OUP user menu

Open-Label Study on the Long-Term Efficacy, Safety, and Impact on Quality of Life of OROS Hydromorphone ER in Patients with Chronic Low Back Pain

Mark Wallace MD, John Thipphawong MD
DOI: http://dx.doi.org/10.1111/j.1526-4637.2010.00956.x 1477-1488 First published online: 1 October 2010

Abstract

Objective. To investigate the efficacy, safety, and impact on quality of life of long-term administration of OROS hydromorphone ER (8–128 mg) in patients with chronic low back pain.

Design. A total of 113 adults with chronic low back pain who completed a 6-week open-label study were enrolled in this 6-month extension study.

Outcome Measures. The primary end point was the daily pain relief rating obtained during monthly study visits. Secondary end points included Investigator and Patient Global Evaluations, Brief Pain Inventory scores obtained at monthly study visits, and quality-of-life measures (Medical Outcomes Study Questionnaire and 36-Item Short-Form Health Survey score) obtained at monthly intervals.

Results. Mean ± SD change from baseline in pain relief with OROS hydromorphone ER for the Month 6 visit was 0.9 ± 2.55 (P = 0.0007) and for the last assessment of the extension study was 0.9 ± 2.53 (P = 0.0002). At the Month 6 visit, 81.3% of investigators and 71.0% of patients rated their satisfaction of pain relief with OROS hydromorphone ER treatment as good, very good, or excellent. Changes on the 36-item Short Form Health Survey, a quality-of-life measure, were statistically significant for the physical composite scores for all extension phase time points, including Month 6 (2.1 ± 5.34; P < 0.0001) and the last assessment (2.4 ± 5.56; P < 0.0001) and mental composite scores for all extension phase time points, including Month 6 (3.3 ± 9.52; P = 0.0006) and the last assessment (3.1 ± 9.5; P = 0.0008). Treatment with OROS hydromorphone ER also resulted in significant improvement in sleep disturbances. Adverse events included gastrointestinal and central nervous system symptoms.

Conclusions. The results support the long-term use of OROS hydromorphone ER in managing chronic moderate to severe low back pain.

  • Chronic Low Back Pain
  • Opioids
  • Hydromorphone
  • OROS Hydromorphone ER
  • Brief Pain Inventory

Introduction

Chronic low back pain is one of the most common causes of disability and has imposed a significant burden on health care expenditures in the United States [1–3]. Moreover, chronic pain can significantly impact an individual's health-related quality of life. Whereas nonsteroidal anti-inflammatory drugs are used for the treatment of mild pain, long- and short-acting opioids are often used in the treatment of patients with moderate to severe chronic pain [1]. Several clinical trials support the safety and efficacy of opioid analgesics in patients with chronic pain. An evidence-based literature review examining the use of chronic opioid analgesic therapy for patients with chronic nonmalignant low back pain concluded that opioids provide substantial pain relief, improve quality of life, and restore the ability to function on a daily basis [4]. In fact, when used judiciously and as per guidelines, the American Academy of Pain Medicine and the American Pain Society recommend opioids for the treatment of refractory chronic noncancer pain in the general population, including older patients [5]. However, the fluctuating plasma drug levels produced by immediate-release (IR) opioid formulations have been associated with episodes of inadequate analgesia and adverse events (AEs) [6]. In more recent years, extended-release (ER) opioid formulations have been developed that may overcome these limitations by providing around-the-clock pain relief [7].

