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Efficacy and Safety of a Once-Daily Morphine Formulation in Chronic, Moderate-to-Severe Osteoarthritis Pain

Results from a Randomized, Placebo-Controlled, Double-Blind Trial and an Open-Label Extension Trial

      Abstract

      A randomized, 4-week, double-blind trial followed by an open-label extension trial assessed the efficacy and safety of a once-daily, extended-release morphine formulation (Avinza™ (previously referred to as Morphelan™)) in 295 patients with chronic, moderate-to-severe osteoarthritis pain who had failed to obtain adequate pain relief with NSAIDs and acetaminophen. Participants received one of four treatments: Avinza 30 mg once daily (QAM or QPM), MS Contin® 15 mg twice daily, or placebo twice daily. Patients (n =181) received Avinza QAM or QPM during the 26-week open-label extension trial and could increase their dose to optimize pain control. Avinza and MS Contin reduced pain and improved several sleep measures versus placebo. Analgesic efficacy was comparable between Avinza and MS Contin; however, Avinza QAM demonstrated greater improvements in overall quality of sleep. The most common adverse events were constipation and nausea. The majority of AEs occurred at a similar incidence among the active treatment groups.

      Keywords

      Introduction

      Osteoarthritis (OA), the most common form of arthritis, causes considerable disability and morbidity in an estimated 16 million individuals affected by the disease in the United States.
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      The role of opioids in the treatment of osteoarthritis.
      Therefore, the use of opioid analgesics is the logical next step in the treatment of OA.
      The role of opioids in the treatment of cancer pain is well established, and indications for their use in chronic, nonmalignant pain are growing. Results of recent trials (placebo-controlled and open-label) support the efficacy of opioid therapy for chronic, nonmalignant pain.
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      Avinza™ (morphine sulfate extended-release capsules (previously referred to as Morphelan™); Elan Pharmaceuticals Research Corp., Gainesville, GA) is a new, dual-release morphine formulation designed specifically for once-daily administration. Avinza contains both immediate- and extended-release components. At steady-state, a single daily dose provides 24-hr therapeutic morphine levels that are comparable to those obtained by administering immediate-release morphine solution 10 mg every four hr for a 24-hr period with fewer peak-to-trough fluctuations.

      Eliot L, Loewen G, Butler J, Tembe E, Devane J. Steady-state pharmacokinetic comparison of Morphelan™ ROER™ (morphine sulfate rapid onset extended release) once-a-day and morphine oral solution administered q4h around-the-clock in healthy volunteers [abstract 205]. Presented at American Academy of Pain Medicine 17th Annual Meeting, Miami, FL. February 15-18, 2001.

      In addition, a steady-state pharmacokinetic study that compared once-daily doses of Avinza to twice-daily MS Contin® (MSC; morphine sulfate controlled-release; Purdue Frederick, Norwalk, CT) found that Avinza produced lower maximum and higher minimum trough morphine concentrations resulting in a reduction in the peak-to-trough fluctuation throughout a 24-hr period than MSC.
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      Steady-state pharmacokinetic comparison of a new extended-release, once-daily morphine sulfate formulation, Morphelan™, and a twice-daily controlled-release morphine formulation in patients with chronic moderate-to-severe pain.
      These results indicate that Avinza is a true once-daily morphine formulation.
      Based upon these findings, two clinical trials of Avinza were conducted: a double-blind trial and an open-label extension trial. The double-blind trial compared efficacy and safety of Avinza to MSC and placebo over a 4-week period in patients with chronic moderate-to-severe OA pain of the hip and/or knee. The open-label extension trial examined the efficacy and tolerability of Avinza over an additional 26 weeks.

      Methods

      Subjects

      Inclusion criteria: patients had to be at least 40 years of age and have both a clinical diagnosis and grade II-IV radiographic evidence of OA of the hip and/or knee; have had prior suboptimal analgesic response to treatment with NSAIDs and acetaminophen or had previously received intermittent opioid analgesic therapy; and have a baseline visual analog scale (VAS) pain intensity score of ≥40 mm in the index joint.
      Exclusion criteria: patients with serious concomitant disease, chronic condition(s) that might interfere with the assessment of pain and other symptoms of OA, prior disease at the index joint, surgery or the likelihood of requiring a surgical procedure of the index joint(s) during the trial; diseases other than OA not well managed with treatment; weight ≤100 lbs; oral, intramuscular, intravenous, intra-articular, or soft-tissue administration of steroids within 1 month of study drug administration (two months, if at index knee or hip joint); intra-articular viscosupplementation (in the index joint) within six months of trial treatment; opioid therapy for longer than three weeks prior to baseline; any history of substance abuse within two years prior to screening; and history of clinically significant intolerance to opioids or any known hypersensitivity to morphine or other opioid analgesics.

