A Study of the Effectiveness and Safety of Sustained-release Hydromorphone (a Strong Opioid) in Patients With Chronic Noncancer Pain.

Janssen Pharmaceutica N.V., Belgium504 enrolled

Overview

The purpose of this study is to compare the effectiveness and safety of sustained- release hydromorphone, formulated to release slowly over time, taken once daily, and controlled- release oxycodone taken twice daily, in patients with chronic non-cancer pain. The study will also determine the dose of sustained-release hydromorphone that provides a level of pain control that is equal to the pain control provided by control-released oxycodone (equi-analgesic dosage).

Conventional immediate-release forms of hydromorphone and oxycodone have a relatively short duration of action that require dosing every 4 to 6 hours. To counterbalance the drawback of repeated opioid intake, sustained-release formulations of oxycodone and hydromorphone were developed that allow twice-daily dosing. Subsequently, a novel, once-daily, extended-release hydromorphone formulation was developed to further enhance ease of treatment and improve effectiveness in the treatment of severe pain. This is a randomized, open-label, comparative, parallel-group, 24-week flexible-dose study in patients with chronic noncancer pain severe enough to require continuous opioid therapy. Patients will receive either 8 mg of sustained-release hydromorphone, taken once daily or 10 mg of controlled-release oxycodone, taken twice daily. Individual adjustments in dosing will be performed to achieve satisfactory pain control, up to a maximum daily dosage of 32 mg for hydromorphone and 80 mg for oxycodone. The primary efficacy outcome will be the determination of the dose of hydromorphone that produces a level of pain control that is equal to the pain control provided by oxycodone (equi-analgesic dose). Safety will be monitored throughout the study. The study hypothesis is that sustained-release hydromorphone taken once daily is well tolerated and is not inferior with regard to pain control to controlled-release oxycodone taken twice daily. Amendment: Amendment was made to the duration of the study from duration of '24 weeks' to '52 weeks' in order to collect long-term safety and efficacy data. OROS hydromorphone 8, 16, or 32 mg tablets QD or SR oxycodone 10, 20, or 40 mg tablets BID. Individual adjustments in dosing performed to achieve satisfactory pain control over 24 weeks. Amendment: treatment duration was extended to 52 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

Conditions

Pain

Interventions

OROS hydromorphone HClDRUG

8 to 32 mg once daily for 52 weeks (flexible dosing)

OxycodoneDRUG

10, 20, or 40 mg twice a day for 52 weeks (flexible dosing)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adult patients with chronic noncancer pain severe enough to require continuous opioid therapy (a score of at least 5 in "pain right now" on a 11 point numeric rating scale) who have never received an opioid or are currently treated with a weak opioid, and who experience insufficient pain control. Exclusion Criteria: * Patients who have been treated with strong opioids (including hydromorphone and oxycodone) within the last 4 weeks prior to study inclusion or who will probably undergo any treatment (e.g. neurological techniques, surgery) within the next 6 months, which may abruptly alter degree or nature of pain experienced * patients with a history of disease(s), current illness, or therapy which would preclude them from participation in the study * and patients who are pregnant or nursing.

Locations (52)

Outcomes

Primary Outcomes

Change From Baseline in Brief Pain Inventory (BPI) Questionnaire Item 6 "Pain Right Now" Score at Week 24 (Per Protocol [PP] Population)

Assessment of non-inferiority of OROS hydromorphone compared with sustained release (SR) oxycodone with regard to pain control by measuring the change from baseline in pain severity, using BPI item 6 "pain right now" score at week 24. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "pain right now".

Time frame: baseline and week 24

Change From Baseline in BPI Questionnaire Item 6 "Pain Right Now" Score at Week 24 (Intent to Treat [ITT] Population)

Assessment of non-inferiority of OROS hydromorphone compared with SR oxycodone with regard to pain control by measuring the change from baseline in pain severity, using BPI item 6 "pain right now" score at week 24. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "pain right now".

Time frame: baseline and week 24

Equi-analgesic Dosage of OROS Hydromorphone Once-daily and SR Oxycodone Twice-daily (PP Population)

If non-inferiority of OROS hydromorphone was established, the daily dose of OROS hydromorphone and SR oxycodone that induced the same pain control was to be calculated (average dose used at week 24). Relative equi-analgesic dose was defined as mean dose/allowed maximum dose\*100. Allowed maximum doses were 32mg OROS hydromorphone and 80mg SR oxycodone respectively.

