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A Comparison of the Analgesic Efficacy of Tramadol Contramid OAD Versus Placebo in Patients with Pain Due to Osteoarthritis
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Journal of Pain and Symptom Management
Vol. 34 No. 3 September 2007
Original Article
A Comparison of the Analgesic Efficacy of Tramadol Contramid OAD Versus Placebo in Patients with Pain Due to Osteoarthritis Francis Burch, MD, Ritchard Fishman, MD, Nicholas Messina, MD, Bruce Corser, MD, Florin Radulescu, MD, Adrian Sarbu, MD, Marcela M. Craciun-Nicodin, MD, Rodica Chiriac, MD, Andre´ Beaulieu, MD, Jude Rodrigues, MD, Philippe Beignot-Devalmont, MD, Alain Duplan, MD, Sybil Robertson, BScN, Louise Fortier, MSc, and Sylvie Bouchard, MD, PhD Radiant Research (F.B.), San Antonio, Texas; Private Practice (R.F.), Pico Rivera, California; Vista Medical Research Inc. (N.M), Mesa, Arizona; and Community Research (B.C.), Cincinnati, Ohio, USA; Centrul de Boli Rheumatismale ‘‘Dr. Ion Stoia’’ (F.R.), Bucharest; Centrul Medical Sana (A.S.), Bucharest; Private Practice (M.M.C.-N.), Bucharest; and Spitalul Clinic de Recuperare (R.C.), Iasi, Romania; Faculty of Medicine (A.B.), Laval University, Laval, Que´bec; and Private Practice (J.R.), Windsor, Ontario, Canada; Private Practice (P.B.-D.), Rouen; and Private Practice, (A.D.), Montbrison, France; Labopharm Inc. (S.R., L.F., S.B.), Laval, Que´bec; Faculte´ de Pharmacie (L.F.), Universite´ de Montre´al, Montre´al; and Lakeshore General Hospital (S.B.), Montre´al, Que´bec, Canada
Abstract One thousand twenty-eight (1,028) patients with pain due to osteoarthritis (OA) of the knee were enrolled in this multicenter, randomized, double-blind, parallel study designed to assess the analgesic efficacy and safety of Tramadol Contramid Ò OAD compared to placebo. An open-label phase was followed by a double-blind phase, in which a total of 646 patients were randomized to double-blind treatment with placebo or Tramadol Contramid OAD. Patients were titrated to their optimal dose (200 mg or 300 mg), which was maintained for 12 weeks. An absolute mean reduction of 3.0 2.1 on a Pain Intensity Numerical Rating Scale (PI-NRS) was noted in the Tramadol Contramid OAD treatment group. The difference between active and placebo groups regarding this absolute mean reduction was statistically significant (P < 0.001) throughout the study. The responder analysis demonstrated that a significantly greater percentage of patients in the active treatment arm achieved a reduction of $1 and $2 points on the PI-NRS score by the end of the study (P ¼ 0.035). A significantly greater percentage of respondents in the Tramadol Contramid OAD group indicated improvement on both the Patient and Physician Global Impressions of Change (P ¼ 0.0002). Both the 200 mg and 300 mg doses contributed to the overall superiority of Tramadol Contramid OAD. The most frequent adverse events were consistent with the known side effects of tramadol and were generally mild to moderate in intensity. These results confirm that Tramadol Contramid OAD given once daily is an efficacious and safe treatment for pain due to OA. J Pain Symptom Manage Address reprint requests to: Sybil Robertson, BScN, Labopharm Inc., 480 boul Armand Frappier, Laval, Que´bec, H7V 4B4, Canada. E-mail: srobertson@ labopharm.com Ó 2007 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
Accepted for publication: November 29, 2006.
0885-3924/07/$esee front matter doi:10.1016/j.jpainsymman.2006.11.017
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Tramadol OAD for Pain
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2007;34:328e338. Ó 2007 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Tramadol, pain, analgesia, osteoarthritis, controlled release, Contramid
Introduction Chronic pain is a major health problem and causes extensive personal suffering, reduced productivity, and significant direct and indirect health care costs. Analgesic treatments include acetaminophen, cyclo-oxygenase (COX)-2 inhibitors, and/or nonsteroidal anti-inflamma tory drugs (NSAIDs), which for the most part require multiple daily administrations. Alternatives to these analgesic agents include tramadol and conventional opioids. Tramadol, a centrally acting, synthetic analgesic is currently marketed in many countries in a variety of formulations suitable for oral, rectal, intramuscular, intravenous, and subcutaneous administration.1 The therapeutic potential of tramadol is based on its complementary mechanisms of action that involve 1) opioid effects (binding to mu opioid receptor sites) and 2) inhibition of reuptake of norepinephrine and serotonin, the neuronal monoamines that inhibit central pain pathways.2 The clinical efficacy of tramadol has been established in a variety of chronic painful conditions, such as cancer pain,3 neuropathic pain,4,5 and musculoskeletal conditions including osteoarthritis (OA).6,7 These findings and those of Roth7 support the role of tramadol in the management of chronic pain attributed to OA.7 Osteoarthritis pain is a leading cause of disability in the USA, with an estimated annual cost of $7.11 billion dollars in lost productive work time.8 The recent guidelines of the American Pain Society recommend tramadol alone or in combination with acetaminophen or NSAIDs when NSAIDs alone do not provide adequate relief of pain.9 Tramadol is an analgesic used for managing moderate to moderately severe pain due to OA.10 As of the year 2000, the American College of Rheumatology guidelines recommend tramadol for the management of moderate to moderately severe pain in patients with OA for whom NSAIDs are contraindicated or for whom pain is not adequately controlled
with more traditional analgesic agents, such as acetaminophen or NSAIDs and COX-2 inhibitors.10e13 NSAIDs (including COX-2 inhibitors) use is limited by the risk of gastrointestinal, renal, and cardiac adverse effects, particularly in elderly patients.14e17 Immediate-release tramadol, available since 1977 in Europe and since 1995 in the USA, usually requires administration four to six times daily. Dosing frequency can be reduced to once daily with Tramadol ContramidÒ OAD, a controlled-release formulation using Contramid, (Labopharm Inc., Que´bec, Canada), a technology developed that provides controlled release of the active ingredient over an extended period. Tramadol Contramid OAD comprises both immediate- and extendedrelease components. Tramadol Contramid OAD (given once a day) provides steady-state bioequivalence, similar bioavailability, and time to maximum concentration compared to immediate-release tramadol given four times a day.18 Initial plasma levels are provided by the immediate-release component and are maintained over 24 hours by the controlledrelease component. Literature suggests that once-daily administration regimens may lead to fewer sleep interruptions, better tolerability, improved compliance, and a better quality of life.19e21 The objective of this multicenter, randomized, double-blind, parallel-design study was to assess the analgesic efficacy and to compare the safety and clinical benefit of Tramadol Contramid OAD to that of placebo in patients with pain due to OA.