      Trial Design

      Institutional review board approval and patient written informed consent were obtained prior to screening. The trial was conducted in accordance with the Declaration of Helsinki. The double-blind trial was a 4-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel trial. Eligible participants entered a washout period of up to seven days and were subsequently randomized to one of four treatments: Avinza 30 mg once daily in the morning (Avinza QAM), Avinza 30 mg once daily in the evening (Avinza QPM), MSC 15 mg twice daily (MSC), or placebo twice daily. Placebo Avinza and placebo MSC matched the appearance of the respective active treatments. Avinza capsules and encapsulated MSC tablets did not look identical; therefore, to maintain the study blind, all patients consumed two capsules (one each representing Avinza and MSC) every morning and evening (Table 1). No dosage adjustments were permitted, and patients unable to tolerate treatment medications were dropped from the trial.
      Table 1Treatment Administration: Double-Blind Trial
      Treatment GroupMorning DoseEvening DoseTotal Daily Morphine Dose
      Avinza QAM30 mg AvinzaPlacebo Avinza
      Placebo Avinza was designed to match the appearance of active Avinza.
      30 mg
      Placebo MSCPlacebo MSC
      Placebo MSC was designed to match the appearance of active MSC.
      Avinza QPMPlacebo Avinza30 mg Avinza30 mg
      Placebo MSCPlacebo MSC
      MSC15 mg MSC15 mg MSC30 mg
      Placebo AvinzaPlacebo Avinza
      PlaceboPlacebo AvinzaPlacebo AvinzaNone
      Placebo MSCPlacebo MSC
      a Placebo Avinza was designed to match the appearance of active Avinza.
      b Placebo MSC was designed to match the appearance of active MSC.
      The primary objectives of the double-blind, four-week trial were to: 1) determine the analgesic efficacy of Avinza administered once daily in comparison to placebo, and 2) compare the safety of once-daily Avinza and twice-daily MSC. The effects of treatment on physical functioning, stiffness, and several sleep measures were evaluated as secondary efficacy measures. Comparison of the analgesic efficacy of Avinza QAM, Avinza QPM, and MSC was a secondary objective of the double-blind trial.
      Patients who successfully completed the double-blind trial were eligible to participate in a 26-week, open-label extension trial. Eligible patients who elected to participate in the open-label trial were assigned to receive Avinza administered QAM or QPM; assignment was based on the patient's randomization number in the double-blind trial (i.e., even number received Avinza QAM and odd number received Avinza QPM). If optimal pain relief in the open-label trial was not achieved, the Avinza dose was allowed to be increased. Patients unable to tolerate Avinza 30 mg were discontinued from the trial. Although efficacy was assessed throughout the course of the open-label trial, safety evaluation was the primary objective.

      Efficacy Assessments

      Efficacy assessments were performed throughout the course of both trials: at baseline and weekly thereafter, up to Week 4 in the double-blind trial and on Weeks 5, 8, 12, 18, 24, and 30 in the open-label trial. Patients visited the clinic for their efficacy assessments. An effort was made to have the patients complete their assessments at the same time of day; however, each patient chose the time of day to visit the clinic. Week 4 efficacy data from the double-blind trial were used as baseline for efficacy comparisons in the open-label trial.
      Analgesia was evaluated by the Western Ontario and McMaster Universities (WOMAC) OA Index Pain Visual Analogue Scale (VAS) subscale and Overall Arthritis Pain Intensity scores. The WOMAC OA Index was also utilized to assess other OA-related symptoms such as physical functioning and stiffness.
      • Bellamy N.
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      • Stitt L.W.
      Validation study of WOMAC a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
      The WOMAC OA Index is a comprehensive, well-validated, self-administered questionnaire consisting of subsets of questions that are answered by the patients using a 100-mm VAS. The WOMAC OA Index Pain consists of five questions (total score: 0–500 mm) relating to overall OA pain and includes assessing pain at rest, while walking on a flat surface, going up or down stairs, at night in bed, and standing. The WOMAC Physical Function Index is a series of 17 questions (total score: 0–1700 mm) that assess an arthritic patient's difficulties in performing activities of daily living. The questions include, but are not limited to, walking on a flat surface, standing or sitting, climbing stairs, getting in and out of bed or bath, and ability to perform domestic duties (i.e., heavy and light). The WOMAC Stiffness Index evaluates morning and afternoon stiffness (total score: 0–200 mm). The Overall Arthritis Pain Intensity estimates the amount of pain that the patient experienced, on average, in the study joint since last visit (total score: 0–100 mm).
      Effects of treatment on sleep were examined by a questionnaire that addressed trouble falling asleep, need for sleep medication, frequency of awakening during the night or morning due to pain, overall quality of sleep, and the number of hours (duration) of sleep each night. Assessments of sleep were recorded on a 100-mm VAS, with the exception of duration of sleep, which was recorded on a 12-point scale.

      Safety Assessments

      Safety was assessed throughout both trials by recording the incidence, prevalence, severity, and relatedness of adverse events (AEs), and assessing changes from baseline in vital signs, laboratory tests, and physical examinations.

      Concomitant Medications

      The use of analgesic preparations other than cardiovascular prophylactic doses of aspirin (up to 325 mg/day) and acetaminophen for non-OA symptomatology (up to 2000 mg/day for a maximum of 3 consecutive days) was prohibited in the double-blind trial. Acetaminophen had to be stopped 24 hours prior to efficacy assessments. Acetaminophen for relief of OA symptoms was allowed up to 4000 mg/day in the open-label trial. Inhaled and topical steroids were permitted during the double-blind and open-label trials for treatment of respiratory and dermatological disorders, respectively. Topical analgesics and physical therapy for the treatment of OA were allowed during the open-label trial.
      Due to the allowance of concomitant NSAID and acetaminophen use in the open-label extension trial, a subset analyses was conducted to determine the impact of concomitant use of NSAIDs and acetaminophen on efficacy by comparing the following two groups: first, a group that included all patient efficacy data and, second, a group that excluded a patient's efficacy data when NSAIDs and/or acetamin- ophen were used concomitantly during the time period that was being assessed. An efficacy measurement was excluded if a patient received an NSAID and/or acetaminophen for equal to or greater than three or more days during any interval between efficacy assessments. Descriptive statistics were reported.

      Statistical Analyses

      Efficacy and safety analyses for both trials were performed on all patients who received at least one dose of study medication. Primary efficacy measures in the double-blind trial were analyzed using repeated measures analysis of covariance (ANCOVA) to determine overall differences among treatment groups throughout the duration of the double-blind trial. The secondary efficacy measures in the double-blind and open-label trials were analyzed using an ANCOVA. In all ANCOVAs, the baseline value of the variable analyzed was used as the covariate. Analyses of primary efficacy measures were based on percent change from baseline values; secondary measures were based on algebraic change from baseline values. A statistically significant difference was defined as the two-sided p ≤ 0.05, and pair-wise comparisons were only conducted if the overall ANCOVA was significant. A series of post-hoc Chi-square tests were conducted to identify differences in the incidence of the most common AEs. This was accomplished by using all possible pair-wise comparisons among the three active treatments in the double-blind trial and the two active treatments in the open-label extension trial. Shifts in laboratory test results from baseline, relative to the normal range, were analyzed with Stuart-Maxwell Chi-square.