Time frame: week 24

Equi-analgesic Dosage of OROS Hydromorphone Once-daily and SR Oxycodone Twice-daily (ITT Population)

Time frame: week 24

Data from ClinicalTrials.gov

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Secondary Outcomes

Change From Baseline in BPI Pain Severity Sub-score "Pain at Its Worst" (BPI Item 3) at Week 24 (ITT Population)

Change from baseline to week 24 in BPI pain severity, pain at its worst (BPI item 3) assessed using the BPI questionnaire. Score values ranges from 0 (no pain) to 10 (pain as bad as you can imagine). Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "pain at its worst".

Time frame: baseline and week 24

Change From Baseline in Sleep Quality at Week 24

Change from baseline in sleep quality was assessed using the Medical Outcomes Study (MOS) questionnaire at week 24, specifically the sleep subscale index I. Score range 0 to 100, where 0 = best sleep quality and 100 = worst sleep quality. Negative change from baseline scores indicate improved sleep quality.

Time frame: baseline and week 24

Change From Baseline in Subject Diary Evening Mean Pain Score "Pain Right Now" at Week 24

Change from baseline to week 24 in subject diary evening mean pain score "pain right now". Subjects rated the severity of "pain right now" on a 10 point numeric scale, with 0 being the least pain and 10 being the most pain. Negative change from baseline scores indicate improvement in subject diary evening mean pain score "pain right now".

Time frame: baseline and week 24

Change From Baseline in Subject Diary Morning Mean Pain Score "Pain Right Now" at Week 24

Change from baseline to week 24 in subject diary morning mean pain score "pain right now". Subjects rated the severity of "pain right now" on a 10 point numeric scale, with 0 being the least pain and 10 being the most pain. Negative change from baseline scores indicate improvement in subject diary evening mean pain score "pain right now".

Time frame: baseline and week 24

Number of Subjects With Dose Escalation

Number of subjects with dose increase in study medication.

Time frame: week 4 and week 24

Change From Baseline in BPI Severity Score "Pain Right Now" (BPI Item 6) at Week 4

Change from baseline in pain severity was assessed using the BPI questionnaire, specifically "pain right now" (BPI item 6) at week 4. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "pain right now".

Time frame: baseline and week 4

Change From Baseline in BPI Pain Severity Score "Pain at Its Least" (BPI Item 4) at Week 4

Change from baseline in pain severity was assessed using the BPI questionnaire, specifically "pain at its least" (BPI item 4) at week 4. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "pain at its least".

Time frame: baseline and week 4

Change From Baseline in BPI Pain Severity "Pain at Its Worst" (BPI Item 3) at Week 4

Change from baseline in pain severity was assessed using the BPI questionnaire, specifically "pain at its worst" (BPI item 3) at week 4. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "pain at its worst".

Time frame: baseline and week 4

Change From Baseline in BPI Pain Severity "Average Pain" (BPI Item 5) at Week 4

Change from baseline in pain severity was assessed using the BPI questionnaire, specifically "average pain" (BPI item 5) at week 4. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "average pain".

Time frame: baseline and week 4

Change From Baseline in BPI Pain Relief Score (BPI Item 8) at Week 4

Change from baseline in pain severity was assessed using the BPI questionnaire, specifically pain relief (BPI item 8) at week 4. Scores could have ranged from 0 to 100, where 0 = no relief and 100 = complete relief. Positive change from baseline scores indicate improvement in pain relief.

Time frame: baseline and week 4

Change From Baseline in BPI Pain Severity Score (Mean of BPI Items 3 to 6) at Week 4

Change from baseline in BPI pain severity was assessed using the BPI questionnaire (mean of BPI items 3 to 6) at week 4. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in pain severity.

Time frame: baseline and week 4

Change From Baseline in BPI Pain Severity "Pain at Its Least" (BPI Item 4) at Week 24

Change from baseline in pain severity was assessed using the BPI questionnaire, specifically "pain at its least" (BPI item 4) at week 24. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "pain at its least".

Time frame: baseline and week 24

Change From Baseline in BPI Pain Severity "Average Pain" (BPI Item 5) at Week 24

Change from baseline in pain severity was assessed using the BPI questionnaire, specifically "average pain" (BPI item 5) at week 24. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative change from baseline scores indicate improvement in "average pain".