Methods Study Conduct This multicenter, randomized, two-arm study consisted of an open-label phase and a double-blind phase. A total of 1,028 patients who met the screening criteria were enrolled at 108 outpatient clinics in the United States,
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Canada, France, and Romania between October 2004 and January 2006. Patients enrolled in this study were from 40 to 80 years old and had pain due to OA of the knee. They also had to be taking NSAIDs, COX-2 inhibitors, or tramadol on a regular basis for OA pain during the 30 days that preceded enrollment. Among the key exclusion criteria were the following: a diagnosis of arthritis other than OA, a history of injury or procedure that would interfere with assessment of pain in the knee, or current or prior substance abuse or dependency. Patients who had been treated with any drug that reduces the seizure threshold within three weeks prior to screening were also excluded. To be enrolled in the study, patients had to have washed out any pre-study analgesics for a minimum of five drug half-lives and have a score of at least 4 on the 11-point Pain Intensity Numerical Rating Scale (PINRS) at screening, with an increase of at least two points after analgesic washout. Patients were asked to ‘‘Select the number that best describes your [their] pain during the past 24 hours’’ by indicating their response on the 11-point PI-NRS from 0 (no pain) to 10 (worst possible pain). During the entire study, patients were not permitted to take pain medication other than the study drug, with the exception of shortacting analgesics for acute pain other than that due to OA. The short-acting analgesics could be taken for a maximum of three consecutive days and not within three days of an assessment visit. The study started with the open-label phase that included titration, taper, and washout of Tramadol Contramid OAD. During the titration period, Tramadol Contramid OAD was increased gradually by increments of 100 mg up to a maximum of 300 mg, with the possibility of decreasing to 200 mg. The final daily dose could be either 200 mg or 300 mg. Titration was followed by a seven-day taper period, during which the dose was progressively decreased. Subsequently, acetaminophen was taken for five days, followed by a full washout period. To proceed to the double-blind phase of the study, patients had to continue to meet the screening eligibility criteria and had to have a score of at least 4 on the PI-NRS after washout and an increase of at least two points since
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the end of the open-label titration period. At the beginning of the double-blind phase, eligible patients were randomized to Tramadol Contramid OAD or placebo in a 2:1 ratio, in blocks of six according to a previously established randomization schedule computergenerated by Aptuit Inc., Allendale, NJ. In accordance with this schedule, patients were assigned study medication by means of a central interactive voice-response system. Participants and site personnel were blinded to treatment assignments. To maintain the double blind, inactive placebo tablets identical to the different dose forms of Tramadol Contramid OAD were packaged and labeled in the same way as the active treatment. To maintain the blind between the open-label and doubleblind phases, patients took acetaminophen 500 mg three times daily for five days. This was followed by a full washout period. During the double-blind phase of the study, patients were titrated with Tramadol Contramid OAD or placebo which was identical in appearance and composition with the exception of the active ingredient. The dose was increased by increments of 100 mg starting at 100 mg and continuing to a final dose of 200 mg or 300 mg OAD. The dose at which patients completed the double-blind titration period was identified as their final dose, which was continued for the entire 12-week maintenance period (Fig. 1). Patients were asked to evaluate the intensity of their pain on the 11-point PI-NRS. Pain intensity was assessed at the end of the doubleblind titration and, along with the physician and patient global ratings, at each visit on Days 21, 42, 63, and 84 of the maintenance period. Assessments of the Patient and Physician Global Impressions of Change were both based on the overall change in status from the beginning of the study using a 7-point categorical scale ranging from 1 (Very much improved) to 7 (Very much worse). The Patient and Physician Global Impressions of Change integrated the effect of treatment on pain, side effects, and the patient’s expectation of pain relief. Safety was assessed by means of physical examinations, clinical laboratory tests, vital signs, adverse events (AEs), and concomitant medication at all study visits. All efficacy and safety assessments were also performed in patients who discontinued the study early.
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Tramadol OAD for Pain
Open-Label Phase
Screening
1. Run in • Titration of Tramadol Contramid OAD by 100 mg increments to a maximum of 300 mg 2. Taper 3. Washout • Flare criteria
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Double-Blind Phase
R A N D O M I Z E
A C T I V E P L A C E B O
Titration of Tramadol Contramid OAD or placebo by 100 mg increments to a maximum of 300 mg
F I N A L D O S E
Maintenance at the optimum dose established during titration
L E V E L
Fig. 1. Study design.
The study protocol was conducted in accordance with the Declaration of Helsinki. Each patient signed a written informed consent form, approved by a properly constituted Research Ethics Board.
Statistical Methodology For the sample size calculation, it was estimated that at least 440 patients would have to enter the double-blind maintenance period. Assuming a dropout rate of 25%, it was estimated that approximately 330 patients would complete the study and that this would provide sufficient power (90%) to demonstrate the superiority of Tramadol Contramid OAD over placebo with respect to the primary efficacy variable: the change from baseline to the end of the study of one point on the 11-point PINRS. Following a pre-planned blinded administrative interim analysis that revealed a higher than expected variability, the protocol was amended to increase the total number of patients to maintain the power of 90%. The primary measure of efficacy was the score on the PI-NRS after 12 weeks of double-blind treatment. Subgroup analyses were performed with respect to PI-NRS to assess whether each of the dosage forms (200 mg and 300 mg) contributed to the overall response of Tramadol Contramid OAD. A responder analysis, comparing the percentage of patients who experienced an improvement of one to five points in the PI-NRS from baseline to the end of the double-blind phase, was performed to assess the significance of the analgesic effect. The safety population included all patients who received at least one dose of study
medication. The efficacy analysis was conducted on the full-analysis population, defined as all patients who received at least one dose of the randomized study medication regardless of the status of the post-dosing assessment. All efficacy tests were two-tailed, with a significance level a ¼ 0.05. The time-weighted average method was used to assess the average effect of Tramadol Contramid OAD or placebo over 12 weeks with respect to the main efficacy parameter (PI-NRS). The proportion of responders in each treatment group was compared using a Chi-squared test. A responder analysis, based on the difference in improvement on the PI-NRS score from baseline over the spectrum of responses from one to five points, was conducted. Time to response in days from the start of doubleblind medication to the protocol-defined response of a two-point decrease in the PI-NRS score was based on an analysis of Kaplan-Meier curves. Data from patients who discontinued treatment early or who completed the study without responding were censored at the time point of their last PI-NRS assessment. Data from patients who did not discontinue due to lack of efficacy were censored at the time point of their last dose of study medication. Between-group differences in Patient and Physician Global Impressions of Change were assessed using an analysis of covariance (ANCOVA) based on rank, with baseline PI-NRS as the covariate. AEs were reported according to the date of onset on which the AE occurred. A table indicating the incidence, severity, outcome, and relation of AEs to study drug was prepared for
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each treatment phase and for each treatment group in the double-blind phase. These values were compared using the Chi-squared test. Similarly, AEs reported by at least 5% of the patients and serious AEs were categorized according to worst intensity and strongest drug relationship and compared between treatment groups.
Results A total of 1,028 patients were enrolled in the open-label phase of this study. Six hundred forty-six (646) patients were randomized to double-blind treatment (Tramadol Contramid OAD: 432, Placebo: 214) of which 591 (91%) completed the titration period, and 491 (76%) completed the 12-week maintenance period. Among patients randomized to Tramadol Contramid OAD, 106/432 (25%) selected 200 mg as the final dose during the open-label titration, and 325/432 (75%) selected 300 mg. The most frequent reasons for discontinuation
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of patients were treatment failure (Tramadol Contramid OAD: 8%, Placebo: 10%) and AEs (Tramadol Contramid OAD: 10%, Placebo: 5%) (Fig. 2). The safety population was 85% Caucasian, and approximately 62% of the patients were female. The mean age was 63 years, and 45% (456 patients) were at least 65 years old, of which 85 patients were at least 75 years old. The two groups were similar in terms of gender, age, body mass index, and race (Table 1). The mean score on the 11-point PI-NRS (0e10 points) at baseline for both active and placebo treatment arms was 7.2. The classes of medication most frequently taken prior to study entry were analgesics, anti-inflammatory drugs, and medications to treat cardiac disorders that were taken by similar percentages of patients across the study population. Regarding the primary efficacy parameter in the study, the Tramadol Contramid OAD groups showed a statistically significant greater absolute mean improvement on the PI-NRS Enrolled (1028)
Assigned to Tramadol Contramid OAD (1028) Entered run-in period (1027) Did not receive Tramadol Contramid OAD (5) Discontinued (381) Adverse event (225) Treatment failure (28) Patient request (48) Other (80)
Randomized (646)
Assigned to placebo (214) Did not receive placebo (0)
Assigned to Tramadol Contramid OAD (432) Did not receive Tramadol Contramid OAD (1)
Safety population (214) Full analysis population (214)
Safety population (432) Full analysis population (431)
Discontinued (49) Adverse event (11) Treatment failure (22) Patient request (6) Other (10)
Discontinued (106) Adverse event (44) Treatment failure (34) Patient request (23) Other (5)
Completed (165/167)1
Completed (326/328)1
1
In each treatment group, 2 patients who discontinued had a PI-NRS assessment at Week 12
Fig 2. Patient disposition.