      Results

      Double-Blind Trial

      A total of 295 patients was randomized and received one of four treatments in the double-blind trial: Avinza QAM (n = 73), Avinza QPM (n = 73), MSC twice daily (n = 76), or placebo (n = 73). There were no statistical differences in patient demographics and baseline characteristics among treatment groups with respect to age, gender, or race (Table 2). One hundred seventy-one patients (58%) were opioid-naive upon entering this trial, whereas 124 patients (42%) had been previously treated with opioids. The most common concomitant medications administered during this trial were: antihypertensives (n = 172, 58%), antidepressants (n = 68, 23%), and aspirin (n = 48, 16%). Acetaminophen was used by 15 patients (5.1%) during the trial. No discernable differences in concomitant medications were observed among treatment groups. A total of 184 patients (62%) completed the double-blind trial with rates of withdrawal among treatment groups being similar (Figure 1).
      Table 2Patient Demographics and Baseline Characteristics: Double-Blind Trial
      CharacteristicPlacebo (n = 73)Avinza QAM (n = 73)Avinza QPM (n = 73)MSC (n = 76)
      Mean age ± SD, y61.9 ± 10.762.6 ± 9.563.1 ± 11.161.9 ± 10.4
      Gender, n (%)
      Male22 (30%)30 (41%)31 (42%)28 (37%)
      Female51 (70%)43 (59%)42 (58%)48 (63%)
      Race, n (%)
      White58 (80%)63 (86%)60 (82%)68 (90%)
      Black14 (19%)7 (10%)11 (15%)8 (11%)
      Other1 (1%)3 (4%)2 (2%)0 (0%)
      WOMAC OA Index Pain (0–500 mm)
      Mean score ± SD317 ± 102313 ± 107326 ± 99.7322 ± 109
      Overall Arthritis Pain Intensity (0–100 mm)
      Mean score ± SD78.3 ± 13.976.5 ± 18.579.3 ± 15.578.8 ± 15.7
      WOMAC Physical Function (0–1700 mm)
      Mean score ± SD1121 ± 3131102 ± 3281126 ± 3281112 ± 343
      WOMAC Stiffness (0–200 mm)
      Mean score ± SD141 ± 37.9141 ± 44.0142 ± 38.9142 ± 45.0
      Abbreviations: SD, standard deviation; WOMAC, Western Ontario and McMaster Universities; OA, osteoarthritis.
      Figure thumbnail gr1
      Fig. 1Patient disposition in the double-blind trial.

      Clinical Efficacy: Double-Blind Trial

      WOMAC OA Index Pain

      Overall, a statistically significant reduction in pain from baseline was demonstrated by Avinza QAM (17%), QPM (20%), and MSC twice daily (18%), as compared to placebo (4%) (Table 3). Decreases in pain intensity were apparent in all treatment groups by Week 1 and further reductions in pain throughout the 4-week period were observed as compared to baseline. (Table 3). Average maximum reductions in pain intensity over the course of the trial ranged from 65 to 77 mm, based on a total score of 500 mm, in patients treated with Avinza (QAM and QPM) and MSC twice daily.
      Table 3Analgesic Efficacy: Double-Blind Trial
      Efficacy MeasurePlaceboAvinza QAMAvinza QPMMSC
      WOMAC OA Index Pain
      Overall−4.35 ± 4.3−17.2 ± 4.2
      Statisitically significant difference over placebo (p ≤ 0.05).
      −20.1 ± 4.2
      Statisitically significant difference over placebo (p ≤ 0.05).
      −18.4 ± 4.2
      Statisitically significant difference over placebo (p ≤ 0.05).
      Week 1−0.53 ± 4.4−13.3 ± 4.3−16.3 ± 4.3−14.5 ± 4.3
      Week 2−3.99 ± 4.4−16.8 ± 4.3−19.8 ± 4.3−18.0 ± 4.3
      Week 3−6.42 ± 4.4−19.2 ± 4.3−22.2 ± 4.3−20.4 ± 4.3
      Week 4−6.48 ± 4.4−19.3 ± 4.3−22.2 ± 4.3−20.5 ± 4.3
      Overall Arthritis Pain Intensity
      Overall−13.7 ± 3.4−25.8 ± 3.4−21.9 ± 3.4−22.3 ± 3.3
      Week 1−11.0 ± 3.5−23.1 ± 3.5−19.2 ± 3.5−19.5 ± 3.5
      Week 2−12.8 ± 3.5−24.9 ± 3.5−21.0 ± 3.5−21.3 ± 3.5
      Week 3−16.5 ± 3.5−28.6 ± 3.5−24.7 ± 3.5−25.0 ± 3.5
      Week 4−14.6 ± 3.5−26.7 ± 3.5−22.8 ± 3.5−23.1 ± 3.5
      Data are presented as % change from baseline (Least Squares Mean ± SE). Abbreviations: WOMAC, Western Ontario and McMaster Universities; OA, osteoarthritis. WOMAC OA Index Pain was scored on a 500-mm scale (0 = no pain, 100 = extreme pain). Overall Arthritis Pain Intensity was assessed on a scale of 0–100 mm (0 = no pain, 100 = extreme pain). Statistical differences between treatment groups were determined for overall results only, not the individual weeks. Negative values indicate a reduction in pain intensity.
      a Statisitically significant difference over placebo (p ≤ 0.05).

