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Efficacy and safety of oxymorphone extended release in chronic low back pain: Results of a randomized, double-blind, placebo- and active-controlled phase III study
Efficacy and Safety of Oxymorphone Extended Release in Chronic Low Back Pain: Results of a Randomized, Double-Blind, Placebo- and Active-Controlled Phase III Study Martin E. Hale,* Chris Dvergsten,† and Joseph Gimbel‡ Abstract: This multicenter, randomized, double-blind, placebo- and active-controlled trial was conducted to compare the analgesic efficacy and safety of oxymorphone extended release (ER) with placebo and oxycodone controlled release (CR) in ambulatory patients with moderate to severe chronic low back pain requiring opioid therapy. Patients (N ⴝ 213) aged 18 to 75 years were randomized to receive oxymorphone ER (10 to 110 mg) or oxycodone CR (20 to 220 mg) every 12 hours during a 7- to 14-day dose-titration phase. Patients achieving effective analgesia at a stable opioid dose entered an 18-day double-blind treatment phase and either continued opioid therapy or received placebo. With stable dosing throughout the treatment phase, oxymorphone ER (79.4 mg/day) and oxycodone CR (155 mg/day) were superior to placebo for change from baseline in pain intensity as measured on a visual analog scale; the LS mean differences were ⴚ18.21 and 18.55 (95% CI, ⴚ25.83 to ⴚ10.58 and ⴚ26.12 to ⴚ10.98, respectively; P ⴝ .0001). Use of rescue medication was 20 mg per day. Adverse events for the active drugs were similar; the most frequent were constipation and sedation. Oxymorphone ER and oxycodone CR were generally safe and effective for controlling low back pain. Oxymorphone ER was equianalgesic to oxycodone CR at half the milligram daily dosage, with comparable safety. Perspective: Definitive studies of long-acting opioids in patients with chronic low back pain are lacking. We report the results of a multicenter, randomized, placebo-controlled, double-blind study evaluating the analgesic efficacy and safety of oxymorphone ER and oxycodone CR in opioid-experienced patients with chronic low back pain. © 2005 by the American Pain Society Key words: Chronic low back pain, oxymorphone, opioids.
E
stimates of the prevalence of low back pain in the United States range from 12% to 35%,4 and low back pain is considered the most common cause of limited activity in adults younger than 45 years of age.4 Back injury treatment failures might lead to complex pain syndromes that in turn increase treatment difficulty.17 Opioids are currently considered an essential part of pain management.3 The use of long-lasting oral opioids that provide increased patient convenience and compliance, coupled with drug rotation and titration strategies for balancing opioid side effects and analgesic efficacy, can lead to significant improvements in pain and quality of life.10,13 The management of low back pain is currently compromised by a relative lack of evidence-based Received May 7, 2004; Revised September 3, 2004; Accepted September 24, 2004. From the *Gold Coast Research, LLC, Weston, Florida; †INC Research, Charlottesville, Virginia; and ‡Arizona Research Center, Phoenix, Arizona. Sponsored by Endo Pharmaceuticals Inc, Chadds Ford, PA, and Penwest Pharmaceuticals Co, Danbury, CT. Address reprint requests to Martin E. Hale, MD, Gold Coast Research, LLC, 2965 Surrey Lane, Weston, FL 33331. E-mail: [email protected] 1526-5900/$30.00 © 2005 by the American Pain Society doi:10.1016/j.jpain.2004.09.005
literature on the efficacy and safety of opioids in the treatment of chronic low back pain, with only 1 wellcontrolled study supporting the use of a single oral opioid (oxycodone controlled release [CR]) in patients with chronic back pain.16 Additional placebo-controlled studies are needed to assess alternate sustained-release oral opioid options for treating chronic low back pain. Oxymorphone hydrochloride, a semisynthetic opioid agonist, modulates pain and exhibits significant specificity at the opioid receptor with less binding to the receptor relative to oxycodone.30 Oxymorphone differs from morphine in a ketone-group substitution at the C-6 position of morphine and saturation of the 7-8 double bond. The ketone-group substitution makes the molecule more lipid soluble, conferring greater potency and a more rapid onset of action than morphine, the hydroxylated parent compound. The moderate lipid solubility of oxymorphone facilitates rapid penetration into the neurovascular membranes of the brain and spinal cord.30 Oxymorphone is well tolerated and has been shown to provide safe and efficacious relief of chronic pain when administered by intravenous patient-controlled analgesia.20,29,31 Oxymorphone immediate release (IR) and oxymorphone extended release (ER) are recent oral formu-
The Journal of Pain, Vol 6, No 1 (January), 2005: pp 21-28
21
22 lations of oxymorphone. Oxymorphone IR has been shown to provide effective pain relief in patients experiencing moderate to severe pain after major orthopedic surgery.15 Oxymorphone ER has a linear and doseproportional pharmacokinetic profile at doses of 5 to 40 mg, with bioavailability and low fluctuation characteristics consistent with a 12-hour dosing frequency.2 Published data on the clinical efficacy of oxymorphone ER support the pharmacokinetic profile. During a 1-year effectiveness study in patients experiencing moderate to severe pain from chronic osteoarthritis pain, patients maintained their average pain at mild levels with administration every 12 hours and with no opioid rescue medication.21 In a short-term randomized double-blind trial with patients experiencing chronic cancer pain, patients achieved acceptable pain relief with administration every 12 hours and minimal use of rescue medication.14 In this multicenter, randomized, double-blind study, the analgesic efficacy and safety of oxymorphone ER were compared with placebo and the active control oxycodone CR in opioid-experienced patients with moderate to severe chronic low back pain.
Material and Methods Study Participants Participating centers enrolled eligible outpatient men and nonpregnant and nonlactating women 18 to 75 years of age with a confirmed diagnosis of moderate to severe low back pain. Patients were of otherwise good health, but back pain had to be present at least 15 days per month and several hours per day for at least the past 2 months. Patients had to be treated with a stable dose of opioids for at least 3 consecutive days before screening. The most common pain etiologies of enrolled patients were degenerative disc disease, disc herniation, fracture, spondylosis, and spinal stenosis. Patients were excluded if they had fibromyalgia, reflex sympathetic dystrophy or causalgia, acute spinal cord compression, cauda equina compression, acute nerve root compression, severe lower extremity weakness or numbness, bowel or bladder dysfunction as a result of cauda equina compression, diabetic amyotrophy, regional pain syndrome, meningitis, diskitis, back pain because of secondary infection or tumor, or pain caused by a confirmed or suspected neoplasm. In addition, patients were ineligible if they had a major organic psychiatric condition, serious or unstable intercurrent illness, medical conditions affecting drug absorption, history of uncontrolled seizure disorders, history of drug or alcohol dependence, or hypersensitivity to opioids. Patients who had undergone a surgical procedure for back pain within 2 months of screening or had nerve/plexus block within 4 weeks of beginning dose titration were also excluded. Patients with active or pending litigation involving back pain were excluded. Adjunctive therapies for back pain, such as physical therapy, were required to remain unchanged during the study, and the doses of benzodiazepines, antidepressants, anticonvulsants, sedatives, or tranquilizers were
Oxymorphone for Low Back Pain also to remain stable during the study. The study was conducted in compliance with the Declaration of Helsinki and its amendments. All the participating centers received institutional review board approval for the study, and all patients provided written informed consent.