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Tramadol OAD for Pain
from baseline to the end of study compared to the placebo group (Tramadol Contramid OAD: 2.9 2.5; placebo 2.4 2.5) (Table 2). Furthermore, the time-weighted average analysis, used to assess the average effect of treatment during the entire 12-week maintenance period, revealed that the difference between the two treatment groups (0.70) was statistically significant (P < 0.0001). A responder analysis was conducted on the primary efficacy parameter, the PI-NRS score. That is, the percentage of patients who achieved a particular predefined response was compared between treatment groups for response levels that ranged from an improvement from baseline of at least one to five points. There was a statistically significant greater percentage of responders in the Tramadol Contramid OAD treatment group compared to placebo irrespective of the response level. The greater the predefined level of response required, the greater the difference in the percentage of responders in the Tramadol Contramid OAD group compared to the placebo group (Table 3). This was true for the Tramadol Contramid OAD treatment group as a whole and for each dose of Tramadol Contramid OAD compared individually to placebo regardless of what predefined response level
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was used: 200 mg, 3%e8% more responders; 300 mg, 5%e17% more responders (Fig. 3). Moreover, in addition to achieving a statistically significant better response at the end of the maintenance phase of treatment, patients randomized to Tramadol Contramid OAD achieved this improvement significantly sooner than patients randomized to placebo. Although the median number of days required for patients to achieve a two-point improvement in PI-NRS scores was similar for active (14 days) and placebo (15 days) arms, it took more than twice as long for placebo-treated patients to achieve a three-point improvement in the PI-NRS score (39 days) than it did for patients treated with Tramadol Contramid OAD (16 days, P < 0.0001). The median time to response was similar in patients treated with either Tramadol Contramid OAD 200 mg or 300 mg. At the end of the 12-week maintenance period, 80% of patients randomized to Tramadol Contramid OAD indicated that their condition had improved, compared to 69% of the patients randomized to placebo. The difference between treatment groups with respect to the Patient Global Impression of Change was statistically significant (P ¼ 0.0002) (Fig. 4). Similar results were obtained with the Physician
Table 1 Demographic Characteristics of the Safety Population Double-Blind Treatment Not Randomized (n ¼ 377)
Placebo (n ¼ 214)
Tramadol Contramid OAD (n ¼ 432)a
Overall (n ¼ 1,023)
142 (38) 235 (62)
81 (38) 133 (62)
157 (36) 275a (64)
380 (37%) 643 (63%)
63 9 65 9 63 9
62 9 63 9 62 9
62 9 62 9 62 9
63 9 63 9 62 9
Ethnic origin Asian: n (%) Black: n (%) Caucasian: n (%) Hispanic: n (%) Other: n (%)
4 (1) 22 (6) 308 (82) 34 (9) 9 (2)
1 (0.5) 12 (6) 185 (86) 15 (7) 1 (0.5)
1 (0.2) 21 (5) 380a (88) 28 (6) 2 (0.5)
6 (0.6) 55 (5) 873 (85) 77 (8) 12 (1)
BMI (mean SD) Male (mean SD) Female (mean SD)
29.9 4.0 29.9 3.9 29.9 4.1
29.5 4.3 29.5 3.9 29.5 4.5
29.7 4.0 30.0 3.8 29.5 4.1
29.7 4.1 29.9 3.8 29.6 4.2
NA
7.2 1.6
7.2 1.6
NA
Characteristic Gender Male n (%) Female n (%) Age (mean SD) Male (mean SD) Female (mean SD)
Baseline PI-NRSb (Mean SD)
a One patient who discontinued for administrative reasons after randomization but before receiving double-blind medication was not included in full analysis population. b Reported for full analysis population.
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Table 2 PI-NRS: Absolute Improvement on PI-NRS Score from Baselinea Tramadol Placebo Contramid OAD Baseline n Mean SD Median Min, Max
214 7.2 1.6 7.0 4, 10
431 7.2 1.6 7.0 3, 10
Absolute improvement (Baselinedlast individual visit) n 196 393 Mean SD 2.29 1.97 3.03 2.12 95% CI [2.02; 2.57] [2.82; 3.24] Median 2.10 3.00 Min, Max 4.0, 8.0 3.9, 9.0 Difference in absolute improvement between Tramadol Contramid OAD and placebo Estimate (mean) 0.70 95% Confidence Interval [1.02; 0.38] b <0.0001 P-value PI-NRS ¼ Pain Intensity Numerical Rating Scale. a Using time-weighted average approach. b Based on ANCOVA.
Global Impression of Change (improvement: Tramadol Contramid OAD: 80% versus placebo: 69%, P ¼ 0.0042). During the 12-week, double-blind, maintenance period of this trial, patients were randomized to treatment with Tramadol Contramid OAD or placebo. Within these treatment groups, an optimal dose (200 mg or 300 mg or corresponding placebo ‘‘dose’’) was selected based upon efficacy and tolerability. Once the optimal dose was selected, the dose level could not be changed during the maintenance period. Most patients in the active group selected the 300 mg dose (300 mg: 325 patients, 200 mg: 106 patients). Because
Table 3 PI-NRS: Responder Analysis Responders Improvement in Tramadol Contramid Placebo PI-NRS Score POAD (n/N ¼ %) (n/N ¼ %) valuea from Baseline $1 point
400/428 ¼ 93.5
$2 points
372/428 ¼ 86.9
$3 points
322/428 ¼ 75.2
$4 points
251/427 ¼ 58.8
$5 points
183/406 ¼ 45.1
187/ 0.036 211 ¼ 88.6 170/ 0.035 211 ¼ 80.6 134/ 0.002 211 ¼ 63.5 99/ 0.005 211 ¼ 46.9 61/ <0.001 203 ¼ 30.1
PI-NRS ¼ Pain Intensity Numerical Rating Scale. a Chi-squared test between respective treatment and placebo.
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the primary confirmatory analysis was to compare Tramadol (at optimal dose) with placebo, no a priori statistical comparison of Tramadol 200 mg versus Tramadol 300 mg was planned. Descriptive results at the end of study indicate an absolute improvement in pain intensity score of 2.9 points with both Tramadol Contramid OAD 200 mg and 300 mg. During the open-label phase of the study, 66% of the safety population experienced an AE, and 83% of these patients indicated that it was mild or moderate in intensity. Overall, during the double-blind phase, 59% of the active-treatment group experienced at least one AE, and 10% withdrew because of an AE irrespective of relationship to treatment. The majority of AEs reported by patients receiving active treatment were mild or moderate during the double-blind phase (88%). In general, among patients randomized to active treatment, the incidence of AEs was higher in the 300 mg (45%) treatment group than in the 200 mg (40%) group. The most commonly reported AEs in the active-treatment group were nausea, constipation, dizziness/vertigo, somnolence, vomiting, and headache in both the open-label and double-blind phases. Among patients randomized to active treatment in the double-blind phase, 15% reported nausea, 14% constipation, 10% dizziness/vertigo, and 7% somnolence (Table 4). Less than 2% of patients randomized to treatment with Tramadol Contramid OAD discontinued the study drug during the maintenance period due to these AEs. No deaths were reported during the study. Eleven serious AEs occurred in 10 patients during the study, among which one was in the placebo group (ischemic stroke, not related). In the active group, the following unrelated serious AEs occurred: diverticulitis, unstable angina, chest pain, breast cancer, grand mal convulsion (two weeks after final treatment dose), prostate cancer, and popliteal bursitis. Three serious AEs that were possibly related to active treatment were reported in two patients: syncope in one patient and renal insufficiency and elevation of liver enzymes with inflammation of the liver in another patient.