      Overall Arthritis Pain Intensity

      Avinza QAM (26%), Avinza QPM (22%), and MSC twice daily (22%) reduced overall arthritis pain intensity as compared with placebo (14%), but these differences were not statistically significant (Table 3). Therefore, post-hoc, pair-wise comparisons were not made. Pain intensity, as measured on a 100-mm scale, was reduced by approximately 20 to 23 mm in the Avinza (QAM and QPM) and MSC treatment groups versus 14 mm in patients administered placebo. Decreases in pain intensity were apparent in all treatment groups by Week 1 and reductions in pain intensity throughout the 4-week period were observed as compared to baseline.

      WOMAC Functional Assessments

      Statistically significant differences in physical function were not achieved among the treatment groups, but strong trends (0.05 < p ≤ 0.10) towards an improvement in physical function were observed for the active treatments (Avinza and MSC) as compared to placebo (Table 4). Mean improvements in physical function (total score: 0–1700 mm) at Week 4 were as follows: Avinza QAM (207 mm, 18%), Avinza QPM (205 mm, 19%), MSC (181 mm, 14%), and placebo (97 mm, 8%). Reductions in stiffness were also observed for all treatment groups, but the changes were not large enough to achieve statistical significance (Table 4).
      Table 4Secondary Efficacy Measures: Double-Blind Trial
      WOMAC OA ScoresANCOVA P-ValuesPlaceboAvinza QAMAvinza QPMMSC
      Stiffness
      Week 10.298−6.13 ± 5.70−19.4 ± 5.26−16.4 ± 4.65−15.2 ± 5.39
      Week 20.250−11.0 ± 5.37−22.8 ± 5.32−25.5 ± 5.34−21.5 ± 5.73
      Week 30.377−13.0 ± 6.02−22.6 ± 5.49−27.0 ± 5.61−20.8 ± 5.8
      Week 40.751−15.7 ± 6.05−23.6 ± 5.58−23.5 ± 5.87−20.5 ± 5.56
      Physical Function
      Week 10.070−44.1 ± 35.7−164 ± 43.3−148 ± 35.3−146 ± 33.0
      Week 20.100−73.4 ± 37.8−192 ± 41.9−189 ± 39.6−166 ± 39.0
      Week 30.085−88.3 ± 44.7−223 ± 42.8−216 ± 42.4−187 ± 41.5
      Week 40.178−96.7 ± 43.0−207 ± 40.7−204 ± 42.6−181 ± 40.1
      Data are presented as change (mm) from baseline (Mean ± SE). Abbreviations: WOMAC, Western Ontario and McMaster Universities; OA, osteoarthritis. WOMAC OA Stiffness (0–200 mm: 0 = no stiffness and 200 = extreme stiffness) and WOMAC OA Physical Function (0–1700 mm; 0 = no difficulty and 1700 = extreme physical functioning difficulty). Negative values indicate a reduction in stiffness and improvement in physical functioning. No statistically significant differences were observed between treatment groups.

      Sleep Measures

      Active treatment groups (Avinza and MSC) provided greater improvements in all sleep measures than did placebo (Figure 2). Avinza QAM provided a statistically significant improvement versus placebo for the following: overall quality of sleep (Weeks 1, 2, 4), less need for sleep medication (Weeks 1, 3, 4), increased hours of sleep (Week 1), and less trouble falling asleep because of pain (Weeks 3, 4). Avinza QPM demonstrated statistically significant improvements in sleep measures versus placebo for the following: overall quality of sleep (Weeks 1, 2, 4), and duration of sleep each night (Week 1). Relative to placebo, MSC provided a statistically significant improvement in overall quality of sleep (Week 2) and patients had less trouble falling asleep because of pain (Weeks 3, 4). Patients receiving Avinza QAM demonstrated a statistically significant improvement in overall quality of sleep compared to MSC (Weeks 1 and 4). No statistical differences were observed between Avinza QAM and QPM.
      Figure thumbnail gr2
      Fig. 2Sleep measures in the double-blind trial. Data are presented as Mean ± SE scored on a 100-mm VAS scale (0–100mm), with the exception of duration of sleep each night which is scored on a 12-pt scale (1 to 12 hr). For quality of sleep each night, positive values indicate an improvement. For trouble falling asleep due to Pain, Need for Sleep Medication, and Awakenings During the Night and Morning due to Pain, negative values indicate an improvement. *Statistically significant (p ≤ 0.05) difference versus placebo. Statistically significant (p ≤ 0.05) difference versus MSC twice daily.

      Safety: Double-Blind Trial

      A total of 197 patients (67%) experienced at least one AE during this trial. Constipation and nausea were reported most frequently (Table 5). With the exception of diarrhea and headache, the incidence of commonly reported (>5% in any treatment group) AEs was higher in all active treatment groups than in the placebo group. Among the 33 pair-wise comparisons the only significant differences observed were a higher rate of constipation with Avinza QAM (49%) versus MSC (29%), a higher rate of vomiting with Avinza QPM (16%) versus Avinza QAM (6%), and a higher rate of asthenia with MSC (9%) versus Avinza QAM (1%). Fifty-eight (20%) patients discontinued the trial prematurely because of an AE: 17, 18, 18 and 5 patients in the Avinza QAM, QPM, MSC and placebo group, respectively. The primary AEs leading to withdrawal in the active treatment groups were nausea (7–14%) and constipation (7–10%). Six patients experienced a serious AE but only one (hospitalized for constipation) was thought to be possibly related to study drug (Avinza QPM); this patient withdrew from the trial due to this event. No clinically relevant changes occurred in vital signs, ECGs, laboratory parameters, or physical examination.
      Table 5AEs Reported in 5% of Patients in Any Treatment Group: Double-Blind Trial
      AE, n (%)Avinza QAM (n = 73)Avinza QPM (n = 73)MSC (n = 76)Placebo (n = 73)
      Constipation36 (49%)29 (40%)22 (29%)a3 (4%)
      Nausea15 (21%)23 (32%)20 (26%)7 (10%)
      Somnolence12 (16%)9 (12%)9 (12%)0 (0%)
      Dizziness7 (10%)7 (10%)9 (12%)1 (1%)
      Vomiting4 (6%)12 (16%)a6 (8%)1 (1%)
      Headache4 (6%)3 (4%)5 (7%)4 (6%)
      Pruritus4 (6%)7 (10%)2 (3%)0 (0%)
      Asthenia1 (1%)4 (6%)7 (9%)a0 (0%)
      Dry mouth4 (6%)3 (4%)2 (3%)1 (1%)
      Pain2 (3%)3 (4%)4 (5%)1 (1%)
      Diarrhea0 (0%)3 (4%)1 (1%)4 (6%)
      aIndicates a significant difference from Avinza QAM by post hoc Chi-square test.
      Comparison only conducted among active treatment groups.