OROS hydromorphone ER (EXALGO; ALZA Corporation, Mountain View, CA) is a formulation that employs the OROS Push-Pull drug delivery system, which comprises a bilayer core consisting of a single drug layer and excipients and a push layer containing a hydrophilic expanding compartment [6,8]. The push layer expands when water from the gastrointestinal tract permeates the outer membrane and pushes the drug layer out at a steady rate through the delivery orifice in the tablet membrane [8]. In a double-blind, randomized pharmacodynamic single-dose study involving 12 healthy adults, hydromorphone plasma concentration using OROS hydromorphone ER peaked at 12.0 hours, while plasma concentration of IR hydromorphone peaked at 0.8 hours [9]. Hydromorphone plasma concentration was maintained at greater than 50% of peak concentration for 21.6–26.5 hours with OROS hydromorphone ER vs 1.1 ± 0.7 hours with IR hydromorphone [9]. Steady-state plasma concentrations are achieved after 3–4 days of once-daily dosing, yielding elevated and consistent plasma concentrations for at least 24 hours after administration [10].

These results suggest that OROS hydromorphone ER provides a continuous delivery of medication over 24 hours, thereby enabling once-daily dosing. The benefit of the continuous release of hydromorphone as measured by the Brief Pain Inventory (BPI) (primary end point) and secondary assessments of pain interference with physical activity and social function, performance status, and cognition were shown in a randomized, double-blind comparison study with controlled-release (CR) morphine in patients with chronic cancer pain [11].

In patients with chronic nonmalignant pain, a dose conversion and titration study concluded that patients treated with opioids can be easily converted to treatment with OROS hydromorphone ER without loss of efficacy or an increase in AEs [12]. In that study, patients with chronic nonmalignant pain were switched to OROS hydromorphone ER using a 5:1 conversion ratio of morphine equivalent to hydromorphone [12]. In a 6-week, randomized, multicenter, open-label, parallel-group trial, OROS hydromorphone ER and twice-daily oxycodone provided similar pain relief for osteoarthritis of the knee or hip and had similar tolerability profiles [13].

In addition, in a 6-week open-label study with OROS hydromorphone ER in patients with chronic low back pain, Wallace et al. reported that daily pain relief scores increased significantly from baseline to end point (0.26 ± 1.084; P = 0.0008) and BPI scores for “worst pain in 24 hours” decreased significantly from baseline to end point (–0.8 ± 2.06; P < 0.0001) [14]. Over 63% of patients and 65% of investigators rated the global effectiveness as good, very good, or excellent. OROS hydromorphone ER was also well tolerated and resulted in significant improvement in patients' health-related quality of life and sleep disturbances [14]. Following this short-term study, a 6-month extension trial was conducted to characterize the long-term efficacy, safety, and impact on quality-of-life measures with OROS hydromorphone ER in patients with moderate to severe chronic low back pain. The results of the extension phase are presented in this article.

Methods

Study Design and Treatment

This was a 6-month, open-label, repeated-dose extension study conducted at 17 centers in the United States between November 2000 and June 2001. All patients gave written informed consent prior to undergoing any treatment or assessments. Patients enrolled in this extension study continued their therapy with OROS hydromorphone ER at the stable dose previously identified by titration in the short-term study (8–128 mg). At the discretion of the investigator, adjustments to dose were performed every 3 days as needed based on five criteria: degree of opioid tolerance, general medical condition and medical status, concurrent medication, type and severity of pain, and amount and frequency of rescue medication needed for breakthrough pain. Dose increases of 25–100% of current baseline dose of OROS hydromorphone ER could be considered. Individual OROS hydromorphone ER tablets ranging from 8–64 mg were provided as study medication. There was no upper limit to the allowable OROS hydromorphone ER dose.

At each visit, patients were dispensed a 1-month supply (35 tablets) of OROS hydromorphone ER. Patients were instructed to swallow the tablet whole with water (8 oz) and to not chew, divide, or crush the tablet. Rescue medication (hydromorphone IR 2, 4, or 8 mg) was permitted and was not to exceed the equivalent of 10–15% of the total 24-hour baseline OROS hydromorphone ER dose. Although rescue medication use was evaluated for the short-term phase, use of rescue medication was not assessed for the extension phase. Patients were evaluated monthly, unused study medication was collected, and a new supply of OROS hydromorphone ER was dispensed.