Study Design After a 2-week screening period, eligible patients entered a dose-titration phase in which they were randomized to their titration and treatment sequence. The goal of this phase was to determine for each patient a fixed dose of either oxymorphone ER or oxycodone CR that was tolerated, provided adequate analgesia, and required either minimal or no rescue pain medication. The investigator initiated this phase at visit 2 by providing blinded study drug to be taken at a dose approximately equivalent to the prestudy opioid medication used by each individual patient. The upper daily limit for inclusion in this study was 660 mg of oral morphine. A dose conversion table was used as a guide for determining the initial dose of study drug. The range of doses for oxymorphone ER was based on previous clinical studies suggesting that the ratio of analgesic potency between oral oxycodone and oxymorphone is approximately 2:114 and between oral morphine and oxymorphone is approximately 3:1 (unpublished data on file; Endo Pharmaceuticals Inc, Chadds Ford, PA). Thus, for patients previously receiving analgesic therapy with morphine, the total daily oxymorphone requirement was not expected to be greater than 220 mg. Eligible patients were randomly assigned to doubleblind titration and treatment groups at visit 2. During the dose-titration phase, patients received daily either double-blinded oxymorphone ER or oxycodone CR every 12 hours in the early morning (about 8 AM) and in the evening (about 8 PM). Patients received oxymorphone ER or oxycodone CR titrated at 10 to 110 mg or 20 to 220 mg, respectively, every 12 hours for 7 to 14 days. Patients achieving a stable dose of oxymorphone ER or oxycodone CR entered the 18-day treatment phase and either continued with their current treatment at the fixed dose determined during the double-blind dosetitration phase or received placebo. During double-blind treatment, one third of the patients received oxymorphone ER, one third received oxycodone CR, and one third received placebo. All study drugs were blinded and were taken every 12 hours in the early morning and in the evening. Visit 3 took place at the end of the titration period, visit 4 was about 4 days after visit 3, and the remaining visits (visits 5 and 6) took place at roughly 1-week intervals. A requirement of the study was that patients maintain a stable dose of oxymorphone ER or oxycodone CR throughout the 18-day double-blind treatment phase. The dose was considered stable when adequate pain relief with tolerable side effects and minimal use of rescue medication (defined as no more than two 15-mg tablets of morphine sulfate [MS]/day) was achieved on the same dose for 4 consecutive days. Rescue medication with oral MS (15 mg every 4 to 6
ORIGINAL REPORT/Hale et al
23
Figure 1. Disposition of patients. The intent-to-treat (ITT) population completed the dose-titration phase, received 1 dose of study medication, and completed at least 1 VAS pain intensity assessment during the treatment phase.
hours) was permitted on an unlimited basis for the first 4 days of the double-blind treatment phase to minimize the risk of opioid withdrawal symptoms in the patients who were randomized from active treatment to placebo. Rescue medication was limited to a total daily dosage of 30 mg/day thereafter. Other opioid or nonopioid analgesics were not permitted during the study. Over-thecounter nonsteroidal anti-inflammatory drugs, aspirin, or acetaminophen were permitted as needed for relief of symptoms other than pain. Low-dose aspirin (ⱕ325 mg/day) was permitted for cardiovascular prophylaxis. Investigators did not adjust the fixed dose of blinded study medication during the double-blind treatment phase. Patients who developed intolerance to their established dose of study drug, or who required more than 2 tablets of rescue medication per day after visit 4, were withdrawn from the study. To ensure that the appropriate number of patients was randomly allocated to each treatment group, a randomization code was generated by INC Research (Charlottesville, VA). The study treatment was blocked by site to help ensure equal distribution of patients to treatment
groups within a site. Unique 4-digit numbers were assigned to each study kit and distributed in numeric order at the site, starting with the lowest numbered kit. All participants, investigators, and staff remained blinded to treatment during the study. The study medications were made indistinguishable by overencapsulating the tablets with gelatin and were color coded to differentiate the dose strengths. To break the randomization code in case of an emergency, the study medication bottles had a scratch-off label.
Main Outcome Measures The primary efficacy variable was the change in pain intensity from baseline to study end point as assessed by a 100-mm visual analog scale (VAS) measured 4 hours after the morning dose. The last 4-hour VAS recorded at the end of the titration period was the baseline score. If the patient used rescue medication between the morning dose and the 4-hour evaluation, the VAS pain intensity score after dosing, but before rescue medication, was used. This was done as necessary for baseline and end point assessments. If the 4-hour postdosing pain
24
Figure 2. Average daily dosage of study medication during the double-blind treatment phase.
score at the last visit was missing, the 4-hour VAS pain intensity score from the patient’s last diary entry was used. Secondary efficacy variables included pain intensity as assessed by a categorical scale, pain relief, Brief Pain Inventory (BPI), patient and physician global evaluations, time to treatment failure, and use of rescue medication. Categorical pain intensity and worst daily pain were measured daily by using a 4-point scale: none (0), mild (1), moderate (2), and severe (3). For current pain relief, a 5-point categorical scale was used: none (0), a little (1), moderate (2), a lot (3), or complete (4). Pain intensity was measured at the same intervals used for VAS; current pain relief was measured before each dose and 4 hours after the morning dose, and worst daily pain was measured once a day in the morning. Patients also completed questions 3 through 6, 8, and 9 of the BPI at each visit from the time of dose titration to study end point.11 Global assessments were conducted by using a 5-point categorical scale: poor (1), fair (2), good (3), very good (4), or excellent (5). A Kaplan-Meier analysis was performed to chart treatment failures. Time to discontinuation was defined as the number of days between the start of the double-blind treatment phase until the day the patient withdrew because of lack of effect. Safety assessments included monitoring vital signs, clinical laboratory parameters, adverse events, and opioid side effects. Adverse events were coded according to the Medical Dictionary for Regulatory Affairs.18 To monitor opioid side effects, patients were asked if they experienced nausea, vomiting, constipation, pruritus, sedation, lightheadedness, or sweating.
Statistical Analysis We calculated that 195 evaluable patients were required to detect a 15-mm difference in the VAS with an SD of 24 mm and 90% power. SAS software, version 6.2 (SAS Institute Inc, Cary, NC), was used for all statistical analyses. All statistical analyses were 2-sided, and treatment group comparisons were performed at a significance level of .05. The primary efficacy variable was analyzed by 2-way analysis of covariance with treatment
Oxymorphone for Low Back Pain
Figure 3. Mean change from baseline in daily pain intensity as measured by VAS in the intent-to-treat population with last observation carried forward.
and center as effects and baseline as covariate. Placebo patients titrated with oxymorphone ER or oxycodone CR were found to be statistically comparable to each other for the primary end point and were, therefore, analyzed as a single group. Least squares (LS) means for treatment groups were estimated, and the pairwise difference between LS means, the P value for differences, and the 95% CI around the difference were calculated. Analysis of daily pain intensity (categorical), pain relief, and global assessments used a rank sum test, stratified with respect to center. Time to treatment failure and time to discontinuation were analyzed by using the Kaplan-Meier method with a log-rank test. Analysis of variance was used to evaluate the use of rescue medication.
Results Demographics/Baseline Characteristics Three hundred thirty patients were randomized, and 329 received at least 1 dose of study medication and were analyzed for safety. The intent-to-treat population included 213 patients who completed the dose titration phase with at least 1 VAS pain intensity assessment during the double-blind treatment; the patient disposition is provided in Fig 1. Demographic and baseline characteristics were similar between treatment groups that included 174 men and 155 women. The mean age ranged from 45.5 to 47.5 years, and the majority of patients were white (308 of 329, 93.6%). The mean duration of back pain was similar in all groups and ranged from 7.7 to 8.3 years. Patients received an average daily dosage of 79.4 mg of oxymorphone ER for 16 days and 155 mg of oxycodone CR for 16.5 days. The average daily dosage remained stable throughout the double-blind treatment (Fig 2).