      Open-Label Extension Trial

      Of the 184 patients who completed the double-blind trial, 181 patients entered the open-label trial and received Avinza QAM (n = 91) or QPM (n = 90). Of these patients, 50 (28%) had taken placebo and 131 (72%) had taken Avinza or MSC in the double-blind trial. Patient demographics and baseline characteristics were comparable between treatment groups with respect to age, gender, and race. Antihypertensives (n = 101, 56%), NSAIDs (n = 46, 25%), antidepressants (n = 44, 24%), antihistamines (n = 34, 19%), and aspirin (n = 32, 18%) were the most commonly used concomitant medications. Acetaminophen use was lower (n = 26, 14%). Eighty-six patients (48%) completed the 26-week open-label trial, with similar rates of withdrawal between the Avinza QAM and QPM groups (Figure 3). Of these completers, 42 (49%) remained on the initial 30 mg Avinza dose throughout the open-label trial. Seven patients increased their daily dose to 120 mg, the highest dose administered during the trial.
      Figure thumbnail gr3
      Fig. 3Patient disposition in the open-label trial.
      Of the 131 patients who were receiving morphine treatment (Avinza and MSC) in the double-blind trial, 125 (95%) patients did not increase their morphine dose during the first week of the trial. In contrast, all patients who received placebo during the double-blind trial had to increase their daily Avinza dose to at least 30 mg in the first week. The mean dose at Week 30 was 49 mg (median: 30 mg). The mean duration of therapy during the open-label trial was 113 days (range: 4–235, median: 121) for the QAM group and 115 days (range: 2–217, median: 170) for the QPM group.

