Comparison of Increasing Doses of Tapentadol Versus a Combination of Tapentadol and Pregabalin

Phase 4

Completed

Conditions: Neuropathic Pain
Low Back Pain

Interventions: Drug: Tapentadol Prolonged Release
Drug: Tapentadol Prolonged Release with Pregabalin
Drug: Tapentadol Prolonged Release open label maintenance

Registration Number: NCT01352741

Lead Sponsor: Grünenthal GmbH

Brief Summary: The main objective of the study is to evaluate the effectiveness, safety, and tolerability of increasing doses of tapentadol prolonged release (PR) (500 mg per day) versus a combination of tapentadol PR (300 mg per day) and pregabalin (to 300 mg per day) in subjects requiring additional analgesia after titration to tapentadol PR 300 mg per day.

This is a clinical effectiveness trial designed to establish a link between anticipated clinical outcomes and the clinical practice by means of selected measures of clinical and subject reported outcomes. Since, severe low back pain with a neuropathic component, the targeted study population, is frequently treated with a combination therapy (monotherapy is often not effective enough) it is of interest to determine if tapentadol alone (combining 2 mechanisms of action in a single molecule) could be as effective as a combination of tapentadol plus pregabalin. Furthermore, the tolerability profiles of monotherapy versus combination are of interest.

Detailed Description: Participants with a diagnosis of chronic low back pain (defined as pain lasting for at least 3 month) and requiring a strong analgesic (World Health Organization \[WHO\] Step III) as judged by the investigator and having a positive or unclear score using the painDETECT diagnostic screening questionnaire will enter the open-label titration tapentadol prolonged release (PR) period. In total participants will have 11 planned scheduled visits scheduled over 105 days. At the Enrollment Visit \[Day -14 (3 to 14 days prior to the Baseline Visit)\] the inclusion and exclusion criteria will be checked to evaluate the participant's eligibility for the trial. Participants on previous analgesics will start a washout period three days up to 2 weeks.The duration of the washout period will depend on previous opioid analgesics and co-analgesics and their respective doses, down-tapering steps. Participants who do not need a washout of previous analgesic treatment (e.g. WHO Step I analgesics), a baseline visit can be scheduled as soon as clinical laboratory monitoring results are available.

At the Baseline Visit (Day 1) participants will start the 3 week open-label titration period tapentadol prolonged release (PR) at doses of 2 x 50 mg per day and will be titrated upwards in steps of 100 mg (2 x 50 mg) on a weekly basis.

Participants who do not qualify for randomization may continue the trial in the open-label continuation arm if they have already reached a satisfactory level of pain relief.

Participants qualifying for randomization in the comparative period (Day 22 to 77) will be allocated to 1 of 2 treatment arms and will continue treatment.

Either they continue on tapentadol prolonged release (PR) with increasing doses of tapentadol PR

* After the randomization visit, participants will titrate up to a total daily dose of 400 mg.

* 1 week after the randomization visit, will titrate up to a total daily dose of 500 mg. Participants in this treatment arm will receive a final dose of 500 mg tapentadol PR per day.

Or start on a combination of tapentadol PR 300 mg per day with pregabalin

* After the randomization visit, participants will continue their previous regimen of tapentadol PR 2 x 150 mg per day plus pregabalin 2 x 75 mg (total daily dose of 150 mg pregabalin).

* 1 week after the randomization visit, participants will continue their previous regimen (end of titration period) of tapentadol PR 2 x 150 mg per day plus pregabalin 2 x 150 mg (total daily dose of 300 mg pregabalin). Participants in this treatment arm will receive a final dose of 300 mg tapentadol PR and 300 mg pregabalin.

Participants in the Comparative Period can be assigned to the open-label pick-up arm and will be treated with a stable dose of tapentadol PR 300 mg per day or 400 mg per day if they experience treatment emergent adverse events (at least possibly related to investigational medicinal product).The open-label pick-up period theoretically starts on Day 29, i.e. one week after the Randomization Visit.

The Final Evaluation (Day 77) is planned to take place 8 weeks after randomization.