Pain Intensity/Pain Relief The mean change in pain intensity (VAS) from baseline to study end point was significantly greater for placebo than for oxymorphone ER or oxycodone CR, with comparable changes in the 2 active treatment groups (Fig 3). For oxymorphone ER and oxycodone CR the LS mean
ORIGINAL REPORT/Hale et al Table 1.
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Brief Pain Inventory at Study End Point MEAN (SD) PAIN ITEM RATING
Pain intensity Worst pain in last 24 h* Least pain in last 24 h* Average pain in last 24 h* Pain right now* Pain relief in last 24 h‡ Pain interference items§ General activity Mood Walking ability Normal work Relations with other people Sleep Enjoyment of life
PLACEBO (N ⫽ 67)
OXYMORPHONE ER (N ⫽ 71)
OXYCODONE CR (N ⫽ 75)
7.9 (1.78) 4.9 (2.60) 6.2 (1.86) 6.4 (2.38) 39.1 (28.05)
7.0 (2.06)† 3.9 (2.26)† 5.1 (1.79)† 5.8 (2.39) 56.8 (22.91)†
7.0 (2.20)† 4.1 (2.22) 5.4 (1.93)† 5.9 (2.38) 54.1 (25.58)†
6.7 (2.49) 5.9 (2.94) 5.6 (2.70) 6.5 (2.60) 5.2 (2.89) 5.8 (3.18) 6.4 (2.97)
5.5 (2.71)† 4.8 (2.90)† 4.9 (2.85) 5.4 (2.84)† 4.1 (2.90)† 4.8 (2.79) 5.0 (2.74)†
5.5 (2.51)† 4.9 (2.47)† 5.1 (2.69) 5.6 (2.47)† 4.1 (2.48)† 5.0 (2.75) 5.3 (2.65)†
Abbreviations: CR, controlled release; ER, extended release; SD, standard deviation. *From 0 (no pain) to 10 (pain as bad as you can imagine). †Results for Brief Pain Inventory were analyzed by analysis of variance; P ⬍ .05 vs placebo. ‡From 0 (no relief) to 100 (complete relief). §From 0 (does not interfere) to 10 (completely interferes).
differences with placebo were ⫺18.21 (95% CI, ⫺25.83 to ⫺10.58; P ⫽ .0001) and ⫺18.55 (95% CI, ⫺26.12 to ⫺10.98; P ⫽ .0001), respectively. The mean percent change in pain intensity from baseline to study end point was significantly greater in the placebo group compared with oxymorphone ER and oxycodone CR, and the LS mean differences versus placebo were ⫺27.69 (95% CI, ⫺45.96 to ⫺9.41; P ⫽ .0032) and ⫺36.36 (95% CI, ⫺54.51 to ⫺18.21; P ⫽ .0001), respectively. Categorical pain ratings were significantly lower in patients receiving oxymorphone ER compared with placebo (P ⫽ .0001). Pain was rated as none or mild in 35% of patients receiving oxymorphone ER and 12% of patients receiving placebo. Pain was rated severe by 45% of patients receiving placebo compared with 14% receiving oxymorphone ER. Similar results were obtained for the oxycodone CR group. In contrast to placebo, both drugs maintained pain relief scores, with 61% of patients receiving oxymorphone ER or oxycodone CR reporting moderate to complete pain relief compared with 28% for placebo (P ⫽ .0006 and .0001, respectively). Patients who received placebo reported significant increases in worst daily pain (change from baseline to final visit) compared with patients receiving oxymorphone ER or oxycodone CR (P ⫽ .0001 and .0002, respectively, for LS mean difference). More than one fourth (28%) of patients who received placebo reported no pain relief compared with 11% of patients who received oxymorphone ER. Patients who received oxycodone CR also had significantly higher pain relief ratings than those who received placebo (P ⫽ .0001), and the distribution of their pain relief ratings was similar to that of patients who received oxymorphone ER.
Pain interference with daily activities worsened when patients switched to placebo. As shown in Table 1, ratings of pain interference provided by patients receiving either oxymorphone ER or oxycodone CR were significantly lower than ratings provided by patients receiving placebo for the following scales: general activity, mood, normal work, relations with other people, and enjoyment of life.
Global Assessments At the study end point, significantly more patients who received oxymorphone ER (59%) and oxycodone CR (63%) rated their medication as “good,” “very good,” or “excellent” compared with placebo (27%; P ⫽ .0001 for each drug). The majority of physicians also rated oxymorphone ER (62%) and oxycodone CR (65%) as good, very good, or excellent compared with 24% for placebo (P ⫽ .0001 for each drug).
Time to Treatment Failure During the double-blind treatment phase, the majority of patients receiving placebo (57%) discontinued therapy because of a lack of analgesic efficacy, compared with 20% of patients receiving oxymorphone ER and 16% of patients receiving oxycodone CR (P ⫽ .0001 for both drugs, no significant difference between active treatments). The median time to treatment failure was 8 days in the placebo group and more than 18 days in the groups receiving oxymorphone ER or oxycodone CR (Fig 4).
Rescue Medication Use During the first 4 days of the double-blind treatment phase when rescue medication use was unrestricted, the
26
Oxymorphone for Low Back Pain Table 2. Number and Percentage of Patients With Opioid-Related Side Effects
Constipation*,† Sedation†,‡
PLACEBO (N ⫽ 108)
OXYMORPHONE ER (N ⫽ 110)
OXYCODONE CR (N ⫽ 111)
12 (11) 2 (2)
39 (35) 19 (17)
32 (29) 22 (20)
Abbreviations: CR, controlled release; ER, extended release. *P ⫽ .010. †Statistically significant difference among treatment groups. P values are from a rank sum test, stratified with respect to center. ‡P ⫽ .005.
Figure 4. Time to treatment failure (Kaplan-Meier analysis) defined as the point at which patients discontinued the study medication because of lack of efficacy.
mean daily dosage of rescue medication was significantly less for patients receiving oxymorphone ER (25.5 mg; P ⫽ .0068) or oxycodone CR (24.4 mg; P ⫽ .0024) than for those receiving placebo (34.8 mg). After the first 4 days, rescue medication was restricted to twice daily, and all treatment groups had similar mean daily dosages of rescue medication (13.8 to 14.7 mg/day, ⬍1 tablet/day).
Compliance Compliance with the treatment regimen was determined from drug-dispensing records and patient diaries and was judged to be acceptable in all patients who completed the study.
Safety Assessments The incidence, severity, and relation of adverse events to study drug did not differ meaningfully between oxymorphone ER and oxycodone CR during the dosetitration phase or between the active study medications and placebo during the double-blind treatment phase. Most adverse events reported with oxymorphone ER (85%) and oxycodone CR (86%) were mild to moderate in severity. During the dose-titration phase, 3 patients reported serious adverse events deemed “probably” or “possibly” related to study medication, 1 who received oxycodone CR (overdose and decreased respiratory rate) and 2 who received oxymorphone ER (abdominal pain, chest pain, elevated serum creatine phosphokinase level, and elevated serum creatine phosphokinase MB isozyme in 1 patient; worsening of back pain in another). In each case, the study medication was discontinued, and the events resolved without sequelae. No treatment-related serious adverse events were observed during the treatment phase, and none of the adverse events in either phase was considered life threatening. During the treatment phase, approximately half the patients reported opioid-associated side effects, including those assigned to placebo group. Only 2 side effects, constipation and sedation, occurred at a statistically higher rate in patients taking oxymorphone ER or oxycodone CR (Table 2). The majority (86%) of opioidassociated side effects reported among the 3 treatment
groups were mild or moderate in severity. There were no clinically meaningful differences between treatment groups in laboratory test results or vital signs.