      Clinical Efficacy: Open-Label Extension Trial

      Statistically significant reductions in pain intensity and stiffness and improvements in physical functioning from Week 4 were observed within the first week (Week 5) of the open-label extension trial and at all subsequent weeks (Figure 4). Mean clinical improvements through Week 12 corresponded with an increase in the mean daily Avinza dose. Subsequently (Weeks 12 through 30), pain intensity, physical function, and stiffness remained stable, which was consistent with a stable average daily dose of Avinza (approximately 50 mg/day) over this time period. Improvements were observed for all sleep measures at Week 5 in comparison to Week 4; however, statistically significant improvements were not observed for all sleep measures at all time points (Table 6).
      Figure thumbnail gr4
      Fig. 4Efficacy in the open-label trial. Efficacy data are presented as Mean changes ± SE from baseline (Week 4). Dose data presented as Mean ± SE, which represents the dose at the time of the efficacy assessments. *Statistically significant differences in efficacy assessments from baseline (Week 4) for both Avinza QAM and QPM (p ≤ 0.05). WOMAC OA Index Pain (0–500 mm), Overall Arthritis Pain Intensity (0–100 mm) and WOMAC Physical Function (0–1,700 mm), WOMAC Stiffness (0–200 mm).
      Table 6Sleep Measures: Open-Label Trial
      Week
      Sleep MeasuresAvinza5812182430
      Quality of Sleep
      For Quality of Sleep and Hours of Sleep Each Night positive values indicate an improvement.
      (mm)
      QAM QPM6.1 ± 2.4 5.7 ± 2.5
      Statistically significant difference from baseline (p ≤ 0.05).
      11.1 ± 2.7
      Statistically significant difference from baseline (p ≤ 0.05).
      9.9 ± 2.7
      Statistically significant difference from baseline (p ≤ 0.05).
      7.7 ± 2.8 6.5 ± 2.98.4 ± 3.0
      Statistically significant difference from baseline (p ≤ 0.05).
      2.9 ± 3.1
      13.9 ± 3.3
      Statistically significant difference from baseline (p ≤ 0.05).
      6.3 ± 3.2
      9.1 ± 3.3 −0.9 ± 3.3
      Trouble Falling Asleep
      For Trouble Falling Asleep due to Pain, Need for Sleep Medication, and Awakenings During the Night and Morning due to pain. Negative values indicate an improvement.
      (mm)
      QAM QPM−6.1 ± 2.3
      Statistically significant difference from baseline (p ≤ 0.05).
      −9.7 ± 2.3
      Statistically significant difference from baseline (p ≤ 0.05).
      −6.4 ± 2.5
      Statistically significant difference from baseline (p ≤ 0.05).
      −8.7 ± 2.5
      Statistically significant difference from baseline (p ≤ 0.05).
      −9.6 ± 2.6
      Statistically significant difference from baseline (p ≤ 0.05).
      −11.7 ± 2.7
      Statistically significant difference from baseline (p ≤ 0.05).
      −10.8 ± 2.7
      Statistically significant difference from baseline (p ≤ 0.05).
      −11.7 ± 2.8
      Statistically significant difference from baseline (p ≤ 0.05).
      −12.2 ± 2.9
      Statistically significant difference from baseline (p ≤ 0.05).
      −12.6 ± 2.9
      Statistically significant difference from baseline (p ≤ 0.05).
      −8.9 ± 3.0
      Statistically significant difference from baseline (p ≤ 0.05).
      −8.8 ± 2.9
      Need for Sleep Medication
      For Trouble Falling Asleep due to Pain, Need for Sleep Medication, and Awakenings During the Night and Morning due to pain. Negative values indicate an improvement.
      (mm)
      QAM QPM−0.8 ± 2.0 −1.5 ± 2.1−2.6 ± 2.2 −5.5 ± 2.3
      Statistically significant difference from baseline (p ≤ 0.05).
      −4.7 ± 2.4 −4.0 ± 2.40.5 ± 2.5 −4.0 ± 2.50.0 ± 2.7 2.2 ± 2.61.0 ± 2.7 −2.9 ± 2.7
      Awakening in the Morning due to Pain
      For Trouble Falling Asleep due to Pain, Need for Sleep Medication, and Awakenings During the Night and Morning due to pain. Negative values indicate an improvement.
      (mm)
      QAM QPM−5.3 ± 2.4
      Statistically significant difference from baseline (p ≤ 0.05).
      −8.4 ± 2.5
      Statistically significant difference from baseline (p ≤ 0.05).
      −5.4 ± 2.6
      Statistically significant difference from baseline (p ≤ 0.05).
      −10.0 ± 2.7
      Statistically significant difference from baseline (p ≤ 0.05).
      −5.4 ± 2.7 −12.2 ± 2.9
      Statistically significant difference from baseline (p ≤ 0.05).
      −6.4 ± 2.9
      Statistically significant difference from baseline (p ≤ 0.05).
      −11.6 ± 2.9
      Statistically significant difference from baseline (p ≤ 0.05).
      −10.3 ± 3.1
      Statistically significant difference from baseline (p ≤ 0.05).
      −10.2 ± 3.0
      Statistically significant difference from baseline (p ≤ 0.05).
      −8.7 ± 3.1
      Statistically significant difference from baseline (p ≤ 0.05).
      −6.2 ± 3.1
      Awakening in the Night due to Pain
      For Trouble Falling Asleep due to Pain, Need for Sleep Medication, and Awakenings During the Night and Morning due to pain. Negative values indicate an improvement.
      (mm)
      QAM QPM−4.9 ± 2.5
      Statistically significant difference from baseline (p ≤ 0.05).
      −8.3 ± 2.5
      Statistically significant difference from baseline (p ≤ 0.05).
      −5.7 ± 2.6
      Statistically significant difference from baseline (p ≤ 0.05).
      −9.8 ± 2.7
      Statistically significant difference from baseline (p ≤ 0.05).
      −4.7 ± 2.8 −10.7 ± 2.9
      Statistically significant difference from baseline (p ≤ 0.05).
      −5.0 ± 2.9
      Statistically significant difference from baseline (p ≤ 0.05).
      10.2 ± 2.9
      Statistically significant difference from baseline (p ≤ 0.05).
      −7.3 ± 3.1
      Statistically significant difference from baseline (p ≤ 0.05).
      −8.1 ± 3.0
      −4.8 ± 3.1 −9.7 ± 3.1
      Hours of Sleep Each Night
      For Quality of Sleep and Hours of Sleep Each Night positive values indicate an improvement.
      (hr)
      QAM QPM0.1 ± 0.1 0.2 ± 0.1
      Statistically significant difference from baseline (p ≤ 0.05).
      0.3 ± 0.1
      Statistically significant difference from baseline (p ≤ 0.05).
      0.2 ± 0.1
      Statistically significant difference from baseline (p ≤ 0.05).
      0.3 ± 0.1
      Statistically significant difference from baseline (p ≤ 0.05).
      0.3 ± 0.1
      Statistically significant difference from baseline (p ≤ 0.05).
      0.2 ± 0.1
      Statistically significant difference from baseline (p ≤ 0.05).
      0.2 ± 0.1
      0.2 ± 0.1
      Statistically significant difference from baseline (p ≤ 0.05).
      0.1 ± 0.1
      0.2 ± 0.1 0.2 ± 0.1
      Data are presented as change (mean ± SE) from baseline (Week 4).
      Hours of sleep each night were assessed on a 12-point scale (1–12 hr), Quality of Sleep (0 = very poor, 100 = excellent) and all other sleep measures were scored on a VAS of 0–100 mm (0 = never, 100 = always).
      a Statistically significant difference from baseline (p ≤ 0.05).
      b For Quality of Sleep and Hours of Sleep Each Night positive values indicate an improvement.
      c For Trouble Falling Asleep due to Pain, Need for Sleep Medication, and Awakenings During the Night and Morning due to pain. Negative values indicate an improvement.
      The subset analysis conducted to determine the effects of concomitant NSAID and acetaminophen use on analgesia demonstrated comparable pain intensity scores between the intent-to-treat group and the subset group that excluded efficacy assessments potentially confounded by NSAID and/or acetaminophen use (Table 7). Of the 181 patients who entered the open-label extension trial, 28 (15%) patients were excluded entirely from the subset analysis due to concomitant NSAID and/or acetaminophen use.
      Table 7Subset Analysis: Effects of Concomitant NSAID and Acetaminophen Use in the Open-label Trial
      Week
      Pain IntensityGroup45812182430
      WOMAC OA Pain Intensity (mm)ITT240 ± 133203 ± 132178 ± 126172 ± 125170 ± 124158 ± 124157 ± 123
      Subset235 ± 130208 ± 131172 ± 126161 ± 119173 ± 119157 ± 125158 ± 121
      Overall Arthritis Intensity (mm)ITT57 ± 2847 ± 2942 ± 2842 ± 2938 ± 2640 ± 2838 ± 29
      Subset55 ± 2848 ± 2939 ± 2739 ± 2539 ± 2540 ± 2740 ± 28
      Data are presented as mean ± SD.
      Abbreviations: WOMAC: Western Ontario and McMaster Universities; OA: osteoarthritis; ITT: Intent-to-treat
      The ITT group includes data from patients who entered the open-label study. The subset group excludes efficacy assessments that were potentially confounded by NSAIDs and/or acetaminophen use.
      WOMAC OA Index Pain Intensity was assessed on a 500-mm VAS scale (0 = no pain and 500 = extreme pain). Overall Arthritis Pain Intensity was assessed on a 100-mm scale (0 = no pain, 100 = extreme pain).