Time frame: baseline and week 24

Change From Baseline in BPI Pain Relief Score (BPI Item 8) at Week 24

Change from baseline in pain severity was assessed using the BPI questionnaire, specifically pain relief (BPI item 8) at week 24. Scores could have ranged from 0 to 100, where 0 = no relief and 100 = complete relief. Positive change from baseline scores indicate improvement in pain relief.

Time frame: baseline and week 24

Change From Baseline in BPI Pain Severity Score (Mean of BPI Items 3 to 6) at Week 24

Change in pain severity was assessed using the BPI questionnaire, specifically average (mean) score of BPI items 3 to 6 (worst pain, least pain, average pain, and pain right now) at week 24. Scores could have ranged from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. Negative scores indicate improvement in pain severity.

Time frame: baseline and week 24

Change From Baseline in BPI Interference Score "Interfered With General Activity" (BPI Item 9a) at Week 4

Change from baseline in interference of pain was assessed using the BPI questionnaire, specifically BPI item 9a "pain interfered with general activity" at week 4. Scores could have ranged from 0 to 10, where 0 = does not interfere and 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with general activity".

Time frame: baseline and week 4

Change From Baseline in Pain Interference "Pain Interfered With Mood" (BPI Item 9b) at Week 4

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9b "pain interfered with mood" at week 4. Scores could have ranged from 0 to 10, where 0 = does not interfere and 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with mood".

Time frame: baseline and week 4

Change From Baseline in Pain Interference "Pain Interfered With Walking Ability" (BPI Item 9c) at Week 4

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9c "pain interfered with walking ability" at week 4. Scores could have ranged from 0 to 10, where 0 = does not interfere and 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with walking ability".

Time frame: baseline and week 4

Change From Baseline in Pain Interference "Pain Interfered With Normal Work" (BPI Item 9d) at Week 4

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9d "pain interfered with normal work" at week 4. Scores could have ranged from 0 to 10, where 0 = does not interfere and 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with normal work".

Time frame: baseline and week 4

Change From Baseline in Pain Interference "Pain Interfered With Relations With Other People" (BPI Item 9e) at Week 4

Change from baseline in pain interference was assessed using BPI questionnaire, specifically BPI item 9e "pain interfered with relations with other people" at week 4. Scores could have ranged from 0 to 10, where 0 = does not interfere and 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with relations with other people".

Time frame: baseline and week 4

Change From Baseline in Pain Interference "Pain Interfered With Sleep" (BPI Item 9f) at Week 4

Change from baseline in pain interference was assessed using BPI questionnaire, specifically BPI item 9f "pain interfered with sleep" at week 4. Scores could have ranged from 0 to 10, where 0 = does not interfere and 10 - completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with sleep".

Time frame: baseline and week 4

Change From Baseline in Pain Interference "Pain Interfered With Enjoyment of Life" (BPI Item 9g) at Week 4

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9g "pain interfered with enjoyment of life" at week 4. Scores could have ranged from 0 to 10, where 0 = does not interfere and 10 = interferes completely. Negative change from baseline scores indicate improvement in "pain interfered with enjoyment of life".

Time frame: baseline and week 4

Change From Baseline in Pain Interference "Pain Interfered With General Activity" (BPI Item 9a) at Week 24

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9a "pain interfered with general activity" at week 24. Scores could have ranged from 0 to 10, where 0 = does not interfere to 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with general activity".

Time frame: baseline and week 24

Change From Baseline in Pain Interference "Pain Interfered With Mood" (BPI Item 9b) at Week 24

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9b "pain interfered with mood" at week 24. Scores could have ranged from 0 to 10, where 0 = does not interfere to 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with mood".

Time frame: baseline and week 24

Change From Baseline in Pain Interference "Pain Interfered With Walking Ability" (BPI Item 9c) at Week 24

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9c "pain interfered with walking ability" at week 24. Scores could have ranged from 0 to 10, where 0 = does not interfere to 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with walking ability".

Time frame: baseline and week 24

Change From Baseline in Pain Interference "Pain Interfered With Normal Work" (BPI Item 9d) at Week 24

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9d "pain interfered with normal work" at week 24. Scores could have ranged from 0 to 10, where 0 = does not interfere to 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with normal work".