Discussion This is the first randomized study to compare sustained-release oral formulations of 2 different opioids in a prospective placebo-controlled trial in chronic low back pain. The primary and multiple secondary end points demonstrate that both oxymorphone ER and oxycodone CR provide significant analgesia with minimal need for rescue medication and comparable adverse event profiles. Although mild to moderate opioid-related adverse events (constipation and sedation) were comparable between the 2 active treatments, oxymorphone ER was equianalgesic to oxycodone CR at almost half the milligram dose. Treatment with oxymorphone ER provided superior analgesic efficacy relative to placebo, as determined by change from baseline in pain intensity, as well as in worst pain rating, BPI items related to pain, and BPI interference of pain in quality of life. Oxycodone CR provided the same degree of analgesia. During the double-blind treatment phase, a satisfactory pain relief was achieved on an average daily dose of approximately 79 mg of oxymorphone ER and 155 mg of oxycodone CR. This result is consistent with a recent report in patients with chronic cancer pain indicating a 2:1 dose ratio for oxycodone relative to oxymorphone.14 Rescue medication was restricted to less than 30 mg of MS per day in both active treatment groups. Rates of opioid-related adverse events were comparable for oxymorphone ER and oxycodone CR, and most were mild or moderate. Both oxymorphone ER and oxycodone CR treatments were associated with low rates of nonopioid-related adverse events, most of which were also mild or moderate. There were no clinically meaningful changes in laboratory, physical examination, or vital signs results for either active treatment group. Our study included a 1- to 2-week titration/stabilization phase followed by 10 days of double-blind treatment, for a total trial duration of 3.5 to 4.5 weeks. This study length is comparable to other investigations of analgesic agents for moderate to severe pain.5,8,9,24,28 It is important to emphasize that longer-term placebo-
ORIGINAL REPORT/Hale et al controlled trials are difficult to perform in patients with moderate to severe pain. Typically, patients with moderate to severe pain who receive placebo drop out quickly because of lack of efficacy, and this was observed in the present trial. During the double-blind treatment phase, 57% of patients who received placebo discontinued therapy because of lack of efficacy, compared with 16% to 20% of those who were treated with active drug. Oxymorphone ER is a new extended-release tablet formulation of oxymorphone hydrochloride (14-hydroxydihydromorphinone) that uses TIMERx matrix technology (Penwest Pharmaceuticals Co, Danbury, CT), which allows for 12-hour administration.1 Oxymorphone is several times more potent than its parent compound morphine, with a more rapid onset of action.30 In contrast to some opioid analgesics, oxymorphone modulates pain by acting with significant specificity at the opioid receptor site, while exhibiting minimal activity at the or ␦ receptors.22,27 Pharmacokinetic data show that oxymorphone ER has a low fluctuation index with dosing every 12 hours at steady state.2 Reduced fluctuations in drug plasma concentrations are predicted to provide more consistent pain relief and, potentially, improvements in quality of life relative to patients taking short-acting opioids.13 In addition, oxymorphone is not significantly metabolized by the cytochrome P450 enzyme system (unpublished data on file; Endo Pharmaceuticals Inc); hence, the potential for drug interactions, analgesic insufficiency, and adverse events might be lower than with opioids that are metabolized primarily by the cytochrome P450 system (eg, oxycodone). Within this context, it is important to note that patient responses to opioids are highly variable. Patients failing to achieve adequate analgesia with acceptable side effects with one opioid can often benefit from a change of opioid medication.10,25 Although it is not clear how much of patient variability is due to genetic differences (in opioid receptor genes or drug metabolism) versus environmental factors (such as concomitant medications), new treatment options are important in helping to clinically manage heterogenous patient responses. The pharmacokinetic and pharmacodynamic properties of oxymorphone ER, as well as the clinical data presented here, indicate that oxymorphone ER might be an appropriate treatment option for moderate to severe pain. Chronic low back pain is often severe, persistent, and disabling, yet the use of opioid analgesics for chronic non-
27 malignant pain, including low back pain, is frequently overlooked.7 The underuse of opioids in the treatment of chronic low back pain is likely exacerbated by the limited information available to healthcare professionals, particularly in the form of well-controlled clinical studies. A review of the literature on oral or transdermal opioid analgesic treatment for chronic low back pain6 identified only a small number of randomized, double-blind16,23 or open label19 studies. The data from our study provide important additional support that long-acting opioids are effective and safe options for the short-term management of chronic low back pain. Longer studies are required to determine whether stable dosing with low use of rescue medication is achieved beyond the 18-day treatment period observed in this study. Although studies of clinical efficacy can help to document the utility of opioids in treating low back pain, undertreatment of the condition is also driven by concerns regarding the misuse of opioid medications.26 According to the National Household Survey on Drug Abuse, the nonmedical use of pain relievers increased from 1.2% to 1.6% from 2000 to 2001. During the same period, there were no statistically significant increases in drug abuse for adults older than 26 years.12 Thus, when adjustments are made for factors like age, the potential for medication abuse might be lower than 1% to 2% in patient populations seeking relief from chronic low back pain. The present study was not designed to address issues related to medication abuse; high-risk patients (eg, those with a history of psychiatric disease) were excluded, the study was of short duration, and specific evaluations related to abuse were not performed. The issue of abuse in chronic opioid therapy patients warrants further scientific study. The results of this study (1) indicate that oxymorphone ER was a generally safe and effective treatment option in a selected group of patients with chronic low back pain requiring opioid treatment; (2) confirm previous findings on the efficacy and safety of oxycodone CR; and (3) indicate that oxymorphone ER produced equal analgesia at almost half the dose of oxycodone CR, suggesting a relative potency ratio of 2:1.
Acknowledgment We thank Beth Cuccia for her management of this clinical trial.