Patient Population

Patients aged ≥18 years with moderate to severe chronic low back pain (≥6 weeks in duration) who completed the 6-week study were eligible for enrollment in the extension study. Additional eligibility criteria included requiring ≥8 and ≤96 mg of hydromorphone HCl every 24 hours to manage chronic low back pain and receiving a stable opioid dose of OROS hydromorphone ER established in the short-term study.

Patients were excluded from the study if they were intolerant of or hypersensitive to hydromorphone; had clinically significant bleeding disorders; had significant central nervous system disorders; had compromised or depressed respiratory function; had clinically significant impairment of hematologic, renal, or hepatic function; or were known active drug abusers. Patients were also excluded if they had more than three episodes of vomiting per day within 3 days prior to the start of the study or had not had a bowel movement within 5 days prior to the start of the study. Women were excluded if they were pregnant or lactating.

Outcome Measures

The primary efficacy variable was the mean pain relief score obtained at monthly study office visits. The rating scale asks patients to rate their pain relief since their last visit. Pain relief was rated on a 5-point scale: 0 (no relief), 1 (slight relief), 2 (moderate relief), 3 (good relief), and 4 (complete relief).

Secondary efficacy variables included BPI and Investigator and Patient Global Evaluations performed monthly, as well as quality-of-life assessment using the 36-item Short-Form Health Survey (SF-36) and sleep assessment using the Medical Outcomes Study (MOS) Questionnaire. The BPI included assessment of pain severity (at its worst in the past 24 hours, at its least in the past 24 hours, on average, and right now on an 11-point scale: 0 [no pain] to 10 [worst pain imaginable]) and impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life using an 11-point scale: 0 [no interference] to 10 [complete interference]). Investigator and patient global evaluations were used to assess the overall effectiveness of the study drug using a 5-point scale (1 [poor] and 5 [excellent]). The SF-36 is a quality-of-life instrument consisting of 11 questions assessing physical and mental functional health. It yields an eight-scale profile of functional health and well-being scores as well as psychometrically based physical and mental health summary measures that were used to determine the impact of pain relief on quality of life. The entire MOS Questionnaire, consisting of a 12-question series, was used to assess patients' sleep. Compared with the lone sleep item on the BPI, which assesses only the degree to which pain interferes with sleep, the 12 questions of the MOS questionnaire provide a multidimensional assessment of sleep and sleep disturbances.

Safety assessments included AE reporting, physical examination, and vital sign measurements. AEs were categorized according to severity (mild, moderate, or severe) and relationship to study medication. An AE was considered serious if it was life threatening or resulted in death, hospitalization or prolongation of hospitalization, persistent or significant disability or incapacity, or congenital anomaly or birth defect.

Statistical Analysis

No power calculations were performed to determine the sample size for this study, as all patients completing the short-term study were eligible for inclusion in the extension phase. The intent-to-treat approach was used in this study; i.e., all patients who received at least one dose of OROS hydromorphone ER were included in the efficacy and safety analyses. Summary statistics (means, standard deviations) were used for continuous baseline and demographic variables, and frequency and percentages were used for categorical baseline measurements. A mixed model analysis of variance (anova) was performed to account for correlated observations within patients and to contrast the average on-treatment response in the long-term study with baseline of the short-term open-label study. The one-sample paired t-test was used to evaluate differences from baseline of the short-term open-label study to each subsequent visit in pain relief rating (primary efficacy variable) and to evaluate differences from baseline of the short-term open-label study to each subsequent visit for BPI ratings, SF-36 scores, and MOS Questionnaire (secondary efficacy variables). Frequency and percentages were used to summarize investigator and patient global evaluations at each visit. AEs were also summarized using the frequency and percentages of patients. Summary statistics were performed for changes in physical examination and vital signs.

Results

Patient Disposition

Of the 131 patients who completed the initial short-term open-label study, a total of 113 were enrolled in the extension study; 1 patient was lost to follow-up after only 1 day in the extension study. Of the 112 patients who continued, 83 (74.1%) completed the 6-month extension study. The reasons for premature study discontinuation from the 6-month extension study are shown in Table 1.