Time frame: baseline and week 24

Change From Baseline in Pain Interference "Pain Interfered With Relations With Other People" (BPI Item 9e) at Week 24

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9e "pain interfered with relations with other people" at week 24. Scores could have ranged from 0 to 10, where 0 = does not interfere to 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with relations with other people".

Time frame: baseline and week 24

Change From Baseline in Pain Interference "Pain Interfered With Sleep" (BPI Item 9f) at Week 24

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9f "pain interfered with sleep" at week 24. Scores could have ranged from 0 to 10, where 0 = does not interfere to 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with sleep".

Time frame: baseline and week 24

Change From Baseline in Pain Interference "Pain Interfered With Enjoyment of Life" (BPI Item 9g) at Week 24

Change from baseline in pain interference was assessed using the BPI questionnaire, specifically BPI item 9g "pain interfered with enjoyment of life" at week 24. Scores could have ranged from 0 to 10, where 0 = does not interfere to 10 = completely interferes. Negative change from baseline scores indicate improvement in "pain interfered with enjoyment of life".

Time frame: baseline and week 24

Change From Baseline in BPI Pain Severity, Relief and Interference Scores (Extension Phase)

Change from baseline in pain severity, pain relief, and pain interference was assessed using the BPI questionnaire at week 52. BPI items 3 to 6, score range 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine; BPI items 9a to 9g, score range from 0 to 10, where 0 = does not interfere and 10 = completely interferes. Negative change from baseline scores indicate improvement in pain severity and pain interference. BPI item 8, score range from 0 to 100, where 0 = no relief and 100 = complete relief. Positive change from baseline scores indicate improvement in pain relief.

Time frame: baseline and week 52

Change From Baseline in Sleep Quality (MOS Index I) at Week 4

Change from baseline in sleep quality was assessed using the sleep subscales of the MOS questionnaire, which consists of 12 items; MOS sleep scale index I (average of item 1, 3, 7, 8, 9, and 12) was assessed at week 4. Score range 0 to 100, where 0 = best sleep quality and 100 = worst sleep quality. Negative change from baseline scores indicate improvement in sleep quality.

Time frame: baseline and week 4

Change From Baseline in Sleep Quality (MOS Index II) at Week 4

Change from baseline in sleep quality was assessed using the sleep subscales of the MOS questionnaire, which consists of 12 items. MOS index II (average of items 1, 3, 4, 5, 6, 7, 8, 9, and 12) was assessed at week 4. Score range 0 to 100, where 0 = best sleep quality and 100 = worst sleep quality. Negative change from baseline scores indicate improvement in sleep quality.

Time frame: baseline and week 4

Change From Baseline in Sleep Quality (MOS Index II) at Week 24

Change from baseline in sleep quality was assessed using the sleep subscales of the MOS questionnaire, which consists of 12 items. MOS index II (average of items 1, 3, 4, 5, 6, 7, 8, 9, and 12) was assessed at week 24. Score range 0 to 100, where 0 = best sleep quality and 100 = worst sleep quality. Negative change from baseline scores indicate improvement in sleep quality.

Time frame: baseline and week 24

Change From Baseline in Sleep Quality, Sleep Disturbance at Week 24

Change from baseline in sleep quality (sleep disturbance) was assessed using the MOS questionnaire at week 24. Score range 0 to 100, where 0 = best sleep quality and 100 = worst sleep quality. Negative change from baseline scores indicate improvement in sleep disturbance.

Time frame: baseline and week 24

Change From Baseline in Sleep Quality, Snoring at Week 24

Change from baseline in sleep quality (snoring) was assessed using the MOS questionnaire at week 24. Score range 0 to 100, where 0 = best sleep quality and 100 = worst sleep quality. Negative change from baseline scores indicate improvement in snoring.

Time frame: baseline and week 24

Change From Baseline in Sleep Quality, Sleep Shortness of Breath or Headache at Week 24

Change from baseline in sleep quality (sleep shortness of breath or headache) was assessed using the MOS questionnaire at week 24. Score range 0 to 100, where 0 = best sleep quality and 100 = worst sleep quality. Negative change from baseline scores indicate improvement in sleep shortness of breath or headache.