      Safety: Open-Label Extension Trial

      Constipation and nausea were the most frequent AEs reported (Table 8). The incidence of AEs was similar between Avinza QAM and QPM. The total number of patients experiencing an AE in the Avinza QAM (n = 75, 82%) and QPM (n = 72, 80%) groups was similar. AEs reported were mild (n = 33, 22%), moderate (n = 78, 53%), and severe (n = 24, 20%). Of the 181 patients randomized, 56 (31%) discontinued prematurely due to AEs: 32 in the Avinza QAM group and 24 in the Avinza QPM group. The number of patients withdrawing due to AEs was higher for those patients who had previously received placebo (n = 23, 13%) and MSC (n=16, 9%) than those that had received Avinza QAM (n = 10, 6%) or QPM (n = 7, 4%) in the double-blind trial. Four patients experienced serious AEs that were considered possibly related to Avinza: 1) enteritis and gastritis, 2) dehydration, diarrhea, hyponatremia, nausea and vomiting, 3) constipation, and 4) dehydration, sweating, and vomiting. All four patients recovered. No clinically meaningful changes in vital signs, physical examination, laboratory values, or ECGs were observed.
      Table 8AEs Reported in 5% of Patients in Any Treatment Group: Open-Label Trial
      AE, n (%)Avinza QAM (n = 91)Avinza QPM (n = 90)Overall (n = 181)
      Constipation34 (37%)29 (32%)63 (35%)
      Nausea11 (12%)18 (20%)29 (16%)
      Diarrhea14 (15%)9 (10%)23 (13%)
      Somnolence14 (15%)9 (10%)23 (13%)
      Dizziness5 (6%)11 (12%)16 (9%)
      Abdominal pain7 (8%)8 (9%)15 (8%)
      Pain5 (6%)10 (11%)15 (8%)
      Headache9 (10%)5 (6%)14 (8%)
      Infection6 (7%)7 (8%)13 (7%)
      Insomnia5 (6%)6 (7%)11 (6%)
      Peripheral edema4 (4%)7 (8%)11 (6%)
      Vomiting4 (4%)7 (8%)11 (6%)
      Dry mouth3 (3%)5 (6%)8 (4%)
      Accidental injury2 (2%)5 (6%)7 (4%)
      No statistical differences were observed between the active treatment groups.