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5. Arkinstall W, Sandler A, Goughnour B, Babul N, Harsanyi Z, Darke AC: Efficacy of controlled-release codeine in chronic non-malignant pain: a randomized, placebocontrolled clinical trial. Pain 62:169-178, 1995 6. Bartleson JD: Evidence for and against the use of opioid
28 analgesics for chronic nonmalignant low back pain: a review. Pain Med 3:260-271, 2002 7. Brown RL, Fleming MF, Patterson JJ: Chronic opioid analgesic therapy for chronic low back pain. J Am Board Fam Pract 9:191-204, 1996 8. Caldwell JR, Hale ME, Boyd RE, Hague JM, Iwan T, Shi M, Lacouture PG: Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial. J Rheumatol 26:862-869, 1999 9. Caldwell JR, Rapoport RJ, Davis JC, Offenberg HL, Marker HW, Roth SH, Yuan W, Eliot L, Babul N, Lynch PM: 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. J Pain Symptom Manage 23:278291, 2002 10. Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, Mercadante S, Pasternak G, Ventafridda V: Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 19:2542-2554, 2001 11. Cleeland CS, Ryan KM: Pain assessment: Global use of the Brief Pain Inventory. Ann Acad Med (Singapore) 23:129138, 1994 12. Department of Health and Human Services: Results from the 2001 national household survey on drug abuse: Volume 1. Summary of national findings. Department of Health and Human Services. Available at: http://www.DrugAbuseStatistics.SAMHSA.gov. Accessed April 17, 2003 13. Ferrell B, Wisdom C, Wenzl C, Brown J: Effects of controlled-released morphine on quality of life for cancer pain. Oncol Nurs Forum 16:521-526, 1989 14. Gabrail NY, Dvergsten C, Ahdieh H: Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study. Curr Med Res Opin 20:911918, 2004 15. Gimbel J, Ahdieh H: Efficacy and safety of oral immediate-release oxymorphone in postsurgical pain. Anesth Analg 99:1472-1477, 2004 16. Hale ME, Fleischmann R, Salzman R, Wild J, Iwan T, Swanton RE, Kaiko RF, Lacouture PG: Efficacy and safety of controlled-release versus immediate-release oxycodone: randomized, double-blind evaluation in patients with chronic back pain. Clin J Pain 15:179-183, 1999 17. Hines R, Keaney D, Moskowitz MH, Prakken S: Use of lidocaine patch 5% for chronic low back pain: a report of four cases. Pain Med 3:361-365, 2002 18. International Conference on Harmonization: Medical Dictionary for Regulatory Activities (MedDRA). Northrup
Oxymorphone for Low Back Pain Grumman. Available at: http://www.meddramsso.com/ newwebaug2001/meddramsso/meddra/index.htm. Accessed October 4, 2003 19. Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP: Opioid therapy for chronic noncancer back pain: a randomized prospective study. Spine 23:2591-2600, 1998 20. Lampert BA, Sundstrom FD, Merrill J, Meinhardt D, Boyd-Long L: Oxymorphone in patient-controlled analgesia. Anesthesiol Rev 15:35-39, 1988 21. McIlwain H, Ahdieh H: Safety, tolerability, and effectiveness of oxymorphone extended release for moderate to severe osteoarthritis pain: a one-year study. Am J Ther. In press 22. Metzger TG, Paterlini MG, Ferguson DM, Portoghese PS: Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the “address” recognition locus. J Med Chem 44:857-862, 2001 23. Moulin DE, Iezzi A, Amireh R, Sharpe WK, Boyd D, Merskey H: Randomised trial of oral morphine for chronic noncancer pain. Lancet 347:143-147, 1996 24. Peloso PM, Bellamy N, Bensen W, Thomson GT, Harsanyi Z, Babul N, Darke AC: Double blind randomized placebo control trial of controlled release codeine in the treatment of osteoarthritis of the hip or knee. J Rheumatol 27:764-771, 2000 25. Quang-Cantagrel ND, Wallace MS, Magnuson SK: Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review. Anesth Analg 90:933937, 2000 26. Resnik DB, Rehm M, Minard RB: The undertreatment of pain: Scientific, clinical, cultural, and philosophical factors. Med Health Care Philos 4:277-288, 2001 27. Ross FB, Smith MT: The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain 73:151-157, 1997 28. Roth SH, Fleischmann RM, Burch FX, Dietz F, Bockow B, Rapoport RJ, Rutstein J, Lacouture PG: Around-the-clock, controlled-release oxycodone therapy for osteoarthritisrelated pain: placebo-controlled trial and long-term evaluation. Arch Intern Med 160:853-860, 2000 29. Sinatra R, Chung KS, Silverman DG, Brull SJ, Chung J, Harrison DM, Donielson D, Weinstock A: An evaluation of morphine and oxymorphone administered via patientcontrolled analgesia (PCA) or PCA plus basal infusion in postcesarean-delivery patients. Anesthesiology 71:502-507, 1989 30. Sinatra RS, Hyde NH, Harrison DM: Oxymorphone revisited. Semin Anesth 7:209-215, 1988 31. Sinatra RS, Lodge K, Sibert K, Chung KS, Chung JH, Parker A Jr, Harrison DM: A comparison of morphine, meperidine, and oxymorphone as utilized in patient-controlled analgesia following cesarean delivery. Anesthesiology 70: 585-590, 1989
E
stimates of the prevalence of low back pain in the United States range from 12% to 35%,4 and low back pain is considered the most common cause of limited activity in adults younger than 45 years of age.4 Back injury treatment failures might lead to complex pain syndromes that in turn increase treatment difficulty.17 Opioids are currently considered an essential part of pain management.3 The use of long-lasting oral opioids that provide increased patient convenience and compliance, coupled with drug rotation and titration strategies for balancing opioid side effects and analgesic efficacy, can lead to significant improvements in pain and quality of life.10,13 The management of low back pain is currently compromised by a relative lack of evidence-based Received May 7, 2004; Revised September 3, 2004; Accepted September 24, 2004. From the *Gold Coast Research, LLC, Weston, Florida; †INC Research, Charlottesville, Virginia; and ‡Arizona Research Center, Phoenix, Arizona. Sponsored by Endo Pharmaceuticals Inc, Chadds Ford, PA, and Penwest Pharmaceuticals Co, Danbury, CT. Address reprint requests to Martin E. Hale, MD, Gold Coast Research, LLC, 2965 Surrey Lane, Weston, FL 33331. E-mail: [email protected] 1526-5900/$30.00 © 2005 by the American Pain Society doi:10.1016/j.jpain.2004.09.005
literature on the efficacy and safety of opioids in the treatment of chronic low back pain, with only 1 wellcontrolled study supporting the use of a single oral opioid (oxycodone controlled release [CR]) in patients with chronic back pain.16 Additional placebo-controlled studies are needed to assess alternate sustained-release oral opioid options for treating chronic low back pain. Oxymorphone hydrochloride, a semisynthetic opioid agonist, modulates pain and exhibits significant specificity at the opioid receptor with less binding to the receptor relative to oxycodone.30 Oxymorphone differs from morphine in a ketone-group substitution at the C-6 position of morphine and saturation of the 7-8 double bond. The ketone-group substitution makes the molecule more lipid soluble, conferring greater potency and a more rapid onset of action than morphine, the hydroxylated parent compound. The moderate lipid solubility of oxymorphone facilitates rapid penetration into the neurovascular membranes of the brain and spinal cord.30 Oxymorphone is well tolerated and has been shown to provide safe and efficacious relief of chronic pain when administered by intravenous patient-controlled analgesia.20,29,31 Oxymorphone immediate release (IR) and oxymorphone extended release (ER) are recent oral formu-
The Journal of Pain, Vol 6, No 1 (January), 2005: pp 21-28
21
22 lations of oxymorphone. Oxymorphone IR has been shown to provide effective pain relief in patients experiencing moderate to severe pain after major orthopedic surgery.15 Oxymorphone ER has a linear and doseproportional pharmacokinetic profile at doses of 5 to 40 mg, with bioavailability and low fluctuation characteristics consistent with a 12-hour dosing frequency.2 Published data on the clinical efficacy of oxymorphone ER support the pharmacokinetic profile. During a 1-year effectiveness study in patients experiencing moderate to severe pain from chronic osteoarthritis pain, patients maintained their average pain at mild levels with administration every 12 hours and with no opioid rescue medication.21 In a short-term randomized double-blind trial with patients experiencing chronic cancer pain, patients achieved acceptable pain relief with administration every 12 hours and minimal use of rescue medication.14 In this multicenter, randomized, double-blind study, the analgesic efficacy and safety of oxymorphone ER were compared with placebo and the active control oxycodone CR in opioid-experienced patients with moderate to severe chronic low back pain.