Time frame: baseline and week 24

Change From Baseline in Sleep Quality, Sleep Adequacy at Week 24

Change from baseline in sleep quality (sleep adequacy) was assessed using the MOS questionnaire at week 24. Score range 0 to 100, where 0 = worst sleep quality and 100 = best sleep quality. Positive change from baseline scores indicate improvement in sleep adequacy.

Time frame: baseline and week 24

Change From Baseline in Sleep Quality, Sleep Somnolence at Week 24

Change from baseline in sleep quality (sleep somnolence) was assessed using the MOS questionnaire at week 24. Score range 0 to 100, where 0 = best sleep quality and 100 = worst sleep quality. Negative change from baseline scores indicate improvement in sleep somnolence.

Time frame: baseline and week 24

Change From Baseline in Sleep Quality, Sleep Quantity at Week 24

Change from baseline in sleep quality (sleep quantity) was assessed using the MOS questionnaire at week 24. Score range 0 to 100, where 0 = worst sleep quality and 100 = best sleep quality. Positive change from baseline scores indicate improvement in sleep quantity.

Time frame: baseline and week 24

Number of Subjects Indicating That They Had Optimal Sleep at Week 24

Number of subjects indicating that they had optimal sleep was assessed based on the number of hours of sleep reported on the MOS questionnaire at week 24. Optimal sleep was defined as 7 to 8 hours sleep per night.

Time frame: baseline and week 24

Change From Baseline in Sleep Quality at Week 52

Change from baseline in sleep quality was assessed using the MOS questionnaire at week 52. Score range 0 to 100. For disturbance, snoring, shortness of breath or headache, and somnolence, 0 = best sleep quality and 100 = worst sleep quality; negative change from baseline scores indicate improvement in sleep quality for these measures. For adequacy and quantity, 0 = worst sleep quality and 100 = best sleep quality; positive change from baseline scores indicate improvement in sleep quality for these measures.

Time frame: baseline and week 52

Number of Subjects Indicating Optimal Sleep at Week 52

Number of subjects who experienced optimal sleep was assessed based on the number of hours of sleep reported on the MOS questionnaire at week 52. Optimal sleep was defined as 7-8 hours sleep per night.

Time frame: week 52

Change From Baseline in Subject Diary Mean Pain Evening, Morning, and All Day Scores at Week 24

Change from baseline to week 24 in subject diary evening, morning and all day mean pain scores for pain right now, at its worst, at its least, and average. Subjects rated the severity of pain on a 10 point numeric scale, with 0 being the least pain and 10 being the most pain. Negative change from baseline scores indicate improvement in subject diary mean pain scores.

Time frame: baseline and week 24

Change From Baseline in Subject Diary Mean Pain Score for "Pain at Its Worst" From Morning to Evening at Weeks 4, 8, 12, 16, 20, and 24

Change from baseline in subject diary mean pain score "pain at its worst" from morning to evening at weeks 4, 8, 12, 16, 20, and 24. Subjects rated the severity of "pain right now" on a 10 point numeric scale, with 0 being the least pain and 10 being the most pain. Negative change from baseline scores indicate improvement in subject diary mean pain score "pain at its worst".

Time frame: baseline and weeks 4, 8, 12, 16, 20, and 24

Number of Subjects With Dose Escalation at Week 4 (ITT Population)

The number of subjects with dose increase in study medication was assessed at week 4.

Time frame: week 4

Number of Subjects With Dose Escalation at Week 24 (ITT Population)

The number of subjects with dose increase in study medication was assessed at week 24.

Time frame: week 24

Change From Baseline in Quality of Life (QoL) "Bodily Pain" at Week 4

Change from baseline in QoL was assessed using the Short Form (SF)-36 QoL questionnaire, specifically the SF-36 bodily pain index. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in bodily pain.

Time frame: baseline and week 4

Change From Baseline in QoL "General Health Perceptions" at Week 4

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 general health perceptions score at week 4. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in general health perceptions.

Time frame: baseline and week 4

Change From Baseline in QoL "Health Transition" at Week 4

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 health transition score at week 4. Scores could range from 0 to 100, with higher scores indicating a better QoL. Positive change from baseline scores indicate improvement in health transition.

Time frame: baseline and week 4

Change From Baseline in QoL "Mental Health" at Week 4

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 mental health score at week 4. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in mental health score.

Time frame: baseline and week 4

Change From Baseline in QoL "Physical Functioning" at Week 4

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 physical functioning score at week 4. Scores could range from 0 to 100, with high scores indicating a better QoL. Positive change from baseline scores indicate improvement in physical functioning.