      Discussion

      The safety and efficacy of Avinza once daily and MSC twice daily were assessed in patients who previously had suboptimal analgesic response to treatment with NSAIDs and acetaminophen or had previously received intermittent opioid analgesic therapy. The analgesic effects of the active treatments were comparable, and demonstrated greater analgesic efficacy than placebo (as assessed by the WOMAC OA Index Pain subscale). The WOMAC health status instrument was designed specifically to measure clinically important and patient-relevant outcomes in patients with osteoarthritis of the hip or knee
      • Bellamy N.
      • Buchanan W.W.
      • Goldsmith C.H.
      • Campbell J.
      • Stitt L.W.
      Validation study of WOMAC a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
      and is the preferred measure of pain in clinical OA pain trials.
      • Creamer P.
      • Lethbridge-Cejku M.
      • Hochberg M.C.
      Determinants of pain severity in knee osteoarthritis effect of demographics and psychosocial measures using 3 pain measures.
      The WOMAC OA Index Pain subscale, which is comprised of five different assessments of pain (pain while walking on a flat surface, going up or down stairs, at night in bed, at rest, and standing), is a more sensitive scale to detect change in OA pain than other instruments that measure single joint pain alone. It has recently been suggested that a 20% average reduction in pain intensity is clinically meaningful in many analgesic trials.
      • Roth S.H.
      • Fleischman R.M.
      • Burch F.X.
      • Dietz F.
      • Bockow B.
      • Rapport R.J.
      • et al.
      Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain placebo-controlled trial and long-term evaluation.
      Generally, clinically meaningful reductions in pain intensity were observed in the Avinza and MSC groups despite the low daily dose of morphine (30 mg daily) administered in the double-blind trial.
      Patients who completed the double-blind trial were given the opportunity to enter a 26-week open-label extension trial to receive once-daily Avinza (QAM or QPM). The open-label trial was designed to mimic real-life treatment conditions by permitting patients to increase the daily opioid dose to optimize their pain control. However, of the patients who completed the trial, nearly half (49%) remained on the initial 30-mg once daily dose, which suggests that this modest amount of morphine was adequate for many patients for controlling OA pain throughout the 30-week period.
      Results from the open-label extension trial suggest that upward dose titration can provide additional analgesia in those patients that do not optimally respond to a single daily 30 mg dose. Stable analgesia was observed in the open-label trial, which was consistent with the relatively stable average daily Avinza dose following dose titration to optimal pain control, suggesting that tolerance was not experienced in the majority of patients. These results are consistent with previously conducted long-term controlled-release opioid trials, which have shown analgesic maintenance for extended periods (up to 18 months) in patients on stable daily doses.
      • Roth S.H.
      • Fleischman R.M.
      • Burch F.X.
      • Dietz F.
      • Bockow B.
      • Rapport R.J.
      • et al.
      Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain placebo-controlled trial and long-term evaluation.
      • Zenz M.
      • Strumpf M.
      • Tryba M.
      Long-term oral opioid therapy in patients with chronic nonmalignant pain.
      A potential confounding factor for efficacy assessments in the open-label trial was the allowance of concomitant administration of NSAIDs and acetaminophen. However, the results from the subset analysis confirmed that concomitant NSAID and acetaminophen use did not contribute to the improvement in efficacy observed during the open-label trial relative to baseline.
      Effective analgesia often reduces disability and potentially improves the patient's quality of life.
      • Roth S.H.
      • Reder R.F.
      The role of opioids in the treatment of osteoarthritis.
      Therefore, striving to improve physical functioning by reducing pain is an important aspect of therapy. During the double-blind trial Avinza and MSC produced improvements in physical function, although the improvements were not statistically significant in comparison to placebo. In contrast, statistically significant improvements in physical functioning were observed in the open-label trial with Avinza, which coincided with a reduction in pain intensity and stiffness, and is likely attributable to the ability of patients to increase their daily dose to optimal pain control.
      Sleep disturbances appear in up to 50% to 70% of chronic pain patients.
      • Cohen M.J.M.
      • Menefee L.A.
      • Doghramji K.
      • Anderson W.R.
      • Frank E.D.
      Sleep in chronic pain problems and treatments.
      • Pilowsky I.
      • Crettenden I.
      • Townley M.
      Sleep disturbance in pain clinic patients.
      Poor sleep may lead to increased pain, physical disability, and psychological disturbances that accompany chronic pain.
      • Pilowsky I.
      • Crettenden I.
      • Townley M.
      Sleep disturbance in pain clinic patients.
      The double-blind trial demonstrated that Avinza and MSC improved all sleep measures assessed as compared to placebo; however, the greatest improvements in sleep measures were experienced by patients treated with Avinza QAM. There is no obvious pharmacological reason that can explain the greater improvements in overall quality of sleep observed in the Avinza QAM group in comparison to the Avinza QPM and MSC groups. Further studies assessing differences in sleep parameters between once-daily Avinza administered at various times and twice-daily administration of MSC are warranted.
      In general, the active treatments had similar safety profiles in the double-blind trial and a higher incidence of typical opioid AEs than the placebo-treated patients. Some AEs were reported at a significantly different incidence among the active treatment groups; however, it is unclear if these results are due to true treatment differences or if they are a reflection of the large number of post-hoc statistical comparisons that were conducted. In theory, two (5%) of the 33 post-hoc Chi-square tests are expected to show a statistical significance by chance alone. Constipation was one of the primary reasons for AE-related patient withdrawals, but this was not surprising since prophylactic management of constipation was not undertaken. While the incidence of patient withdrawals in both the Avinza double-blind and open-label trials was similar to findings in previous trials with oxycodone and codeine,
      • Roth S.H.
      • Fleischman R.M.
      • Burch F.X.
      • Dietz F.
      • Bockow B.
      • Rapport R.J.
      • et al.
      Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain placebo-controlled trial and long-term evaluation.
      • Lacouture P.
      • Roth S.
      • Burch F.
      • Fleishmann R.
      • Iwan T.
      • Kaiko R.
      A short-term trial, placebo-controlled, repeated dose, dose-response evaluation of controlled-release (CR) oxycodone in patients with osteoarthritis.
      it still indicates that some patients who receive Avinza or MSC therapy may require treatment discontinuation due to AEs. More proactive and prophylactic treatment of constipation may result in a higher tolerability of patients to Avinza or MSC and thus allow a higher percentage of patients to obtain benefit from the products.
      The safety and efficacy profiles of Avinza and MSC were generally similar in the double-blind trial. This is consistent with the active ingredient of all active treatments being morphine, However, some differences in the efficacy profile (sleep parameters) and in the frequency of some AEs (constipation, vomiting and asthenia) were noted among the groups. Avinza and MSC have been demonstrated in other studies to provide similar overall systemic exposure to morphine, with Avinza having a lower fluctuation in plasma morphine concentrations and fewer peak-to-trough fluctuations than MSC. However, because plasma morphine and metabolite concentrations were not collected during the current studies, no assessment of the relationship between the differences in the safety and efficacy profiles relative to any potential differences in the plasma morphine concentration profiles of the three active treatments could be conducted.
      As with all medications, the risks of AEs associated with Avinza once daily need to be weighed versus the benefits of analgesia and improvements in overall quality of sleep and activities of daily living for each individual patient. These studies provide support to the acceptable risk-benefit profile and clinical benefits of Avinza as a once-daily, extended-release morphine formulation for the treatment of patients with chronic, moderate-to-severe OA pain who are eligible for opioid therapy. Avinza once daily should be an useful adjunct to arthritis practice.

      Acknowledgements

      The authors would like to thank Greg Whiting, Jeff Lazar, Beth Vause, and Doreen Gousset for their assistance in data interpretation. The following additional investigators participated in the trial: Kenneth Bahrt, MD, Anderson & Collins Clinical Research, Inc., South Plainfield, NJ; Howard M. Busch, DO, PA, Clinical Studies, Boynton Beach, FL; Ronald L. Collins, MD, Columbia Arthritis Center, P.A., Columbia, SC; Julian A. Colton, MD, St. Petersburg, FL; John J. Condemi, MD, AAIR Research Center, Rochester, NY; Patricia Coleman, MD, Wood Clinical Practice Michigan Corp., East Lansing, MI; John E. Ervin, MD, The Center for Pharmaceutical Research, Kansas City, MO; Justus J. Fiechtner, MD, MPH, East Lansing, MI; Edward Gillie, MD, Medical Studies, Florida, Ft. Myers, FL; Alben G. Goldstein, MD, Metropolitan Clinical Research, Falls Church, VA; Maria Gutierrez, MD, Clinical Studies, Ft. Lauderdale, FL; Richard A. H. Jimenez, MD, Edmonds, WA; Jeffrey Kaine, MD, Sarasota Arthritis Research Center, Sarasota, FL; Michael Lockwood, MD, Arnett Clinic, Lafayette, IN; David M. MacPeek, MD, Pleasant Plains Mall, Toms River, NJ; William S. Makarowski, MD, Rheumatology Associates of N.W. Pennsylvania, Erie, PA; David R. Mandel, MD, Mayfield Village, OH; Margaret Michalska, MD, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL; Michael J. Miller, MD, Virginia Physicians, Richmond, VA; David H. Sikes, MD, Florida Medical Clinic, PA, Zephyrhills, FL; Robert G. Trapp, MD, Springfield, IL.

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