Discussion The primary endpoint in this study was achievedda greater reduction of the pain
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Tramadol OAD for Pain
335
100 93.8 92.2 88.6
Percentage of responders
90
88 83.5 80.6
80
76.6 70.9
70
63.5
60.6
60
52.9
50
47.2
46.9
40
38.1
30
30.0
20
Placebo Tramadol Contramid OAD 200 mg Tramadol Contramid OAD 300 mg
10 0
1
2
3
5
4
Difference in PI-NRS Score
Fig. 3. PI-NRS: responder analysis.
the full difference between treatment groups that is associated with the arbitrary selection of a given response level as a cutoff point.22 In this study, the responder analysis demonstrated that a greater percentage of patients in the Tramadol Contramid OAD treatment group achieved a predefined level of response than did patients in the placebo group regardless of which response level was selected. Furthermore, the greater the reduction in the PI-NRS score considered, the greater the difference between the percentage of responders in the two treatment groups. A statistically significant difference in favor of Tramadol Contramid OAD was demonstrated for each of the five successive reductions of the PI-NRS score examined.
intensity score occurred with Tramadol Contramid OAD compared to placebodand the difference was statistically significant. This statistically significant difference was demonstrated with the time-weighted average approach that evaluates the average analgesic effect over the entire treatment period. Other methods of analysis confirmed the significant difference in favor of Tramadol Contramid OAD with respect to this primary efficacy measure. Responder analyses are considered to be an optimal approach to express the clinical significance of an analgesic effect and to compare the treatment response to the response in the control group over the full range of response cutoff points. Furthermore, responder analyses reduce over- or underestimation of
Percentage of patients
40 35
34.8
Placebo Tramadol Contramid OAD
30
28.1
27.6 25.4
25 20.2
20.0
20 15
12.9
11.5
10 5 0 None
Minimal
Much
Very much
Global Impression of Change P = 0.0002 for the difference between the two groups (ANCOVA based on ranks; baseline PI-NRS as covariate).
Fig. 4. Patient Global Impression of Change at last double-blind visit.
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Table 4 Most Common Adverse Events During the Double-Blind Phasea Tramadol Contramid OAD Placebo
Nausea: n (%) Constipation: n (%) Dizziness/vertigo: n (%) Somnolence: n (%)
n ¼ 432
n ¼ 214
66 61 42 29
12 9 8 8
(15.3) (14.1) (9.7) (6.7)
(5.6) (4.2) (3.7) (3.7)
a Reported by $5% of patients during the three-month maintenance period irrespective of relationship to the treatment.
The significant difference detected with the time-weighted average approach combined with the results of the responder analysis indicate that the superiority of Tramadol Contramid OAD over placebo is consistent over the spectrum of pain intensities and the entire 12-week treatment period that were studied. Furthermore, the improvement from baseline with either the 200 mg or the 300 mg dose was greater than the improvement noted in the placebo group. In general, it took more time for patients in the placebo arm to achieve the same level of improvement on the PI-NRS score than it did for patients in the active treatment arm. Moreover, the median time to response was similar among patients who received either Tramadol Contramid OAD 200 mg or Tramadol Contramid OAD 300 mg, thus suggesting the contribution of the two dose levels to the overall reduction in time to achieve that level of response. The overall test for comparison of the Patient Global Impression of Change achieved statistical significance between Tramadol Contramid OAD and placebo. Eighty percent (80%) of the patients indicated that their pain symptoms had improved with Tramadol Contramid OAD, whereas 69% of patients indicated that improvement had occurred with placebo. These results were confirmed with the Physician Global Impression of Change and indicate an overall high level of satisfaction with the analgesic effects of Tramadol Contramid OAD. Sixty-six percent (66%) of patients in the open-label phase and 59% of the patients randomized to Tramadol Contramid OAD experienced an AE of which 59% and 43%,
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respectively, were considered to be at least possibly related to Tramadol Contramid OAD. This is comparable to the frequencies of AEs, between 45% and 79%, that have been reported in the literature for other marketed formulations of tramadol.6,21,23 Eighty-eight percent (88%) of the AEs reported by patients randomized to Tramadol Contramid OAD were mild to moderate. The discontinuation rates during the doubleblind phase of the study were low in both the active (25%) and placebo (23%) arms and are comparable to discontinuation rates from other studies involving titration to optimum dose of once-daily formulations of tramadol.21,24 In a recent 12-week fixed dose study of another extended-release formulation of tramadol, 100 mg to 400 mg once a day versus placebo, between 71% and 84% of patients in the active treatment group experienced an AE regardless of the relationship to study treatment. Discontinuations due to AEs in that study were in the order of 20% to 30%, higher than for the treatment group reported herein.25 The AEs reported by at least 5% of the patients dosed with Tramadol Contramid OAD during the double-blind phase were nausea (15%), constipation (14%), dizziness/vertigo (10%), and somnolence (7%). No new or unexpected AEs were reported. Following treatment for up to 90 days with Ultram, nausea, constipation, dizziness/vertigo, and somnolence occurred in more than 20% of patients, and vomiting affected 17% of patients.26 A criticism of enrichment designs, such as the one used in this study, is that they may lack generalizability. In a disease state such as pain, the balance between efficacy and tolerability is an important consideration in the selection of the pharmacological treatment. In this case, an enrichment design may be used to identify the population of patients who, based upon efficacy and tolerability, are most appropriately treated with a particular drug and, therefore, are most representative of the patient population who will eventually use it. Effective blinding was ensured in the trial through the use of indistinguishable placebo and active treatments. Furthermore, a sevenday washout period between the open-label and double-blind treatments was included. Another approach to maintaining the blind would have been to use an active placebo so
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that patients in the placebo arm would have experienced similar AEs to those experienced by patients in the active arm. Although this approach may provide added assurance that the blind is maintained, it is controversial in that it involves exposing patients to an active substance and its associated risks without any anticipated benefit.27 Tramadol Contramid OAD is the only analgesic developed with the Contramid delivery system, and combines both immediate and extended release of tramadol over 24-hours for consistent relief of persistent pain. It is, therefore, possible that, as a result of the reduction in peak and trough plasma concentrations, more consistent pain relief throughout the entire dosing interval can be achieved. The analgesic efficacy of Tramadol Contramid OAD 100 mg to 400 mg was established in a previous optimal-dose non-inferiority study.20 Tramadol Contramid OAD demonstrated a statistically significant greater average reduction in the PI-NRS score compared to placebo over the entire treatment period. The responder analysis showed that consistent analgesia is provided over the spectrum of pain intensities with Tramadol Contramid OAD. The Global Impressions of Change indicate a high level of satisfaction with the analgesic effect among both patients and their physicians. The relatively low incidence of the most common AEs reported during the double-blind phase and their generally low intensity support the safety of Tramadol Contramid OAD. This study has shown that, with once-daily administration, Tramadol Contramid OAD provides efficacious analgesia and has a relatively good safety profile. Thus, Tramadol Contramid OAD could be an acceptable alternative for management of pain.
Acknowledgments The authors would like to acknowledge the following practitioners for their participation in the study: Serban Stroescu, MD, Phyllis Troia, MD, Leah Schmidt, DO, Mark Shirley, DO, Charles Larrison, MD, Darren Pearson, MD, Allan Soo, MD, John Crane, MD, Douglas Haselwood, MD, Rashid Khairi, MD, Lisa Cohen, DO, James Farrell, DO, Paul Pickrell, MD, Clara Garcia, MD, Frederick Murphy,
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MD, Adesh Jain, MD, Edward Portnoy, MD, and Chae Haen, MD, and John L. Moore for his contribution to the preparation of this manuscript.