After the Final Evaluation a Follow-up Period (blinded tapering down/out of IMP in Week 12 and Follow-up Visit (up to Day 91) will take place. Tapering down/out of medication will be performed according to the Summary of Product Characteristics.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 622

Inclusion Criteria

Subjects must have a diagnosis of chronic low back pain; chronic pain defined as pain lasting for at least 3 months.
Subject's pain must require a strong analgesic (defined as World Health Organization (WHO) step III) as judged by the investigator.
The painDETECT diagnostic screening questionnaire score must be:
- "positive" or
- "unclear".or If the subject is being treated with a stable regimen of centrally acting analgesics (opioids) and/or co-analgesics, even a "negative" painDETECT score (but of at least 9) at the enrollment visit will be acceptable.
If under regular daily pretreatment with a WHO step II/step III opioid analgesic and/or a centrally acting co-analgesic:
- Subjects must be taking a WHO step II or step III analgesic or co- analgesic on a daily basis for at least 2 weeks prior to the enrollment visit.
- Subjects pretreated with a WHO step II opioid analgesic and/or a centrally acting co-analgesic must have reported an average pain intensity score of at least 5 points (NRS-3≥5) during the last 3 days prior to the enrollment visit. or If under regular, daily pretreatment with a WHO step I analgesic monotherapy or if no regular analgesic pretreatment is reported:
- Subjects must have an average pain intensity score of at least 6 points NRS-3≥6) in the last 3 days prior to the enrollment visit.

Exclusion Criteria

Presence of concomitant painful conditions other than low back pain that could confound the subject's trial assessments or self-evaluation of the index pain, e.g., syndromes with widespread pain such as fibromyalgia.
Low back pain caused by cancer and/or metastatic diseases.
Any painful procedures planned during the trial period (e.g., major surgery) that may, in the opinion of the investigator, affect the effectiveness or safety assessments of the Investigational Medicinal Product (IMP).
Pending litigation or application for insurance/governmental benefits due to chronic pain or disability and, if granted, benefits might be influenced by a successful participation in the trial.
Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, lactose intolerance.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tapentadol Prolonged Release	Tapentadol Prolonged Release	Tapentadol Prolonged Release (100 - 500 mg per day) Oral administration twice daily
Tapentadol Prolonged Release	Tapentadol Prolonged Release open label maintenance	Tapentadol Prolonged Release (100 - 500 mg per day) Oral administration twice daily
Tapentadol Prolonged Release with Pregabalin	Tapentadol Prolonged Release with Pregabalin	Tapentadol Prolonged Release (100 - 300 mg per day) with Pregabalin (150 - 300 mg per day) Both administered orally twice a day.
Tapentadol Prolonged Release with Pregabalin	Tapentadol Prolonged Release open label maintenance	Tapentadol Prolonged Release (100 - 300 mg per day) with Pregabalin (150 - 300 mg per day) Both administered orally twice a day.

Primary Outcome Measures

Name	Time	Method
Change in the Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)	Randomization (Day 22); Final Evaluation Visit (Day 77)	The primary endpoint is defined as the comparison of tapentadol prolonged release (PR) 300 mg plus 200 mg per day and the combination of tapentadol PR 300 mg per day and pregabalin 300 mg per day regarding the change in NRS-3 pain intensity scores (recalled average pain intensity score during the last 3 days on 11-point NRS, where 0 is the no pain and 10 is pain as bad as you can imagine) from the randomization visit to the final evaluation visit. Theoretically a maximum decrease of -10 and an increase of +4 in the pain intensity would have been possible. A negative sign indicates a decrease in pain intensity from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline visit).