View this table:
Table 1

Patient disposition for the 6-month extension study

Patients (N = 112)*
Patients who completed the study, n (%)83 (74.1)
Reason for termination, n (%)
  Adverse event12 (10.7)
  Lost to follow-up4 (3.6)
  Protocol violation3 (2.7)
  Withdrawal of consent5 (4.5)
  Lack of efficacy3 (2.7)
  Disease progression1 (0.9)
  Administrative reasons1 (0.9)
  • * One patient was lost to follow-up after only 1 day in the extension study.

Baseline Demographics and Study Medication Dose

Demographic and baseline characteristics, including the nature of the predominant pain, appear in Table 2. Most patients were white (95.6%) with a mean age of 47.5 ± 10.91 years. Failed back syndrome, degenerative disk disease, or herniated disk was responsible for the back pain in >75% of patients.

View this table:
Table 2

Demographics and baseline characteristics for the 6-month extension study

Patients (N = 113)
Sex, n (%)
  Female72 (63.7)
  Male41 (36.3)
Age (years)
  Mean (SD)47.5 (10.91)
  Range27–85
Race, n (%)
  White108 (95.6)
  Black4 (3.5)
  Asian1 (0.9)
  Other0
Weight (kg), mean (SD)87.3 (21.75)
Height (cm), mean (SD)173.1 (9.62)
Primary diagnosis of chronic low back pain, n (%)
  Failed back syndrome38 (33.6)
  Degenerative disk disease32 (28.3)
  Herniated disk16 (14.2)
  Muscular/ligaments8 (7.1)
  Facet arthropathy4 (3.5)
  Spinal stenosis3 (2.7)
  Osteoporosis/compression fractures3 (2.7)
  Ankylosing spondylitis3 (2.7)
  Other6 (5.3)
Nature of predominant pain, n (%)
  Mixed59 (52.2)
  Bone27 (23.9)
  Soft tissue15 (13.3)
  Neuropathic12 (10.6)
  Unknown0

For patients who participated in both the short-term and extension studies, the mean ± SD daily dose of OROS hydromorphone ER for the titration phase was 35.3 ± 21.13 and 44.9 ± 26.23 mg for the maintenance phase of the short-term study. The mean ± SD total daily dose of OROS hydromorphone ER at baseline (final visit of short-term study) and at the end of the extension phase alone (i.e., Month 6) was 52.9 ± 35.1 and 48.6 ± 29.32 mg, respectively. When the maintenance phases for the short-term and extension studies were combined, the mean ± SD total daily dose of OROS hydromorphone ER over the entire maintenance phase was 42.3 ± 24.71 mg.

Pain Relief Scores

Significant improvements in mean pain relief ratings observed in the short-term study (P < 0.001 at the short-term study final visit) were sustained to the Month 6 study visit (Table 3). The mean ± SD change from baseline for the Month 6 visit was 0.53 ± 1.012 (P < 0.0001; one-sample paired t-test) and for the last assessment of the extension study was 0.56 ± 0.984 (P < 0.0001; one-sample paired t-test). The mean change from baseline (0.60; 95% confidence interval [CI] 0.47–0.72; P < 0.0001) in the extension study remained significant using mixed-model anova analysis.

View this table:
Table 3

Mean pain relief rating* for patients receiving treatment with OROS hydromorphone ER for chronic low back pain

Baseline (N = 113)Month 1 (n = 103)Month 2 (n = 96)Month 3 (n = 88)Month 4 (n = 88)Month 5 (n = 85)Month 6 (n = 102)Last Assessment (n = 112)
Pain relief rating
  Mean (SD)1.93 (0.768)2.59 (0.720)2.58 (0.777)2.51 (0.816)2.48 (0.711)2.59 (0.776)2.45 (0.804)2.49 (0.794)
Change from baseline
  Mean (SD)0.66 (1.062)0.66 (0.950)0.65 (0.959)0.61 (0.915)0.72 (0.881)0.53 (1.012)0.56 (0.984)
  P<0.0001<0.0001<0.0001<0.0001<0.0001<0.0001<0.0001
  • * Pain was rated on a 5-point scale, with 0 indicating no relief and 4 indicating complete relief. Last assessment is defined as the last available evaluation from the extension study.