References 1. Raffa RB, Freidrichs E. The basic science aspect of tramadol hydrochloride. Pain Rev 1996;3: 249e271. 2. Raffa RB, Freidrichs E. Opioid and non-opioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 1992;260:275e285. 3. Grond S, Zech D, Lynch J, et al. Tramadol: a weak opioid for relief of cancer pain. Pain Clin 1992;5:241e247. 4. Harati Y, Gooch C, Swensen M, et al. Double-blind randomized trial of tramadol in the treatment of the pain of diabetic neuropathy. Neurology 1998; 50:1842e1846. 5. Sindrup H, Andersen G, Madsen C, et al. Tramadol relieves pain and allodynia in polyneuropathy: a randomized double-blind controlled trial. Pain 1999;83:85e90. 6. Jensen EM, Ginsberg F. Tramadol versus dextropropoxyphene in the treatment of osteoarthritis: a short term double-blind study. Drug Invest 1994; 8:211e218. 7. Roth SH. Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis. J Rheumatol 1998;25:1358e1363. 8. Ricci JA, Stewart WF, Chee E, et al. Pain exacerbation as a major source of lost productive time in US workers with arthritis. Arthritis Rheum 2005; 53:673e681. 9. American Pain Society. Patient guide: managing osteoarthritis pain. Available from http://www.am painsoc.org/pub/osteoarthritis.htm. Accessed July 16, 2006. 10. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000; 43:1905e1915. 11. Bradley JD, Brandt KD, Katz BP, et al. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 1991;325:87e91. 12. Brandt KD. Osteoarthritis. In: Isselbacher KJ, Martin JB, Braunwald E, et al, eds. Harrison’s principles of internal medicine, 13th ed. New York: McGraw-Hill Inc., 1994: 1692e1698.
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13. Brandt KD. Management of osteoarthritis. In: Kelley WN, Harris ED, Ruddy S, et al, eds. Textbook of rheumatology, 4th ed. Philadelphia: WB Saunders Company, 1993: 1385e1399. 14. Griffin MR, Piper JM, Daugherty JR, et al. Nonsteroidal anti-inflammatory drug use and increased risk of peptic ulcer disease in elderly persons. Ann Intern Med 1991;114:257e263. 15. Roth SH. Nonsteroidal anti-inflammatory drugs: gastropathy, deaths, and medical practice. Ann Intern Med 1991;114:257e263. 16. Roth SH, Bennett RE. Nonsteroidal antiinflammatory drug gastropathy: recognition and response. Arch Intern Med 1988;109:353e354. 17. Schafer AI. Effects of nonsteroidal anti-inflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 1995;35:209e219. 18. Karhu D, Bouchard S. Pharmacokinetic evaluation of a novel once-a-day tramadol hydrochloride formulation. American College of Clinical Pharmacology 34th Annual Meeting, September 11, 2005, Rockville, MD [conference poster]. 19. Malonne H, Coffiner M, Fontaine D, et al. Long-term tolerability of tramadol LP, a new once-daily formulation, in patients with osteoarthritis or low back pain. J Clin Pharm Ther 2005;30(2): 113e120. 20. Mongin G, Yakusevich V, Kope A, et al. Efficacy and safety assessment of a novel once-daily tablet formulation of tramadol. Clin Drug Invest 2004; 24(9):545e548. 21. Babul N, Noveck R, Chipman H, et al. Efficacy and safety of extended-release, once-daily tramadol
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in chronic pain: a randomized 12-week clinical trial in osteoarthritis of the knee. J Pain Symptom Manage 2004;28:59e71. 22. Farrar JT, Dworkin RH, Max MB. Use of cumulative proportion of responders analysis graph to present pain data over a range of cut-off points: making clinical trial data more understandable. J Pain Symptom Manage 2006;31:369e377. 23. Malonne H, Coffiner M, Sonet B, et al. Efficacy and tolerability of sustained-release tramadol in the treatment of symptomatic osteoarthritis of the hip or knee: a multicenter, randomized, double-blind, placebo-controlled study. Clin Ther 2004;26: 1774e1782. 24. Adler L, McDonald C, O’Brien C, Wilson M. A comparison of once-daily tramadol with normal release tramadol in the treatment of pain in osteoarthritis. J Rheumatol 2002;29:2196e2199. 25. Gana TJ, Pascual MLG, Fleming RRB, et al. Extended release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Curr Med Res Opin 2006;22:1391e1401. 26. UltramÒ: Tramadol hydrochloride tablets. In: LaGow B, Chesanow N, Fleming H, et al, eds. Physician’s desk reference, 59th ed. Montvale, NJ: Thomson, 2005: 2551e2554. 27. Lemmens HJM, Wada DR, Munera C, et al. Enriched analgesic efficacy studies: an assessment by clinical trial simulation. Contemp Clin Trials 2006; 27:165e173.
Journal of Pain and Symptom Management
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Original Article
A Comparison of the Analgesic Efficacy of Tramadol Contramid OAD Versus Placebo in Patients with Pain Due to Osteoarthritis Francis Burch, MD, Ritchard Fishman, MD, Nicholas Messina, MD, Bruce Corser, MD, Florin Radulescu, MD, Adrian Sarbu, MD, Marcela M. Craciun-Nicodin, MD, Rodica Chiriac, MD, Andre´ Beaulieu, MD, Jude Rodrigues, MD, Philippe Beignot-Devalmont, MD, Alain Duplan, MD, Sybil Robertson, BScN, Louise Fortier, MSc, and Sylvie Bouchard, MD, PhD Radiant Research (F.B.), San Antonio, Texas; Private Practice (R.F.), Pico Rivera, California; Vista Medical Research Inc. (N.M), Mesa, Arizona; and Community Research (B.C.), Cincinnati, Ohio, USA; Centrul de Boli Rheumatismale ‘‘Dr. Ion Stoia’’ (F.R.), Bucharest; Centrul Medical Sana (A.S.), Bucharest; Private Practice (M.M.C.-N.), Bucharest; and Spitalul Clinic de Recuperare (R.C.), Iasi, Romania; Faculty of Medicine (A.B.), Laval University, Laval, Que´bec; and Private Practice (J.R.), Windsor, Ontario, Canada; Private Practice (P.B.-D.), Rouen; and Private Practice, (A.D.), Montbrison, France; Labopharm Inc. (S.R., L.F., S.B.), Laval, Que´bec; Faculte´ de Pharmacie (L.F.), Universite´ de Montre´al, Montre´al; and Lakeshore General Hospital (S.B.), Montre´al, Que´bec, Canada
Abstract One thousand twenty-eight (1,028) patients with pain due to osteoarthritis (OA) of the knee were enrolled in this multicenter, randomized, double-blind, parallel study designed to assess the analgesic efficacy and safety of Tramadol Contramid Ò OAD compared to placebo. An open-label phase was followed by a double-blind phase, in which a total of 646 patients were randomized to double-blind treatment with placebo or Tramadol Contramid OAD. Patients were titrated to their optimal dose (200 mg or 300 mg), which was maintained for 12 weeks. An absolute mean reduction of 3.0 2.1 on a Pain Intensity Numerical Rating Scale (PI-NRS) was noted in the Tramadol Contramid OAD treatment group. The difference between active and placebo groups regarding this absolute mean reduction was statistically significant (P < 0.001) throughout the study. The responder analysis demonstrated that a significantly greater percentage of patients in the active treatment arm achieved a reduction of $1 and $2 points on the PI-NRS score by the end of the study (P ¼ 0.035). A significantly greater percentage of respondents in the Tramadol Contramid OAD group indicated improvement on both the Patient and Physician Global Impressions of Change (P ¼ 0.0002). Both the 200 mg and 300 mg doses contributed to the overall superiority of Tramadol Contramid OAD. The most frequent adverse events were consistent with the known side effects of tramadol and were generally mild to moderate in intensity. These results confirm that Tramadol Contramid OAD given once daily is an efficacious and safe treatment for pain due to OA. J Pain Symptom Manage Address reprint requests to: Sybil Robertson, BScN, Labopharm Inc., 480 boul Armand Frappier, Laval, Que´bec, H7V 4B4, Canada. E-mail: srobertson@ labopharm.com Ó 2007 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
Accepted for publication: November 29, 2006.