Material and Methods Study Participants Participating centers enrolled eligible outpatient men and nonpregnant and nonlactating women 18 to 75 years of age with a confirmed diagnosis of moderate to severe low back pain. Patients were of otherwise good health, but back pain had to be present at least 15 days per month and several hours per day for at least the past 2 months. Patients had to be treated with a stable dose of opioids for at least 3 consecutive days before screening. The most common pain etiologies of enrolled patients were degenerative disc disease, disc herniation, fracture, spondylosis, and spinal stenosis. Patients were excluded if they had fibromyalgia, reflex sympathetic dystrophy or causalgia, acute spinal cord compression, cauda equina compression, acute nerve root compression, severe lower extremity weakness or numbness, bowel or bladder dysfunction as a result of cauda equina compression, diabetic amyotrophy, regional pain syndrome, meningitis, diskitis, back pain because of secondary infection or tumor, or pain caused by a confirmed or suspected neoplasm. In addition, patients were ineligible if they had a major organic psychiatric condition, serious or unstable intercurrent illness, medical conditions affecting drug absorption, history of uncontrolled seizure disorders, history of drug or alcohol dependence, or hypersensitivity to opioids. Patients who had undergone a surgical procedure for back pain within 2 months of screening or had nerve/plexus block within 4 weeks of beginning dose titration were also excluded. Patients with active or pending litigation involving back pain were excluded. Adjunctive therapies for back pain, such as physical therapy, were required to remain unchanged during the study, and the doses of benzodiazepines, antidepressants, anticonvulsants, sedatives, or tranquilizers were
Oxymorphone for Low Back Pain also to remain stable during the study. The study was conducted in compliance with the Declaration of Helsinki and its amendments. All the participating centers received institutional review board approval for the study, and all patients provided written informed consent.
Study Design After a 2-week screening period, eligible patients entered a dose-titration phase in which they were randomized to their titration and treatment sequence. The goal of this phase was to determine for each patient a fixed dose of either oxymorphone ER or oxycodone CR that was tolerated, provided adequate analgesia, and required either minimal or no rescue pain medication. The investigator initiated this phase at visit 2 by providing blinded study drug to be taken at a dose approximately equivalent to the prestudy opioid medication used by each individual patient. The upper daily limit for inclusion in this study was 660 mg of oral morphine. A dose conversion table was used as a guide for determining the initial dose of study drug. The range of doses for oxymorphone ER was based on previous clinical studies suggesting that the ratio of analgesic potency between oral oxycodone and oxymorphone is approximately 2:114 and between oral morphine and oxymorphone is approximately 3:1 (unpublished data on file; Endo Pharmaceuticals Inc, Chadds Ford, PA). Thus, for patients previously receiving analgesic therapy with morphine, the total daily oxymorphone requirement was not expected to be greater than 220 mg. Eligible patients were randomly assigned to doubleblind titration and treatment groups at visit 2. During the dose-titration phase, patients received daily either double-blinded oxymorphone ER or oxycodone CR every 12 hours in the early morning (about 8 AM) and in the evening (about 8 PM). Patients received oxymorphone ER or oxycodone CR titrated at 10 to 110 mg or 20 to 220 mg, respectively, every 12 hours for 7 to 14 days. Patients achieving a stable dose of oxymorphone ER or oxycodone CR entered the 18-day treatment phase and either continued with their current treatment at the fixed dose determined during the double-blind dosetitration phase or received placebo. During double-blind treatment, one third of the patients received oxymorphone ER, one third received oxycodone CR, and one third received placebo. All study drugs were blinded and were taken every 12 hours in the early morning and in the evening. Visit 3 took place at the end of the titration period, visit 4 was about 4 days after visit 3, and the remaining visits (visits 5 and 6) took place at roughly 1-week intervals. A requirement of the study was that patients maintain a stable dose of oxymorphone ER or oxycodone CR throughout the 18-day double-blind treatment phase. The dose was considered stable when adequate pain relief with tolerable side effects and minimal use of rescue medication (defined as no more than two 15-mg tablets of morphine sulfate [MS]/day) was achieved on the same dose for 4 consecutive days. Rescue medication with oral MS (15 mg every 4 to 6
ORIGINAL REPORT/Hale et al
23
Figure 1. Disposition of patients. The intent-to-treat (ITT) population completed the dose-titration phase, received 1 dose of study medication, and completed at least 1 VAS pain intensity assessment during the treatment phase.
hours) was permitted on an unlimited basis for the first 4 days of the double-blind treatment phase to minimize the risk of opioid withdrawal symptoms in the patients who were randomized from active treatment to placebo. Rescue medication was limited to a total daily dosage of 30 mg/day thereafter. Other opioid or nonopioid analgesics were not permitted during the study. Over-thecounter nonsteroidal anti-inflammatory drugs, aspirin, or acetaminophen were permitted as needed for relief of symptoms other than pain. Low-dose aspirin (ⱕ325 mg/day) was permitted for cardiovascular prophylaxis. Investigators did not adjust the fixed dose of blinded study medication during the double-blind treatment phase. Patients who developed intolerance to their established dose of study drug, or who required more than 2 tablets of rescue medication per day after visit 4, were withdrawn from the study. To ensure that the appropriate number of patients was randomly allocated to each treatment group, a randomization code was generated by INC Research (Charlottesville, VA). The study treatment was blocked by site to help ensure equal distribution of patients to treatment
groups within a site. Unique 4-digit numbers were assigned to each study kit and distributed in numeric order at the site, starting with the lowest numbered kit. All participants, investigators, and staff remained blinded to treatment during the study. The study medications were made indistinguishable by overencapsulating the tablets with gelatin and were color coded to differentiate the dose strengths. To break the randomization code in case of an emergency, the study medication bottles had a scratch-off label.
Main Outcome Measures The primary efficacy variable was the change in pain intensity from baseline to study end point as assessed by a 100-mm visual analog scale (VAS) measured 4 hours after the morning dose. The last 4-hour VAS recorded at the end of the titration period was the baseline score. If the patient used rescue medication between the morning dose and the 4-hour evaluation, the VAS pain intensity score after dosing, but before rescue medication, was used. This was done as necessary for baseline and end point assessments. If the 4-hour postdosing pain
24
Figure 2. Average daily dosage of study medication during the double-blind treatment phase.
score at the last visit was missing, the 4-hour VAS pain intensity score from the patient’s last diary entry was used. Secondary efficacy variables included pain intensity as assessed by a categorical scale, pain relief, Brief Pain Inventory (BPI), patient and physician global evaluations, time to treatment failure, and use of rescue medication. Categorical pain intensity and worst daily pain were measured daily by using a 4-point scale: none (0), mild (1), moderate (2), and severe (3). For current pain relief, a 5-point categorical scale was used: none (0), a little (1), moderate (2), a lot (3), or complete (4). Pain intensity was measured at the same intervals used for VAS; current pain relief was measured before each dose and 4 hours after the morning dose, and worst daily pain was measured once a day in the morning. Patients also completed questions 3 through 6, 8, and 9 of the BPI at each visit from the time of dose titration to study end point.11 Global assessments were conducted by using a 5-point categorical scale: poor (1), fair (2), good (3), very good (4), or excellent (5). A Kaplan-Meier analysis was performed to chart treatment failures. Time to discontinuation was defined as the number of days between the start of the double-blind treatment phase until the day the patient withdrew because of lack of effect. Safety assessments included monitoring vital signs, clinical laboratory parameters, adverse events, and opioid side effects. Adverse events were coded according to the Medical Dictionary for Regulatory Affairs.18 To monitor opioid side effects, patients were asked if they experienced nausea, vomiting, constipation, pruritus, sedation, lightheadedness, or sweating.
