mg oxycodone/naloxone to a level that provide adequate analgesia. Titration will be after a minimum of 3 days on a dose. Participants will be permitted a maximum dose of 50 mg/ 20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants will remain on the stable dose for 9 weeks.<br>* Other names: Targin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Average Pain Intensity Score on an 11-point Numeric Rating Scale (NRS-3) | For this pain assessment, the participant indicated the level of average pain experienced over the previous 3 days on an 11-point Numeric Rating Scale (NRS-3) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. The value reported represents the change from the randomization visit (i.e., the last 3 days in the washout period prior to Investigational Medicinal Product initiation and titration) to the end of the continuation period (i.e., up to 9 weeks on the stable dose). The theoretical values range from -10 to 10. A negative sign indicates a decrease in pain from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline Visit). | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) Total Score | The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assessed the severity of symptoms of constipation. Participants were asked How severe have each of these symptoms been in the last two weeks? e.g. Pain in your stomach. There are 3 subscales: 4 questions on abdominal symptoms, 3 on rectal symptoms and 5 on stool symptoms. Responses were rated on a 5-point Likert scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). If the changes in the overall or subscale scores are positive then there is a worsening in symptoms associated with constipation. The change in the assessment of constipation symptoms (PAC-SYM) total score from the Randomization Visit to the Final Evaluation Visit. The PAC-SYM overall score is the sum of scores of all non-missing items divided by the number of non-missing items (if at least 6 items were non-missing). | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recalled Average Pain Intensity | The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS), on this scale 0 indicates no pain and 10 indicates pain as bad as you can imagine. This scale recalls the average pain intensity during the last 3 days. The participant was asked: Please rate your pain intensity by assessing the one number that best describes your pain on average during the last 3 days (the last 72 hours prior to the visit). | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change in Recalled Average Pain Intensity at the End of Treatment | The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS), on this scale 0 indicates no pain and 10 indicates pain as bad as you can imagine. This scale recorded the average pain intensity recalled by the participant during the previous 3 days. The participant was asked: Please rate your pain intensity by assessing the one number that best describes your pain on average during the last 3 days (the last 72 hours prior to the visit). A negative sign indicates a decrease in pain from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (baseline visit). | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Average Pain Intensity Over Three Days for Pain Radiating Towards or Into the Leg | Typical dermatomal pain was defined as being pain that radiates beyond the knee towards the foot (sciatica) or pain evoked by stretching of the sciatic nerve. The participant was asked to rate their pain intensity over the past 3 days with regards to this particular pain characteristic. The recalled average pain intensity over the past 3 days for the pain radiating towards or into the leg was assessed by the participant using an 11-point Numeric rating scale, where 0 = no pain and 10 = pain as bad as you can imagine. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change of Average Pain Intensity Over Three Days for Pain Radiating Towards or Into the Leg at the End of Treatment | Typical dermatomal pain was defined as being pain that radiates beyond the knee towards the foot (sciatica) or pain evoked by stretching of the sciatic nerve. Therefore, the participant was asked to rate their pain intensity over the past 3 days with regards to this particular pain characteristic. The recalled average pain intensity during the last 24 hours was assessed using an 11-point Numeric rating scale, where 0 = no pain and 10 = pain as bad as you can imagine. A negative sign indicates that there was a decrease in the average pain radiating towards or into the leg. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Worst Pain Intensity Over the Past 24 Hours | The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric rating scale, where 0 = no pain and 10 = pain as bad as you can imagine. The participant was asked: Please rate your pain intensity by assessing the one number that best describes your worst pain during the last 24 hours prior to the visit | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change in Worst Pain Intensity Over the Past 24 Hours at the End of Treatment | The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric rating scale, where 0 = no pain and 10 = pain as bad as you can imagine. The participant was asked: Please rate your pain intensity by assessing the one number that best describes your worst pain during the last 24 hours prior to the visit. A negative change indicates that the pain intensity decreased from the start of the trial. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| painDETECT Final Assessment | The painDETECT was a participant completed questionnaire. The questionnaire consists of 14 questions in four domains. Based on these questions a final assessment score was calculated. The minimum score ranged from zero to a maximum of 38. Participants with a score between 0 and 12 were scored as being negative (had no neuropathic pain component). A value between 19 and 38 was rated as being positive (neuropathic component present). Values from 13 to 18 were scored as being unclear. The theoretical range of change in this trial ranged from -38 to 15. A negative change indicated a decrease in their neuropathic component of pain. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change in painDETECT Final Assessment at the End of Treatment | The painDETECT was a participant completed questionnaire. The questionnaire consists of 14 questions in four domains. Based on these questions a final assessment score was calculated. The minimum score ranged from zero to a maximum of 38. Participants with a score between 0 and 12 were scored as being negative (had no neuropathic pain component). A value between 19 and 38 was rated as being positive (neuropathic component present). Values from 13 to 18 were scored as being unclear. The theoretical range of change in this trial ranged from -38 to 15. A negative change indicated a decrease in their neuropathic component of pain. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change in Hospital Anxiety and Depression Scale at the End of Treatment: Depression | The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe depression. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate depression. A score of 11 or above is considered to be a case of depression. A decrease in values over time indicates that there has been an improvement. A negative change value indicates a decrease in the depression score since the start of treatment. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Patient Global Impression of Change at the End of Treatment | In the Patient Global Impression of Change (PGIC) the participant indicated the perceived change over the treatment period. PGIC is a 7 point scale depicting a patient's rating of overall improvement. Patients rate their change as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Clinician Global Impression of Change at the End of Treatment | In the Clinician Global Impression of Change (CGIC) the clinician indicated the perceived change over the treatment period. The clinician was requested to choose one of seven categories for each participant. The Clinician rated the participants change as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Sleep Evaluation at the End of Treatment: Change in the Overall Quality of Sleep | The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor. The improvement, no change or worsening is reported based on the replies scored by the participants given at their End of Continuation Visit. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Sleep Evaluation: Number of Awakenings | The participants were requested to answer the following question: How many times did you wake up during the night? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline) and for the night prior to the End of the Continuation Visit (12 weeks after randomization). | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Sleep Evaluation at the End of Treatment: Change in the Number of Awakenings | The participants were requested to answer the question: How many times did you wake up during the night? The values were calculated from the data that participants self-reported. The change from baseline in the number of times of waking up during the night in a treatment group is reported. A negative symbol indicates that there was a reduction in the number of awakenings. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Sleep Evaluation: Number of Hours Slept | The participants were requested to answer the following question: How long did you sleep last night [hours]? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline) and for the night prior to the End of the Continuation Visit (12 weeks after randomization). | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Sleep Evaluation at the End of Treatment: Change in the Number of Hours Slept | The sleep evaluation questionnaire was completed by the participant. The answer was in response to the question: Sleep evaluation: How long did you sleep last night [hours]? The value reported is the change in the number of hours of sleep from baseline. The positive value indicates that there was an increase in the number of hours of sleep in a treatment group. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Sleep Evaluation: Latency (Time Taken to Fall Asleep) | The sleep evaluation questionnaire was completed by the participant. The participant was asked: How long after bedtime/lights out did you fall asleep last night [hours]? The values are for the night prior to the Randomization Visit (Baseline) and for the night prior to the Final Evaluation Visit (12 weeks after randomization). The higher the value the longer it took to fall asleep. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Sleep Evaluation at the End of Treatment: Change in Latency (Change in the Time Taken to Fall Asleep) | The sleep evaluation questionnaire was completed by the participant. The participant was asked: How long after bedtime/lights out did you fall asleep last night [hours]? The values are for the night prior to the visits. The negative change from baseline indicates that the time to falling asleep decreased from baseline in a treatment group. | Baseline (Randomization Visit); End of Continuation Visit (Week 12) | 