0885-3924/07/$esee front matter doi:10.1016/j.jpainsymman.2006.11.017
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2007;34:328e338. Ó 2007 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Tramadol, pain, analgesia, osteoarthritis, controlled release, Contramid
Introduction Chronic pain is a major health problem and causes extensive personal suffering, reduced productivity, and significant direct and indirect health care costs. Analgesic treatments include acetaminophen, cyclo-oxygenase (COX)-2 inhibitors, and/or nonsteroidal anti-inflamma tory drugs (NSAIDs), which for the most part require multiple daily administrations. Alternatives to these analgesic agents include tramadol and conventional opioids. Tramadol, a centrally acting, synthetic analgesic is currently marketed in many countries in a variety of formulations suitable for oral, rectal, intramuscular, intravenous, and subcutaneous administration.1 The therapeutic potential of tramadol is based on its complementary mechanisms of action that involve 1) opioid effects (binding to mu opioid receptor sites) and 2) inhibition of reuptake of norepinephrine and serotonin, the neuronal monoamines that inhibit central pain pathways.2 The clinical efficacy of tramadol has been established in a variety of chronic painful conditions, such as cancer pain,3 neuropathic pain,4,5 and musculoskeletal conditions including osteoarthritis (OA).6,7 These findings and those of Roth7 support the role of tramadol in the management of chronic pain attributed to OA.7 Osteoarthritis pain is a leading cause of disability in the USA, with an estimated annual cost of $7.11 billion dollars in lost productive work time.8 The recent guidelines of the American Pain Society recommend tramadol alone or in combination with acetaminophen or NSAIDs when NSAIDs alone do not provide adequate relief of pain.9 Tramadol is an analgesic used for managing moderate to moderately severe pain due to OA.10 As of the year 2000, the American College of Rheumatology guidelines recommend tramadol for the management of moderate to moderately severe pain in patients with OA for whom NSAIDs are contraindicated or for whom pain is not adequately controlled
with more traditional analgesic agents, such as acetaminophen or NSAIDs and COX-2 inhibitors.10e13 NSAIDs (including COX-2 inhibitors) use is limited by the risk of gastrointestinal, renal, and cardiac adverse effects, particularly in elderly patients.14e17 Immediate-release tramadol, available since 1977 in Europe and since 1995 in the USA, usually requires administration four to six times daily. Dosing frequency can be reduced to once daily with Tramadol ContramidÒ OAD, a controlled-release formulation using Contramid, (Labopharm Inc., Que´bec, Canada), a technology developed that provides controlled release of the active ingredient over an extended period. Tramadol Contramid OAD comprises both immediate- and extendedrelease components. Tramadol Contramid OAD (given once a day) provides steady-state bioequivalence, similar bioavailability, and time to maximum concentration compared to immediate-release tramadol given four times a day.18 Initial plasma levels are provided by the immediate-release component and are maintained over 24 hours by the controlledrelease component. Literature suggests that once-daily administration regimens may lead to fewer sleep interruptions, better tolerability, improved compliance, and a better quality of life.19e21 The objective of this multicenter, randomized, double-blind, parallel-design study was to assess the analgesic efficacy and to compare the safety and clinical benefit of Tramadol Contramid OAD to that of placebo in patients with pain due to OA.
Methods Study Conduct This multicenter, randomized, two-arm study consisted of an open-label phase and a double-blind phase. A total of 1,028 patients who met the screening criteria were enrolled at 108 outpatient clinics in the United States,
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Canada, France, and Romania between October 2004 and January 2006. Patients enrolled in this study were from 40 to 80 years old and had pain due to OA of the knee. They also had to be taking NSAIDs, COX-2 inhibitors, or tramadol on a regular basis for OA pain during the 30 days that preceded enrollment. Among the key exclusion criteria were the following: a diagnosis of arthritis other than OA, a history of injury or procedure that would interfere with assessment of pain in the knee, or current or prior substance abuse or dependency. Patients who had been treated with any drug that reduces the seizure threshold within three weeks prior to screening were also excluded. To be enrolled in the study, patients had to have washed out any pre-study analgesics for a minimum of five drug half-lives and have a score of at least 4 on the 11-point Pain Intensity Numerical Rating Scale (PINRS) at screening, with an increase of at least two points after analgesic washout. Patients were asked to ‘‘Select the number that best describes your [their] pain during the past 24 hours’’ by indicating their response on the 11-point PI-NRS from 0 (no pain) to 10 (worst possible pain). During the entire study, patients were not permitted to take pain medication other than the study drug, with the exception of shortacting analgesics for acute pain other than that due to OA. The short-acting analgesics could be taken for a maximum of three consecutive days and not within three days of an assessment visit. The study started with the open-label phase that included titration, taper, and washout of Tramadol Contramid OAD. During the titration period, Tramadol Contramid OAD was increased gradually by increments of 100 mg up to a maximum of 300 mg, with the possibility of decreasing to 200 mg. The final daily dose could be either 200 mg or 300 mg. Titration was followed by a seven-day taper period, during which the dose was progressively decreased. Subsequently, acetaminophen was taken for five days, followed by a full washout period. To proceed to the double-blind phase of the study, patients had to continue to meet the screening eligibility criteria and had to have a score of at least 4 on the PI-NRS after washout and an increase of at least two points since
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the end of the open-label titration period. At the beginning of the double-blind phase, eligible patients were randomized to Tramadol Contramid OAD or placebo in a 2:1 ratio, in blocks of six according to a previously established randomization schedule computergenerated by Aptuit Inc., Allendale, NJ. In accordance with this schedule, patients were assigned study medication by means of a central interactive voice-response system. Participants and site personnel were blinded to treatment assignments. To maintain the double blind, inactive placebo tablets identical to the different dose forms of Tramadol Contramid OAD were packaged and labeled in the same way as the active treatment. To maintain the blind between the open-label and doubleblind phases, patients took acetaminophen 500 mg three times daily for five days. This was followed by a full washout period. During the double-blind phase of the study, patients were titrated with Tramadol Contramid OAD or placebo which was identical in appearance and composition with the exception of the active ingredient. The dose was increased by increments of 100 mg starting at 100 mg and continuing to a final dose of 200 mg or 300 mg OAD. The dose at which patients completed the double-blind titration period was identified as their final dose, which was continued for the entire 12-week maintenance period (Fig. 1). Patients were asked to evaluate the intensity of their pain on the 11-point PI-NRS. Pain intensity was assessed at the end of the doubleblind titration and, along with the physician and patient global ratings, at each visit on Days 21, 42, 63, and 84 of the maintenance period. Assessments of the Patient and Physician Global Impressions of Change were both based on the overall change in status from the beginning of the study using a 7-point categorical scale ranging from 1 (Very much improved) to 7 (Very much worse). The Patient and Physician Global Impressions of Change integrated the effect of treatment on pain, side effects, and the patient’s expectation of pain relief. Safety was assessed by means of physical examinations, clinical laboratory tests, vital signs, adverse events (AEs), and concomitant medication at all study visits. All efficacy and safety assessments were also performed in patients who discontinued the study early.
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Open-Label Phase
Screening
1. Run in • Titration of Tramadol Contramid OAD by 100 mg increments to a maximum of 300 mg 2. Taper 3. Washout • Flare criteria
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Double-Blind Phase
R A N D O M I Z E
A C T I V E P L A C E B O
Titration of Tramadol Contramid OAD or placebo by 100 mg increments to a maximum of 300 mg
F I N A L D O S E
Maintenance at the optimum dose established during titration
L E V E L
Fig. 1. Study design.