  • Based on one sample paired t-test.

  • ER = extended-release.

BPI

Pain Intensity Scores

Statistically significant improvements from baseline in BPI pain intensity scores (worst pain in the last 24 hours, least pain in the past 24 hours, pain on average, and pain right now) were observed for all subsequent postbaseline visits and for the last assessment during the extension phase (P < 0.05; Figure 1). These changes in pain intensity remained statistically significant (P < 0.0001 for each item) when a mixed-model anova analysis was performed. The mean ± SD change from baseline in how much relief was provided with OROS hydromorphone ER for the Month 6 visit was 0.9 ± 2.55 (P = 0.0007) and for the last assessment of the extension study was 0.9 ± 2.53 (P = 0.0002).

Figure 1

Mean BPI pain scores (items 3–6) for patients receiving treatment with OROS hydromorphone ER for chronic low back pain. Scores are shown for worst and least pain in the past 24 hours (A) as well as for pain right now and pain on average (B). Pain was rated on the 11-point BPI pain scale, with 0 indicating no pain and 10 indicating the worst pain imaginable. P < 0.001 vs short-term study baseline for all evaluations including the last assessment of the extension study. Last assessment is defined as the last available postbaseline evaluation from the extension study. BPI = Brief Pain Inventory; ER = extended-release.

Pain Interference Scores

Statistically significant improvements from baseline were observed for BPI interference scores (general activity, normal work, mood, relations with other people, walking ability, enjoyment of life, and sleep) at all subsequent postbaseline visits and for the last assessment of the extension phase (P < 0.01; Figure 2). These changes in pain interference remained statistically significant (P < 0.0001 for each item) when a mixed-model anova analysis was performed.

Figure 2

Mean BPI interference of pain scores (items 9A-G) for patients receiving treatment with OROS hydromorphone ER for chronic low back pain. Scores are shown for general activities, normal work, and walking ability (A) as well as for enjoyment of life, mood, and relations with people (B). Pain was rated on the 11-point BPI pain scale, with 0 indicating no pain and 10 indicating the worst pain imaginable. P < 0.001 vs short-term study baseline for all evaluations including the last assessment of the extension study. Last assessment is defined as the last available postbaseline evaluation from the extension study. BPI = Brief Pain Inventory; ER = extended-release.

Investigator and Patient Global Evaluations

The improvements in overall global evaluation of OROS hydromorphone ER, as assessed by investigators and patients over the short-term study, were sustained over the course of the 6-month extension (Figure 3). For patients who participated in the short-term and extension phases of the study, investigator and patient global evaluations (using all categories from poor to excellent) revealed a significant improvement at Visit 3 of the short-term study (P < 0.0001), which was maintained at all subsequent visits, including the last assessment of the extension phase (P < 0.0001 for all time points). Improvements as assessed by investigators (mean change 0.97; 95% CI 0.84–1.10; P < 0.0001) and patients (mean change 0.85; 95% CI 0.71–0.99; P < 0.0001) remained statistically significant after mixed-model anova analysis. At the Month 6 visit, 81.3% of investigators and 71.0% of patients rated their satisfaction of pain relief with OROS hydromorphone ER treatment as good, very good, and excellent.

Figure 3

Patient (A) and investigator (B) global evaluations for patients receiving treatment with OROS hydromorphone ER for chronic low back pain. Last assessment is defined as the last available postbaseline evaluation from the extension study. ER = extended-release.