Secondary Outcome Measures

Name	Time	Method
End of Open-label Pick-up Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)	Final Evaluation Visit (Day 77)	The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine.
Double-blind Comparative Period: Change in NRS-3 Pain Intensity Score for the Radiating Pain	Randomization Visit (Day 22); End of Evaluation Visit (Day 77)	NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on 11-point NRS, where 0 is the no pain and 10 is pain as bad as you can imagine) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot). The value reported represents the change from the randomization visit (i.e., the last 3 days in the titration period) to the end of the double-blind comparative period (i.e., the last 3 days in the comparative period). 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).
Open-label Titration Period: Radiating Pain	Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)	The NRS-3 pain intensity score at the visits in the open-label titration period for the two comparative double-blind period treatment groups analyzed is reported. NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on an 11-point NRS) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot) is reported. Where 0 = no pain and 10 indicates pain as bad as you can imagine.
Open-label Titration Period: painDETECT Assessments	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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".
Open-label Titration Period: Sleep Evaluation Questionnaire - Latency	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the sleep latency. To assess latency the participant was asked: How long after bedtime/lights out did you fall asleep last night \[hours\]?
Open-label Titration Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)	Enrollment (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)	The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine. This is the treatment period prior to the primary outcome period.
Double-blind Comparative Period: Change in painDETECT Final Assessment	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	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 19. A negative change indicated a decrease in their neuropathic component of pain.
Open-label Continuation Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)	Enrollment (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine.
Double-blind Comparative Period: Change in Worst Pain Intensity Over the Past 24 Hours	Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	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.
Open-label Titration Period: Comparative Double-blind Period Population painDETECT Assessment	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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".
Open-label Titration Period: Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment in the Double-blind Comparative Period Population	Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	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 100. 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 100.
Open-label Titration Period: Radiating Mean Pain Intensity Score for the Comparative Period Population	Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)	The NRS-3 pain intensity score at the visits in the open-label titration period for the two comparative double-blind period treatment groups analyzed is reported. NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on an 11-point NRS) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot) is reported. Where 0 = no pain and 10 indicates pain as bad as you can imagine.
Open-label Titration Period: Comparative Double-blind Period Population Worst Mean Pain Intensity Scores Over the Past 24 Hours	Enrollment Visit (Day-12); Baseline Visit (day 1); Randomization Visit (Day 22)	The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric Rating Scale (NRS), 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 past 24 hours prior to the visit".
Double-blind Comparative Period: Change in Short Form Health Survey (SF-12) Mental Health Composite Score (MCS)	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	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 mental health summary scores were calculated from the individual responses to two of the 12 questions. 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 mental health.
Double-blind Comparative Period: Change EuroQol-5 Dimension (EQ-5D) Health Status Index	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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.
Double-blind Comparative Period: Patient Global Impression of Change (PGIC)	Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)	In the Patient Global Impression of Change (PGIC) the participant indicated the perceived change over the treatment period. PGIC is a 7 point scale where the patient's rates overall improvement. Patients rate their change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse."
Open-label Titration Period: Hospital Anxiety and Depression Scale - Anxiety in the Double-blind Comparative Period Population	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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.
Open-label Titration Period: Worst Mean Pain Intensity Scores Over the Past 24 Hours	Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)	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".
Open-label Titration Period: Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment	Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)	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 100. 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 100.
Double-blind Comparative Period: Changes in the Short Form Health Survey (SF-12) Physical Health Composite Score (PCS)	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	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 summary scores were calculated from the individual responses to those questions covering physical health. 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.
Open-label Titration Period: Comparative Double-blind Period Population Short Form Health Survey (SF-12) Mental Health Composite Score (MCS)	Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)	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 mental health summary scores were calculated from the individual responses to two of the 12 questions. 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 mental health.
Double-blind Comparative Period: Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment	Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	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. Spontaneous Pressing Pain Subscore). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 and 100. 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) subscores 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 10 (100 for the overall score) . A negative change indicates that the intensity of the symptom has decreased since the start of treatment.
Open-label Titration Period: Comparative Double-blind Period Population Short Form Health Survey (SF-12) Physical Health Composite Score (PCS)	Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)	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 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.
Open-label Titration Period: EuroQol-5 Dimension (EQ-5D) Health Status Index Score for the Double-blind Comparative Period Population	Enrollment Visit (day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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.
Double-blind Comparative Period: Clinician Global Impression of Change (CGIC)	Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)	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."
Double-blind Comparative Period: Change in Hospital Anxiety and Depression Scale - Anxiety in the Double-blind Comparative Period Population	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	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.
Open-label Titration Period: Hospital Anxiety and Depression Scale - Depression in the Double-blind Comparative Period Population	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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.
Double-blind Comparative Period: Change in Hospital Anxiety and Depression Scale - Depression in the Double-blind Comparative Period Population	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)	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.
Open-label Titration Period: Sleep Evaluation Questionnaire - Latency in the Double-blind Comparative Period Population	Enrollment Visit (Day -12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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. Sleep evaluation questionnaire (SQ) items
Open-label Titration Period: Sleep Evaluation - Number of Awakenings in the Double-blind Comparative Period Population	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. 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), for the night prior to the Baseline Visit (Day 1) and the night prior to the Randomization Visit (Day 22). The participant was asked at each visit: "How many times did you wake up during the night?"
Double-blind Comparative Period: Sleep Evaluation Questionnaire - Change in the Number of Hours Slept	Baseline Visit (Day -12); Randomization Visit (Day 1); Final Evaluation Visit (Day 77)	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.
Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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.
Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population	Randomization Visit (Day 22)	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.
Double-blind Comparative Period Sleep Evaluation Questionnaire: Change in Latency	Baseline Visit (Day 1); Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)	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.
Open-label Titration Period: Sleep Evaluation Questionnaire - Number of Awakenings	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. 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), for the night prior to the Baseline Visit (Day 1) and the night prior to the Randomization Visit (Day 22). The participant was asked at each visit: "How many times did you wake up during the night?"
Double-blind Comparative Period: Change in the Number of Awakenings	Baseline Visit (Day 1); Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. Participants were asked: How many times did you wake up during the night? The change in the Number of Awakenings was calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline), for the night prior to the Baseline Visit (Day 1) and the night prior to the Final Evaluation Visit (Day 77). A negative change indicates that the number of awakenings in a treatment group have gone down since the Baseline or Randomization Visit. In general pain can interfere with sleep, one potential indicator is the number of awakenings.
Open-label Titration Period: Sleep Evaluation Questionnaire - Time Slept	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. The participant was asked: "How long did you sleep last night?" \[Answered in hours and minutes\].
Open-label Titration Period: Sleep Evaluation Questionnaire - Number of Hours Slept in the Double-blind Comparative Period Population	Enrollment Visit (Day -12); Baseline Visit (Day 1); Randomization Visit (Day 22)	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).
Double-blind Comparative Period: Change in the Overall Quality of Sleep	Randomization Visit (Day 22) to Final Evaluation (Day 77)	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 improvement, no change or worsening is reported based on the replies scored by the participants given at their End of Continuation Visit.
Open-label Titration Period: Subject's Satisfaction With Treatment	End of Open-label Titration Period at Randomization Visit (Day 22)	Participants rated their satisfaction with the study drug (IMPs) by answering the following question on a 5-point rating scale: "How would you rate your overall satisfaction with your current pain treatment?": Excellent, Very Good, Good, Fair and Poor.
Double-blind Comparative Period: Subject's Satisfaction With Treatment	End of Comparative Period at Final Evaluation Visit (Day 77)	Participants rated their satisfaction with the study drug (IMPs) by answering the following question on a 5-point rating scale: "How would you rate your overall satisfaction with your current pain treatment?": Excellent, Very Good, Good, Fair and Poor.