| Comparison of the Number of Participants Affected by Gastrointestinal Treatment Emergent Adverse Events (TEAEs) Typical for Opioids | In this outcome measure the number of participants affected by early gastrointestinal-related treatment emergent adverse events (TEAEs). As the trial population was opioid-naïve this was considered of interest. The composition score from participant who reported: Mild, moderate to severe nausea and/or Mild, moderate to severe vomiting and/or Mild, moderate to severe constipation was evaluated. | Baseline (Randomization Visit) to End of Titration Period (End of Week 3) | 
| Composite Event Based Comparison of Gastrointestinal Treatment Emergent Adverse Events (TEAEs) Typical for Opioids | In this outcome measure the early gastrointestinal-related treatment emergent events (TEAEs) were evaluated. As the trial population was opioid-naïve this was considered of interest. The composition score of reported events of Mild, moderate to severe nausea and/or Mild, moderate to severe vomiting and/or Mild, moderate to severe constipation was evaluated. | Baseline (Randomization Visit); End of Week 3 (End of Titration Period) | 
| Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment | In the Neuropathic Pain Symptom Inventory (NPSI) the participant rated their symptoms of neuropathic pain. Ten pain questions were answered on an 11-point scale; from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity, e.g. worst burning imaginable). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 and 1. For pain descriptions burning, pressing, paroxysmal (pain like electric shocks or stabbing), evoked (due to touch) and paresthesia (sensation that is not unpleasant) or dysesthesia (unpleasant) sub-scores are reported. The overall values reported for all participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 1. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment at the End of Treatment | In the Neuropathic Pain Symptom Inventory (NPSI) the participant rated their symptoms of neuropathic pain. Ten pain questions were answered on an 11-point scale, from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity, e.g. worst burning imaginable). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 and 1. For pain descriptions burning, pressing, paroxysmal (pain like electric shocks or stabbing), evoked (due to touch) and paresthesia (sensation that is not unpleasant) or dysesthesia (unpleasant) sub-scores are reported. The overall values reported for all participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 1. A negative change indicates that the intensity of the symptom has decreased since the start of treatment. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Short Form Health Survey (SF-12) | The Short Form Health Survey (SF-12) has several brief broad questions on 8 aspects of health (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health) that a participant was asked to score over the last week. The physical and mental summary scores were calculated from the individual responses. A higher score indicates a better participant perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Changes in the Short Form Health Survey (SF-12) at the End of Treatment | The Short Form Health Survey (SF-12) has several brief broad questions on 8 aspects of health (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health) that a participant was asked to score over the last week. The physical and mental summary scores were calculated from the individual responses. A higher score indicates a better participant perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state. The change in the SF-12 score shows an improvement in health from baseline if the values are positive. The higher the value the greater the improvement since starting the trial. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| EuroQol-5 (EQ-5D) Health Status Index Outcome | The participant scored the EuroQol-5 questionnaire. The EuroQol-5 questionnaire uses a health state classification with 5 dimensions. Each dimension was assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1 (with 1 indicating full health and 0 representing dead). The higher the values (the closer the value is to 1) the better the health status in a treatment group. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change in EuroQol-5 (EQ-5D) Health Status Index Outcome at the End of Treatment | The participant scored the EuroQol-5 questionnaire. The EuroQol-5 questionnaire uses a health state classification with 5 dimensions. Each dimension was assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1 (with 1 indicating full health and 0 representing dead). The higher the values (the closer the value is to 1) the better the health status in a treatment group. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Hospital Anxiety and Depression Scale: Anxiety | The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate anxiety. A score of 11 or above is considered to be a case of anxiety. A decrease in values over the trial period indicate that there has been an improvement. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Change in Hospital Anxiety and Depression Scale at the End of Treatment: Anxiety | The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate anxiety. A score of 11 or above is considered to be a case of anxiety. A negative sign indicates that there has been a decrease in anxiety since the start of treatment. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 
| Hospital Anxiety and Depression Scale: Depression | The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe depression. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate depression. A score of 11 or above is considered to be a case of depression. A decrease in values over time indicates that there has been an improvement. | Baseline (Randomization Visit); End of Continuation Period (Week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe chronic low back pain, Neuropathic pain, Constipation