Health-Related Quality of Life

The 36-Item Short-Form Health Survey Scores

Statistically significant improvements in several physical health domains, as well as in physical composite scores from baseline, were observed for all extension phase time points (Table 4) including Month 6 (mean ± SD for composite score 2.1 ± 5.34; P < 0.0001) and last assessment (2.4 ± 5.56; P < 0.0001). Similarly, significant improvements from baseline in several mental health domains, as well as in mental composite scores, were seen for all extension phase time points (Table 4), including Month 6 (mean ± SD for composite score 3.3 ± 9.52; P = 0.0006) and the last assessment (3.1 ± 9.5; P = 0.0008). When an anova analysis was performed, these changes from baseline in individual physical (P < 0.05) and mental health (P < 0.001) domains, as well as in physical and mental composite scores (P < 0.0001 for both), remained statistically significant.

View this table:
Table 4

SF-36 Health Survey mean scores for patients receiving treatment with OROS hydromorphone ER for chronic low back pain

SF-36 DomainBaseline (n = 113)Visit 7 (n = 113)Month 6 (n = 105)Last Assessment (n = 112)
Mental domains, mean (SD)
  Vitality40.1 (10.82)46.5 (11.89)*44.5 (13.42)*44.5 (13.49)*
  Social functioning30.8 (11.30)36.4 (10.26)*35.1 (11.12)*35.2 (11.52)*
  Emotional27.0 (3.33)27.7 (3.38)*27.3 (3.50)27.3 (3.48)
  Mental health47.3 (14.61)53.6 (13.14)*51.6 (15.24)*51.3 (15.24)*
  Mental composite score41.5 (10.82)46.6 (10.01)*44.7 (11.59)*44.5 (11.58)*
Physical domains, mean (SD)
  Physical functioning26.2 (7.90)28.5 (9.23)*29.2 (9.96)*29.5 (10.34)*
  Role physical28.4 (1.09)29.1 (1.98)*28.8 (1.89)28.9 (1.91)*
  Bodily pain29.7 (5.82)35.9 (6.75)*34.5 (7.19)*34.7 (7.41)*
  General health39.4 (11.06)40.7 (11.10)*39.9 (11.24)39.9 (11.38)
  Physical composite score28.1 (5.70)30.2 (6.83)*30.3 (6.83)*30.6 (7.16)*
  • * P < 0.05.

  • Last assessment is defined as the last available postbaseline evaluation from the extension study.

  • ER = extended-release; SF-36 = 36-Item Short-Form Health Survey.

MOS Sleep Questionnaire

Significant reductions from baseline to the final visit of the extension study were seen for problems with sleep adequacy, sleep disturbance, sleep index I, and sleep index II (Figure 4a). At Month 6, the change from baseline for these items (mean ± SD) was –7.3 ± 24.54 (P = 0.003), –9.0 ± 23.71 (P = 0.0002), –5.3 ± 15.82 (P = 0.0009), and –6.4 ± 16.08 (P = 0.0001), respectively (Figure 4a).

Figure 4

MOS Sleep Questionnaire (A) and BPI sleep item (B) scores for patients receiving treatment with OROS hydromorphone ER for chronic low back pain. Last assessment is defined as the last available postbaseline evaluation from the extension study. BPI = Brief Pain Inventory; ER = extended-release; MOS = Medical Outcomes Study.

BPI Sleep Item

Statistically significant improvement from baseline to the final visit of the extension study was seen for the BPI sleep item, question 9F, which assesses the degree to which pain interferes with sleep (Figure 4b). At Month 6, the change from baseline for this question (mean ± SD) was –1.2 ± 2.59 (P < 0.0001).