Trial Locations

Locations (59): Site 306
🇵🇱
Ostrów Mazowiecka, Poland
Site 504
🇦🇹
Wien, Austria
Site 505
🇦🇹
Wien, Austria
Site 503
🇦🇹
Senftenberg, Austria
Site 502
🇦🇹
Wien, Austria
Site 907
🇪🇸
Granada, Spain
Site 115
🇩🇪
Cottbus, Germany
Site 113
🇩🇪
Leipzig, Germany
Site 506
🇦🇹
Klagenfurt, Austria
Site 702
🇩🇰
Copenhagen, Denmark
Site 703
🇩🇰
Ringsted, Denmark
Site 605
🇧🇪
Dour, Belgium
Site 501
🇦🇹
Wien, Austria
Site 603
🇧🇪
Gozee, Belgium
Site 601
🇧🇪
Pellenberg, Belgium
Site 704
🇩🇰
Frederiksberg, Denmark
Site 602
🇧🇪
Genk, Belgium
Site 701
🇩🇰
Glostrup, Denmark
DE 118
🇩🇪
Berlin, Germany
Site 107
🇩🇪
Berlin, Germany
Site 111
🇩🇪
Böhlen, Germany
Site 103
🇩🇪
Hamburg, Germany
Site 101
🇩🇪
Kiel, Germany
Site 105
🇩🇪
Köln, Germany
Site 114
🇩🇪
Kiel, Germany
Site 308
🇵🇱
Krakow, Poland
Site 116
🇩🇪
Köln, Germany
Site 803
🇳🇱
Amsterdam, Netherlands
Site 108
🇩🇪
Schönau, Germany
Site 112
🇩🇪
Westerstede, Germany
Site 106
🇩🇪
Rendsburg, Germany
Site 117
🇩🇪
Weimar, Germany
Site 109
🇩🇪
Lübeck, Germany
Site 104
🇩🇪
Wiesbaden, Germany
Site 805
🇳🇱
Enschede, Netherlands
Site 802
🇳🇱
Heerenveen, Netherlands
Site 801
🇳🇱
Sliedrecht, Netherlands
Site 309
🇵🇱
Bydgoszcz, Poland
Site 312
🇵🇱
Gdansk, Poland
Site 303
🇵🇱
Katowice, Poland
Site 310
🇵🇱
Krakow, Poland
Site 311
🇵🇱
Krakow, Poland
Site 301
🇵🇱
Warsaw, Poland
Site 307
🇵🇱
Lublin, Poland
Site 304
🇵🇱
Poznan, Poland
Site 305
🇵🇱
Wroclaw, Poland
Site 904
🇪🇸
A Coruna, Spain
Site 905
🇪🇸
Barcelona, Spain
Site 902
🇪🇸
Centelles, Spain
Site 909
🇪🇸
Madrid, Spain
Site 910
🇪🇸
Madrid, Spain
Site 911
🇪🇸
Valencia, Spain
Site 903
🇪🇸
Oviedo, Spain
Site 604
🇧🇪
Ham, Belgium
Site 110
🇩🇪
Hamburg, Germany
Site 804
🇳🇱
Eindhoven, Netherlands
Site 302
🇵🇱
Warszawa, Poland
Site 908
🇪🇸
Alicante, Spain
Site 901
🇪🇸
Badalona, Spain