Time frame: baseline and week 4

Change From Baseline in QoL "Role Emotional" at Week 4

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 "role emotional" score at week 4. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in "role emotional".

Time frame: baseline and week 4

Change From Baseline in QoL "Role Physical" at Week 4

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 role physical score at week 4. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in role physical.

Time frame: baseline and week 4

Change From Baseline in QoL "Social Functioning" at Week 4

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 social functioning score at week 4. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in social functioning.

Time frame: baseline and week 4

Change From Baseline in QoL "Vitality" at Week 4

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 vitality score at week 4. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in vitality.

Time frame: baseline and week 4

Change From Baseline in QoL "Bodily Pain" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 bodily pain index score at week 24. Score could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in bodily pain.

Time frame: baseline and week 24

Change From Baseline in QoL "General Health Perceptions" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 general health perceptions at week 24. Scores could range from 0 to 100 with a higher score indicating a better QoL. Positive change from baseline scores indicate improvement in health perceptions.

Time frame: baseline and week 24

Change From Baseline in QoL "Health Transition" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 health transition score at week 24. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in health transition.

Time frame: baseline and week 24

Change From Baseline in QoL "Mental Health" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 mental health score at week 24. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline score indicates improvement in mental health.

Time frame: baseline and week 24

Change From Baseline in QoL "Physical Functioning" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 physical functioning score at week 24. Scores could range from 0 to 100, with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in physical functioning.

Time frame: baseline and week 24

Change From Baseline in QoL "Role Emotional" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 "role emotional" score at week 24. Scores could range from 0 to 100 with a higher score indicating a better QoL. Positive change from baseline scores indicate improvement in "role emotional."

Time frame: baseline and week 24

Change From Baseline in QoL "Role Physical" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 role physical score at week 24. Scores could range from 0 to 100 with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in role physical.

Time frame: baseline and week 24

Change From Baseline in QoL "Social Functioning" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 social functioning score at week 24. Scores could range from 0 to 100 with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in social functioning.

Time frame: baseline and week 24

Change From Baseline in QoL "Vitality" at Week 24

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire, specifically SF-36 vitality score at week 24. Scores could range from 0 to 100 with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in vitality.

Time frame: baseline and week 24

Change From Baseline in QoL at Week 52

Change from baseline in QoL was assessed using the SF-36 QoL questionnaire at week 52. Scores could range from 0 to 100 with a high score indicating a better QoL. Positive change from baseline scores indicate improvement in QoL.

Time frame: baseline and week 52

Clinical Global Assessment of Efficacy

Overall clinical efficacy was assessed by the Investigator using the following global ratings: very good, good, moderate, poor, or very poor, at weeks 4, 24, and 52.

Time frame: weeks 4, 24, and 52

Change in Dose of Study Treatment

Number of subjects with change in dose of study treatment was assessed at weeks 4, 24, and 52.

Time frame: weeks 4, 24, and 52

Change in Dose of Study Treatment During Titration Phase (First 4 Weeks of Study) and Overall Treatment Phase I (First 24 Weeks of Study)

Number of subejcts with change in dose of study treatment was assessed and stratified by time on study, at least 4 weeks versus dropped out at highest dose before week 4, at weeks 4 and 24.

Time frame: weeks 4 and 24

Number of Drop-outs

Number of drop-outs according to reasons for drop-out and due to inefficacy at maximal dosage was assessed at weeks 24 and 52.

Time frame: baseline to week 24 (core); week 24 to week 52 (extension)

Number of Days With add-on Pain Medication

Number of days with add-on pain medication during the first 24 weeks of the study was assessed at week 24.

Time frame: week 24

Amount of add-on Pain Medication

Total amount of add-on pain medication (paracetamol) for the first 24 weeks was assessed at week 24.

Time frame: 24 weeks

Mode and Convenience of Drug Intake.

Subjects filled out a questionnaire based on the mode and convenience of drug intake and could rate their responses as very convenient, convenient, neither convenient or inconvenient, inconvenient, and very inconvenient.

Time frame: weeks 4, 24, and 52

Resource Utilization of Pain Management

Resource utilization was defined as the number of additional visits including additional telephone visits during the treatment period. This was assessed at week 24.

Time frame: week 24