AEs

Overall, 79 (69.9%) patients in this study reported at least one AE (Table 5), of which 36 (31.9%) were considered by the investigator to be related to OROS hydromorphone ER treatment. Seventeen (15.0%) patients experienced a severe AE, of which 5 (4.4%) were considered by the investigator to be related to OROS hydromorphone ER treatment, and 8 (7.1%) patients experienced a serious AE, of which 3 (2.7%) were considered by the investigator to be related to the study drug treatment. Serious AEs leading to termination included confusion, stroke, renal calculi, chest pain, small bowel obstruction, diverticulitis, and gastroenteritis. Of these, confusion, small bowel obstruction, and diverticulitis were considered by the investigator to be at least possibly related to study medication. The most common (≥5%) treatment-related AEs included nausea (7.1%), constipation (6.2%), and somnolence (4.4%). Most AEs reported during this study were of mild severity. Twelve patients (10.6%) discontinued the long-term extension study due to AEs (Table 1). No clinically significant findings were noted for vital sign measurements or physical examinations during the course of the extension study. No deaths occurred in the extension study.

View this table:
Table 5

Treatment-emergent adverse events reported by ≥5% of patients

Adverse event, n (%)Patients (N = 113)
Any adverse event79 (69.9)
Nausea11 (9.7)
Vomiting10 (8.8)
Constipation8 (7.1)
Diarrhea7 (6.2)
Insomnia6 (5.3)

Discussion

Hydromorphone is a semisynthetic opioid that has been used effectively and safely for the management of acute, chronic cancer, and chronic noncancer pain [15–18]. The pharmacokinetic characteristics of OROS hydromorphone ER suggest that it can be a valuable treatment option for patients who require around-the-clock opioids for control of persistent moderate to severe chronic pain [6]. When used appropriately, this formulation can be a helpful treatment strategy in appropriately selected opioid-tolerant patients with chronic low back pain.

Evidence for the short-term efficacy and safety of OROS hydromorphone ER in the treatment of patients with chronic moderate to severe low back pain has been reported. A recently published 12-week, multicenter, double-blind, placebo-controlled study in opioid-tolerant patients reported significant improvement in pain intensity with OROS hydromorphone ER compared with placebo (P < 0.001) [19]. Additionally, the 6-week multicenter, nonrandomized, noncomparative, open-label, repeat-dose study on which this extension trial is based showed significant improvements in mean pain relief ratings (P < 0.001) with OROS hydromorphone ER [14]. Overall, the results of the current extension study of the 6-week trial are consistent with the findings of these short-term studies. The results of the present open-label extension study suggest that the effects of OROS hydromorphone ER in the treatment of patients with chronic moderate to severe low back pain are sustained for up to 6 months. Notably, the mean dose of OROS hydromorphone ER remained relatively stable throughout the 6-month study duration in this population.

A systematic review of hydromorphone revealed few studies examining the use of the opioid in chronic pain. Indeed, nearly all of the studies identified by the review focused only on the use of hydromorphone in chronic cancer pain [16]. A subsequent review of oral, topical, or transdermal opioid treatment (both IR and ER preparations) for chronic back pain found no significant reductions in pain from baseline, although none of the trials included in the analysis was longer than 16 weeks in duration [20]. Thus, the results of the present study with OROS hydromorphone ER may begin to establish support for the long-term efficacy and safety of ER opioids for chronic low back pain.

A long-term open-label extension study by Wallace et al. was similar in design to the current study [21]. In that trial, 388 patients from three short-term OROS hydromorphone ER trials were enrolled, 106 (27.3%) patients completed 1 year of treatment, and 282 (72.7%) discontinued before completing 1 year of treatment. The study included patients with cancer and noncancer pain, with 50% of enrolled patients experiencing back pain. In contrast, 100% of patients in the current study experienced noncancer low back pain exclusively. The two studies also differ with regard to the metrics used. Both studies incorporated the BPI and patient and investigator evaluations to measure pain relief; however, the current study also incorporated a quality-of-life measure (SF-36) and a sleep assessment (MOS Questionnaire), whereas the other study did not. The inclusion of quality-of-life assessments provides additional information about the degree to which pain relief is clinically meaningful for patients and the potential impact of longer-term OROS hydromorphone ER treatment on patient functioning.