The study protocol was conducted in accordance with the Declaration of Helsinki. Each patient signed a written informed consent form, approved by a properly constituted Research Ethics Board.
Statistical Methodology For the sample size calculation, it was estimated that at least 440 patients would have to enter the double-blind maintenance period. Assuming a dropout rate of 25%, it was estimated that approximately 330 patients would complete the study and that this would provide sufficient power (90%) to demonstrate the superiority of Tramadol Contramid OAD over placebo with respect to the primary efficacy variable: the change from baseline to the end of the study of one point on the 11-point PINRS. Following a pre-planned blinded administrative interim analysis that revealed a higher than expected variability, the protocol was amended to increase the total number of patients to maintain the power of 90%. The primary measure of efficacy was the score on the PI-NRS after 12 weeks of double-blind treatment. Subgroup analyses were performed with respect to PI-NRS to assess whether each of the dosage forms (200 mg and 300 mg) contributed to the overall response of Tramadol Contramid OAD. A responder analysis, comparing the percentage of patients who experienced an improvement of one to five points in the PI-NRS from baseline to the end of the double-blind phase, was performed to assess the significance of the analgesic effect. The safety population included all patients who received at least one dose of study
medication. The efficacy analysis was conducted on the full-analysis population, defined as all patients who received at least one dose of the randomized study medication regardless of the status of the post-dosing assessment. All efficacy tests were two-tailed, with a significance level a ¼ 0.05. The time-weighted average method was used to assess the average effect of Tramadol Contramid OAD or placebo over 12 weeks with respect to the main efficacy parameter (PI-NRS). The proportion of responders in each treatment group was compared using a Chi-squared test. A responder analysis, based on the difference in improvement on the PI-NRS score from baseline over the spectrum of responses from one to five points, was conducted. Time to response in days from the start of doubleblind medication to the protocol-defined response of a two-point decrease in the PI-NRS score was based on an analysis of Kaplan-Meier curves. Data from patients who discontinued treatment early or who completed the study without responding were censored at the time point of their last PI-NRS assessment. Data from patients who did not discontinue due to lack of efficacy were censored at the time point of their last dose of study medication. Between-group differences in Patient and Physician Global Impressions of Change were assessed using an analysis of covariance (ANCOVA) based on rank, with baseline PI-NRS as the covariate. AEs were reported according to the date of onset on which the AE occurred. A table indicating the incidence, severity, outcome, and relation of AEs to study drug was prepared for
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each treatment phase and for each treatment group in the double-blind phase. These values were compared using the Chi-squared test. Similarly, AEs reported by at least 5% of the patients and serious AEs were categorized according to worst intensity and strongest drug relationship and compared between treatment groups.
Results A total of 1,028 patients were enrolled in the open-label phase of this study. Six hundred forty-six (646) patients were randomized to double-blind treatment (Tramadol Contramid OAD: 432, Placebo: 214) of which 591 (91%) completed the titration period, and 491 (76%) completed the 12-week maintenance period. Among patients randomized to Tramadol Contramid OAD, 106/432 (25%) selected 200 mg as the final dose during the open-label titration, and 325/432 (75%) selected 300 mg. The most frequent reasons for discontinuation
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of patients were treatment failure (Tramadol Contramid OAD: 8%, Placebo: 10%) and AEs (Tramadol Contramid OAD: 10%, Placebo: 5%) (Fig. 2). The safety population was 85% Caucasian, and approximately 62% of the patients were female. The mean age was 63 years, and 45% (456 patients) were at least 65 years old, of which 85 patients were at least 75 years old. The two groups were similar in terms of gender, age, body mass index, and race (Table 1). The mean score on the 11-point PI-NRS (0e10 points) at baseline for both active and placebo treatment arms was 7.2. The classes of medication most frequently taken prior to study entry were analgesics, anti-inflammatory drugs, and medications to treat cardiac disorders that were taken by similar percentages of patients across the study population. Regarding the primary efficacy parameter in the study, the Tramadol Contramid OAD groups showed a statistically significant greater absolute mean improvement on the PI-NRS Enrolled (1028)
Assigned to Tramadol Contramid OAD (1028) Entered run-in period (1027) Did not receive Tramadol Contramid OAD (5) Discontinued (381) Adverse event (225) Treatment failure (28) Patient request (48) Other (80)
Randomized (646)
Assigned to placebo (214) Did not receive placebo (0)
Assigned to Tramadol Contramid OAD (432) Did not receive Tramadol Contramid OAD (1)
Safety population (214) Full analysis population (214)
Safety population (432) Full analysis population (431)
Discontinued (49) Adverse event (11) Treatment failure (22) Patient request (6) Other (10)
Discontinued (106) Adverse event (44) Treatment failure (34) Patient request (23) Other (5)
Completed (165/167)1
Completed (326/328)1
1
In each treatment group, 2 patients who discontinued had a PI-NRS assessment at Week 12
Fig 2. Patient disposition.
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from baseline to the end of study compared to the placebo group (Tramadol Contramid OAD: 2.9 2.5; placebo 2.4 2.5) (Table 2). Furthermore, the time-weighted average analysis, used to assess the average effect of treatment during the entire 12-week maintenance period, revealed that the difference between the two treatment groups (0.70) was statistically significant (P < 0.0001). A responder analysis was conducted on the primary efficacy parameter, the PI-NRS score. That is, the percentage of patients who achieved a particular predefined response was compared between treatment groups for response levels that ranged from an improvement from baseline of at least one to five points. There was a statistically significant greater percentage of responders in the Tramadol Contramid OAD treatment group compared to placebo irrespective of the response level. The greater the predefined level of response required, the greater the difference in the percentage of responders in the Tramadol Contramid OAD group compared to the placebo group (Table 3). This was true for the Tramadol Contramid OAD treatment group as a whole and for each dose of Tramadol Contramid OAD compared individually to placebo regardless of what predefined response level
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was used: 200 mg, 3%e8% more responders; 300 mg, 5%e17% more responders (Fig. 3). Moreover, in addition to achieving a statistically significant better response at the end of the maintenance phase of treatment, patients randomized to Tramadol Contramid OAD achieved this improvement significantly sooner than patients randomized to placebo. Although the median number of days required for patients to achieve a two-point improvement in PI-NRS scores was similar for active (14 days) and placebo (15 days) arms, it took more than twice as long for placebo-treated patients to achieve a three-point improvement in the PI-NRS score (39 days) than it did for patients treated with Tramadol Contramid OAD (16 days, P < 0.0001). The median time to response was similar in patients treated with either Tramadol Contramid OAD 200 mg or 300 mg. At the end of the 12-week maintenance period, 80% of patients randomized to Tramadol Contramid OAD indicated that their condition had improved, compared to 69% of the patients randomized to placebo. The difference between treatment groups with respect to the Patient Global Impression of Change was statistically significant (P ¼ 0.0002) (Fig. 4). Similar results were obtained with the Physician
Table 1 Demographic Characteristics of the Safety Population Double-Blind Treatment Not Randomized (n ¼ 377)
Placebo (n ¼ 214)
Tramadol Contramid OAD (n ¼ 432)a
Overall (n ¼ 1,023)
142 (38) 235 (62)
81 (38) 133 (62)
157 (36) 275a (64)
380 (37%) 643 (63%)
63 9 65 9 63 9
62 9 63 9 62 9
62 9 62 9 62 9
63 9 63 9 62 9
Ethnic origin Asian: n (%) Black: n (%) Caucasian: n (%) Hispanic: n (%) Other: n (%)
4 (1) 22 (6) 308 (82) 34 (9) 9 (2)
1 (0.5) 12 (6) 185 (86) 15 (7) 1 (0.5)
1 (0.2) 21 (5) 380a (88) 28 (6) 2 (0.5)
6 (0.6) 55 (5) 873 (85) 77 (8) 12 (1)
BMI (mean SD) Male (mean SD) Female (mean SD)
29.9 4.0 29.9 3.9 29.9 4.1
29.5 4.3 29.5 3.9 29.5 4.5
29.7 4.0 30.0 3.8 29.5 4.1
29.7 4.1 29.9 3.8 29.6 4.2
NA
7.2 1.6
7.2 1.6
NA
Characteristic Gender Male n (%) Female n (%) Age (mean SD) Male (mean SD) Female (mean SD)
Baseline PI-NRSb (Mean SD)
a One patient who discontinued for administrative reasons after randomization but before receiving double-blind medication was not included in full analysis population. b Reported for full analysis population.