Statistical Analysis We calculated that 195 evaluable patients were required to detect a 15-mm difference in the VAS with an SD of 24 mm and 90% power. SAS software, version 6.2 (SAS Institute Inc, Cary, NC), was used for all statistical analyses. All statistical analyses were 2-sided, and treatment group comparisons were performed at a significance level of .05. The primary efficacy variable was analyzed by 2-way analysis of covariance with treatment
Oxymorphone for Low Back Pain
Figure 3. Mean change from baseline in daily pain intensity as measured by VAS in the intent-to-treat population with last observation carried forward.
and center as effects and baseline as covariate. Placebo patients titrated with oxymorphone ER or oxycodone CR were found to be statistically comparable to each other for the primary end point and were, therefore, analyzed as a single group. Least squares (LS) means for treatment groups were estimated, and the pairwise difference between LS means, the P value for differences, and the 95% CI around the difference were calculated. Analysis of daily pain intensity (categorical), pain relief, and global assessments used a rank sum test, stratified with respect to center. Time to treatment failure and time to discontinuation were analyzed by using the Kaplan-Meier method with a log-rank test. Analysis of variance was used to evaluate the use of rescue medication.
Results Demographics/Baseline Characteristics Three hundred thirty patients were randomized, and 329 received at least 1 dose of study medication and were analyzed for safety. The intent-to-treat population included 213 patients who completed the dose titration phase with at least 1 VAS pain intensity assessment during the double-blind treatment; the patient disposition is provided in Fig 1. Demographic and baseline characteristics were similar between treatment groups that included 174 men and 155 women. The mean age ranged from 45.5 to 47.5 years, and the majority of patients were white (308 of 329, 93.6%). The mean duration of back pain was similar in all groups and ranged from 7.7 to 8.3 years. Patients received an average daily dosage of 79.4 mg of oxymorphone ER for 16 days and 155 mg of oxycodone CR for 16.5 days. The average daily dosage remained stable throughout the double-blind treatment (Fig 2).
Pain Intensity/Pain Relief The mean change in pain intensity (VAS) from baseline to study end point was significantly greater for placebo than for oxymorphone ER or oxycodone CR, with comparable changes in the 2 active treatment groups (Fig 3). For oxymorphone ER and oxycodone CR the LS mean
ORIGINAL REPORT/Hale et al Table 1.
25
Brief Pain Inventory at Study End Point MEAN (SD) PAIN ITEM RATING
Pain intensity Worst pain in last 24 h* Least pain in last 24 h* Average pain in last 24 h* Pain right now* Pain relief in last 24 h‡ Pain interference items§ General activity Mood Walking ability Normal work Relations with other people Sleep Enjoyment of life
PLACEBO (N ⫽ 67)
OXYMORPHONE ER (N ⫽ 71)
OXYCODONE CR (N ⫽ 75)
7.9 (1.78) 4.9 (2.60) 6.2 (1.86) 6.4 (2.38) 39.1 (28.05)
7.0 (2.06)† 3.9 (2.26)† 5.1 (1.79)† 5.8 (2.39) 56.8 (22.91)†
7.0 (2.20)† 4.1 (2.22) 5.4 (1.93)† 5.9 (2.38) 54.1 (25.58)†
6.7 (2.49) 5.9 (2.94) 5.6 (2.70) 6.5 (2.60) 5.2 (2.89) 5.8 (3.18) 6.4 (2.97)
5.5 (2.71)† 4.8 (2.90)† 4.9 (2.85) 5.4 (2.84)† 4.1 (2.90)† 4.8 (2.79) 5.0 (2.74)†
5.5 (2.51)† 4.9 (2.47)† 5.1 (2.69) 5.6 (2.47)† 4.1 (2.48)† 5.0 (2.75) 5.3 (2.65)†
Abbreviations: CR, controlled release; ER, extended release; SD, standard deviation. *From 0 (no pain) to 10 (pain as bad as you can imagine). †Results for Brief Pain Inventory were analyzed by analysis of variance; P ⬍ .05 vs placebo. ‡From 0 (no relief) to 100 (complete relief). §From 0 (does not interfere) to 10 (completely interferes).
differences with placebo were ⫺18.21 (95% CI, ⫺25.83 to ⫺10.58; P ⫽ .0001) and ⫺18.55 (95% CI, ⫺26.12 to ⫺10.98; P ⫽ .0001), respectively. The mean percent change in pain intensity from baseline to study end point was significantly greater in the placebo group compared with oxymorphone ER and oxycodone CR, and the LS mean differences versus placebo were ⫺27.69 (95% CI, ⫺45.96 to ⫺9.41; P ⫽ .0032) and ⫺36.36 (95% CI, ⫺54.51 to ⫺18.21; P ⫽ .0001), respectively. Categorical pain ratings were significantly lower in patients receiving oxymorphone ER compared with placebo (P ⫽ .0001). Pain was rated as none or mild in 35% of patients receiving oxymorphone ER and 12% of patients receiving placebo. Pain was rated severe by 45% of patients receiving placebo compared with 14% receiving oxymorphone ER. Similar results were obtained for the oxycodone CR group. In contrast to placebo, both drugs maintained pain relief scores, with 61% of patients receiving oxymorphone ER or oxycodone CR reporting moderate to complete pain relief compared with 28% for placebo (P ⫽ .0006 and .0001, respectively). Patients who received placebo reported significant increases in worst daily pain (change from baseline to final visit) compared with patients receiving oxymorphone ER or oxycodone CR (P ⫽ .0001 and .0002, respectively, for LS mean difference). More than one fourth (28%) of patients who received placebo reported no pain relief compared with 11% of patients who received oxymorphone ER. Patients who received oxycodone CR also had significantly higher pain relief ratings than those who received placebo (P ⫽ .0001), and the distribution of their pain relief ratings was similar to that of patients who received oxymorphone ER.
Pain interference with daily activities worsened when patients switched to placebo. As shown in Table 1, ratings of pain interference provided by patients receiving either oxymorphone ER or oxycodone CR were significantly lower than ratings provided by patients receiving placebo for the following scales: general activity, mood, normal work, relations with other people, and enjoyment of life.
Global Assessments At the study end point, significantly more patients who received oxymorphone ER (59%) and oxycodone CR (63%) rated their medication as “good,” “very good,” or “excellent” compared with placebo (27%; P ⫽ .0001 for each drug). The majority of physicians also rated oxymorphone ER (62%) and oxycodone CR (65%) as good, very good, or excellent compared with 24% for placebo (P ⫽ .0001 for each drug).
Time to Treatment Failure During the double-blind treatment phase, the majority of patients receiving placebo (57%) discontinued therapy because of a lack of analgesic efficacy, compared with 20% of patients receiving oxymorphone ER and 16% of patients receiving oxycodone CR (P ⫽ .0001 for both drugs, no significant difference between active treatments). The median time to treatment failure was 8 days in the placebo group and more than 18 days in the groups receiving oxymorphone ER or oxycodone CR (Fig 4).
Rescue Medication Use During the first 4 days of the double-blind treatment phase when rescue medication use was unrestricted, the
26
Oxymorphone for Low Back Pain Table 2. Number and Percentage of Patients With Opioid-Related Side Effects
Constipation*,† Sedation†,‡
PLACEBO (N ⫽ 108)
OXYMORPHONE ER (N ⫽ 110)
OXYCODONE CR (N ⫽ 111)
12 (11) 2 (2)
39 (35) 19 (17)
32 (29) 22 (20)
Abbreviations: CR, controlled release; ER, extended release. *P ⫽ .010. †Statistically significant difference among treatment groups. P values are from a rank sum test, stratified with respect to center. ‡P ⫽ .005.