An analysis of the results of the MOS Questionnaire and the SF-36 provides evidence that the pain relief associated with OROS hydromorphone ER also results in statistically significant improvement in physical functioning, quality of life, and sleep for patients with chronic moderate to severe low back pain. In particular, treatment with OROS hydromorphone ER resulted in statistically significant improvements in the SF-36 domains of vitality, social functioning, mental health, physical functioning, role physical, and bodily pain. Based on the results of the MOS Questionnaire, sleep adequacy, sleep disturbance, sleep index I, and sleep index II all improved significantly from baseline through the final assessment in the extension study.

OROS hydromorphone ER was generally well tolerated and had a favorable safety profile during the long-term treatment of chronic low back pain. Most AEs were of mild intensity and included mainly gastrointestinal and central nervous system events. These AEs are typical of opioids, as reported in other studies [1,5,12,14]. The number of patients experiencing AEs in the extension phase (79; 69.9%) was lower than that seen in the short-term study, in which 162 (78.3%) patients reported at least one AE and 126 (60.9%) patients reported at least one AE considered by the investigators to be related to the study medication [14]. The proportion of patients experiencing AEs judged by investigators to be related to treatment with OROS hydromorphone ER was lower in the extension phase than in the short-term phase of the study (31.9% vs 60.9%).

Although no conclusions can be made from comparisons across different trials, the present study recorded a relatively high completion rate (74.1%) when compared with other long-term studies with opioid formulations. The ACTION trial, a randomized, parallel-group, open-label, multicenter study, compared ER morphine sulfate capsules and twice-daily CR oxycodone HCl tablets in patients with chronic moderate to severe low back pain. Only 132 (33.7%) of 392 randomized patients completed the entire ACTION study, which included an 8-week in-depth evaluation phase and an optional 4-month extension phase [22]. Another open-label, 6-month extension study with an optional 12-month phase evaluated the long-term effects of CR oxycodone in patients with osteoarthritis-related pain. In that trial, in which 45.9% of patients had osteoarthritis of the spine or back, 52.6% of patients discontinued prematurely because of ineffective treatment or unacceptable adverse experiences [23]. The high completion rate seen in the current study of patients with low back pain may have been influenced by the lack of an upper dose limit for OROS hydromorphone ER. Also, concomitant analgesic therapy for rescue medication was permitted during the study but was not tracked.

This study has several potential limitations, including its open-label nonrandomized design. This study did not compare OROS hydromorphone ER to a placebo control or an active control; therefore, no conclusions can be drawn concerning the efficacy or safety of OROS hydromorphone ER in relation with other medications. Additional randomized comparative studies are required to confirm the findings of this long-term extension study.

The present study is also limited by the use of a monthly office visit evaluation as the primary outcome assessment. An inherent bias exists when asking patients once per month to generalize pain relief over an entire month. The pain or the lack of pain that patients are experiencing at that particular office visit may influence their perception of the pain they experienced over the previous month and could lead to inflated or underreported pain levels.

Despite these limitations, the results of this open-label extension study support and extend earlier data demonstrating the efficacy and tolerability of OROS hydromorphone ER in the management of chronic moderate to severe low back pain. Thus, the results of this extension phase of an open-label study suggest that the efficacy and safety of OROS hydromorphone ER are maintained for at least 6 months in patients with chronic low back pain.

Disclosures

John Thipphawong is an employee and shareholder of Johnson and Johnson (ALZA Corporation), which sponsored the development of this drug.

Acknowledgments

This study was supported by Knoll Pharmaceutical Company, ALZA Corporation, and Neuromed Pharmaceuticals. Editorial support for this manuscript was provided by Neuromed Pharmaceuticals and Mallinckrodt Inc., a Covidien Company. The authors wish to acknowledge Cynthia L. Kryder, Medical Writer, and Synchrony Medical LLC, West Chester, PA, for editorial support, and Michael Kutch, Statistician, Applied Clinical Intelligence LLC, Bala Cynwyd, PA, for statistical support in preparation of this manuscript.

References

View Abstract