Figure 4. Time to treatment failure (Kaplan-Meier analysis) defined as the point at which patients discontinued the study medication because of lack of efficacy.
mean daily dosage of rescue medication was significantly less for patients receiving oxymorphone ER (25.5 mg; P ⫽ .0068) or oxycodone CR (24.4 mg; P ⫽ .0024) than for those receiving placebo (34.8 mg). After the first 4 days, rescue medication was restricted to twice daily, and all treatment groups had similar mean daily dosages of rescue medication (13.8 to 14.7 mg/day, ⬍1 tablet/day).
Compliance Compliance with the treatment regimen was determined from drug-dispensing records and patient diaries and was judged to be acceptable in all patients who completed the study.
Safety Assessments The incidence, severity, and relation of adverse events to study drug did not differ meaningfully between oxymorphone ER and oxycodone CR during the dosetitration phase or between the active study medications and placebo during the double-blind treatment phase. Most adverse events reported with oxymorphone ER (85%) and oxycodone CR (86%) were mild to moderate in severity. During the dose-titration phase, 3 patients reported serious adverse events deemed “probably” or “possibly” related to study medication, 1 who received oxycodone CR (overdose and decreased respiratory rate) and 2 who received oxymorphone ER (abdominal pain, chest pain, elevated serum creatine phosphokinase level, and elevated serum creatine phosphokinase MB isozyme in 1 patient; worsening of back pain in another). In each case, the study medication was discontinued, and the events resolved without sequelae. No treatment-related serious adverse events were observed during the treatment phase, and none of the adverse events in either phase was considered life threatening. During the treatment phase, approximately half the patients reported opioid-associated side effects, including those assigned to placebo group. Only 2 side effects, constipation and sedation, occurred at a statistically higher rate in patients taking oxymorphone ER or oxycodone CR (Table 2). The majority (86%) of opioidassociated side effects reported among the 3 treatment
groups were mild or moderate in severity. There were no clinically meaningful differences between treatment groups in laboratory test results or vital signs.
Discussion This is the first randomized study to compare sustained-release oral formulations of 2 different opioids in a prospective placebo-controlled trial in chronic low back pain. The primary and multiple secondary end points demonstrate that both oxymorphone ER and oxycodone CR provide significant analgesia with minimal need for rescue medication and comparable adverse event profiles. Although mild to moderate opioid-related adverse events (constipation and sedation) were comparable between the 2 active treatments, oxymorphone ER was equianalgesic to oxycodone CR at almost half the milligram dose. Treatment with oxymorphone ER provided superior analgesic efficacy relative to placebo, as determined by change from baseline in pain intensity, as well as in worst pain rating, BPI items related to pain, and BPI interference of pain in quality of life. Oxycodone CR provided the same degree of analgesia. During the double-blind treatment phase, a satisfactory pain relief was achieved on an average daily dose of approximately 79 mg of oxymorphone ER and 155 mg of oxycodone CR. This result is consistent with a recent report in patients with chronic cancer pain indicating a 2:1 dose ratio for oxycodone relative to oxymorphone.14 Rescue medication was restricted to less than 30 mg of MS per day in both active treatment groups. Rates of opioid-related adverse events were comparable for oxymorphone ER and oxycodone CR, and most were mild or moderate. Both oxymorphone ER and oxycodone CR treatments were associated with low rates of nonopioid-related adverse events, most of which were also mild or moderate. There were no clinically meaningful changes in laboratory, physical examination, or vital signs results for either active treatment group. Our study included a 1- to 2-week titration/stabilization phase followed by 10 days of double-blind treatment, for a total trial duration of 3.5 to 4.5 weeks. This study length is comparable to other investigations of analgesic agents for moderate to severe pain.5,8,9,24,28 It is important to emphasize that longer-term placebo-
ORIGINAL REPORT/Hale et al controlled trials are difficult to perform in patients with moderate to severe pain. Typically, patients with moderate to severe pain who receive placebo drop out quickly because of lack of efficacy, and this was observed in the present trial. During the double-blind treatment phase, 57% of patients who received placebo discontinued therapy because of lack of efficacy, compared with 16% to 20% of those who were treated with active drug. Oxymorphone ER is a new extended-release tablet formulation of oxymorphone hydrochloride (14-hydroxydihydromorphinone) that uses TIMERx matrix technology (Penwest Pharmaceuticals Co, Danbury, CT), which allows for 12-hour administration.1 Oxymorphone is several times more potent than its parent compound morphine, with a more rapid onset of action.30 In contrast to some opioid analgesics, oxymorphone modulates pain by acting with significant specificity at the opioid receptor site, while exhibiting minimal activity at the or ␦ receptors.22,27 Pharmacokinetic data show that oxymorphone ER has a low fluctuation index with dosing every 12 hours at steady state.2 Reduced fluctuations in drug plasma concentrations are predicted to provide more consistent pain relief and, potentially, improvements in quality of life relative to patients taking short-acting opioids.13 In addition, oxymorphone is not significantly metabolized by the cytochrome P450 enzyme system (unpublished data on file; Endo Pharmaceuticals Inc); hence, the potential for drug interactions, analgesic insufficiency, and adverse events might be lower than with opioids that are metabolized primarily by the cytochrome P450 system (eg, oxycodone). Within this context, it is important to note that patient responses to opioids are highly variable. Patients failing to achieve adequate analgesia with acceptable side effects with one opioid can often benefit from a change of opioid medication.10,25 Although it is not clear how much of patient variability is due to genetic differences (in opioid receptor genes or drug metabolism) versus environmental factors (such as concomitant medications), new treatment options are important in helping to clinically manage heterogenous patient responses. The pharmacokinetic and pharmacodynamic properties of oxymorphone ER, as well as the clinical data presented here, indicate that oxymorphone ER might be an appropriate treatment option for moderate to severe pain. Chronic low back pain is often severe, persistent, and disabling, yet the use of opioid analgesics for chronic non-
27 malignant pain, including low back pain, is frequently overlooked.7 The underuse of opioids in the treatment of chronic low back pain is likely exacerbated by the limited information available to healthcare professionals, particularly in the form of well-controlled clinical studies. A review of the literature on oral or transdermal opioid analgesic treatment for chronic low back pain6 identified only a small number of randomized, double-blind16,23 or open label19 studies. The data from our study provide important additional support that long-acting opioids are effective and safe options for the short-term management of chronic low back pain. Longer studies are required to determine whether stable dosing with low use of rescue medication is achieved beyond the 18-day treatment period observed in this study. Although studies of clinical efficacy can help to document the utility of opioids in treating low back pain, undertreatment of the condition is also driven by concerns regarding the misuse of opioid medications.26 According to the National Household Survey on Drug Abuse, the nonmedical use of pain relievers increased from 1.2% to 1.6% from 2000 to 2001. During the same period, there were no statistically significant increases in drug abuse for adults older than 26 years.12 Thus, when adjustments are made for factors like age, the potential for medication abuse might be lower than 1% to 2% in patient populations seeking relief from chronic low back pain. The present study was not designed to address issues related to medication abuse; high-risk patients (eg, those with a history of psychiatric disease) were excluded, the study was of short duration, and specific evaluations related to abuse were not performed. The issue of abuse in chronic opioid therapy patients warrants further scientific study. The results of this study (1) indicate that oxymorphone ER was a generally safe and effective treatment option in a selected group of patients with chronic low back pain requiring opioid treatment; (2) confirm previous findings on the efficacy and safety of oxycodone CR; and (3) indicate that oxymorphone ER produced equal analgesia at almost half the dose of oxycodone CR, suggesting a relative potency ratio of 2:1.
Acknowledgment We thank Beth Cuccia for her management of this clinical trial.
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