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Table 2 PI-NRS: Absolute Improvement on PI-NRS Score from Baselinea Tramadol Placebo Contramid OAD Baseline n Mean SD Median Min, Max
214 7.2 1.6 7.0 4, 10
431 7.2 1.6 7.0 3, 10
Absolute improvement (Baselinedlast individual visit) n 196 393 Mean SD 2.29 1.97 3.03 2.12 95% CI [2.02; 2.57] [2.82; 3.24] Median 2.10 3.00 Min, Max 4.0, 8.0 3.9, 9.0 Difference in absolute improvement between Tramadol Contramid OAD and placebo Estimate (mean) 0.70 95% Confidence Interval [1.02; 0.38] b <0.0001 P-value PI-NRS ¼ Pain Intensity Numerical Rating Scale. a Using time-weighted average approach. b Based on ANCOVA.
Global Impression of Change (improvement: Tramadol Contramid OAD: 80% versus placebo: 69%, P ¼ 0.0042). During the 12-week, double-blind, maintenance period of this trial, patients were randomized to treatment with Tramadol Contramid OAD or placebo. Within these treatment groups, an optimal dose (200 mg or 300 mg or corresponding placebo ‘‘dose’’) was selected based upon efficacy and tolerability. Once the optimal dose was selected, the dose level could not be changed during the maintenance period. Most patients in the active group selected the 300 mg dose (300 mg: 325 patients, 200 mg: 106 patients). Because
Table 3 PI-NRS: Responder Analysis Responders Improvement in Tramadol Contramid Placebo PI-NRS Score POAD (n/N ¼ %) (n/N ¼ %) valuea from Baseline $1 point
400/428 ¼ 93.5
$2 points
372/428 ¼ 86.9
$3 points
322/428 ¼ 75.2
$4 points
251/427 ¼ 58.8
$5 points
183/406 ¼ 45.1
187/ 0.036 211 ¼ 88.6 170/ 0.035 211 ¼ 80.6 134/ 0.002 211 ¼ 63.5 99/ 0.005 211 ¼ 46.9 61/ <0.001 203 ¼ 30.1
PI-NRS ¼ Pain Intensity Numerical Rating Scale. a Chi-squared test between respective treatment and placebo.
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the primary confirmatory analysis was to compare Tramadol (at optimal dose) with placebo, no a priori statistical comparison of Tramadol 200 mg versus Tramadol 300 mg was planned. Descriptive results at the end of study indicate an absolute improvement in pain intensity score of 2.9 points with both Tramadol Contramid OAD 200 mg and 300 mg. During the open-label phase of the study, 66% of the safety population experienced an AE, and 83% of these patients indicated that it was mild or moderate in intensity. Overall, during the double-blind phase, 59% of the active-treatment group experienced at least one AE, and 10% withdrew because of an AE irrespective of relationship to treatment. The majority of AEs reported by patients receiving active treatment were mild or moderate during the double-blind phase (88%). In general, among patients randomized to active treatment, the incidence of AEs was higher in the 300 mg (45%) treatment group than in the 200 mg (40%) group. The most commonly reported AEs in the active-treatment group were nausea, constipation, dizziness/vertigo, somnolence, vomiting, and headache in both the open-label and double-blind phases. Among patients randomized to active treatment in the double-blind phase, 15% reported nausea, 14% constipation, 10% dizziness/vertigo, and 7% somnolence (Table 4). Less than 2% of patients randomized to treatment with Tramadol Contramid OAD discontinued the study drug during the maintenance period due to these AEs. No deaths were reported during the study. Eleven serious AEs occurred in 10 patients during the study, among which one was in the placebo group (ischemic stroke, not related). In the active group, the following unrelated serious AEs occurred: diverticulitis, unstable angina, chest pain, breast cancer, grand mal convulsion (two weeks after final treatment dose), prostate cancer, and popliteal bursitis. Three serious AEs that were possibly related to active treatment were reported in two patients: syncope in one patient and renal insufficiency and elevation of liver enzymes with inflammation of the liver in another patient.
Discussion The primary endpoint in this study was achievedda greater reduction of the pain
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Tramadol OAD for Pain
335
100 93.8 92.2 88.6
Percentage of responders
90
88 83.5 80.6
80
76.6 70.9
70
63.5
60.6
60
52.9
50
47.2
46.9
40
38.1
30
30.0
20
Placebo Tramadol Contramid OAD 200 mg Tramadol Contramid OAD 300 mg
10 0
1
2
3
5
4
Difference in PI-NRS Score
Fig. 3. PI-NRS: responder analysis.
the full difference between treatment groups that is associated with the arbitrary selection of a given response level as a cutoff point.22 In this study, the responder analysis demonstrated that a greater percentage of patients in the Tramadol Contramid OAD treatment group achieved a predefined level of response than did patients in the placebo group regardless of which response level was selected. Furthermore, the greater the reduction in the PI-NRS score considered, the greater the difference between the percentage of responders in the two treatment groups. A statistically significant difference in favor of Tramadol Contramid OAD was demonstrated for each of the five successive reductions of the PI-NRS score examined.
intensity score occurred with Tramadol Contramid OAD compared to placebodand the difference was statistically significant. This statistically significant difference was demonstrated with the time-weighted average approach that evaluates the average analgesic effect over the entire treatment period. Other methods of analysis confirmed the significant difference in favor of Tramadol Contramid OAD with respect to this primary efficacy measure. Responder analyses are considered to be an optimal approach to express the clinical significance of an analgesic effect and to compare the treatment response to the response in the control group over the full range of response cutoff points. Furthermore, responder analyses reduce over- or underestimation of
Percentage of patients
40 35
34.8
Placebo Tramadol Contramid OAD
30
28.1
27.6 25.4
25 20.2
20.0
20 15
12.9
11.5
10 5 0 None
Minimal
Much
Very much
Global Impression of Change P = 0.0002 for the difference between the two groups (ANCOVA based on ranks; baseline PI-NRS as covariate).
Fig. 4. Patient Global Impression of Change at last double-blind visit.
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Table 4 Most Common Adverse Events During the Double-Blind Phasea Tramadol Contramid OAD Placebo
Nausea: n (%) Constipation: n (%) Dizziness/vertigo: n (%) Somnolence: n (%)
n ¼ 432
n ¼ 214
66 61 42 29
12 9 8 8
(15.3) (14.1) (9.7) (6.7)
(5.6) (4.2) (3.7) (3.7)
a Reported by $5% of patients during the three-month maintenance period irrespective of relationship to the treatment.
The significant difference detected with the time-weighted average approach combined with the results of the responder analysis indicate that the superiority of Tramadol Contramid OAD over placebo is consistent over the spectrum of pain intensities and the entire 12-week treatment period that were studied. Furthermore, the improvement from baseline with either the 200 mg or the 300 mg dose was greater than the improvement noted in the placebo group. In general, it took more time for patients in the placebo arm to achieve the same level of improvement on the PI-NRS score than it did for patients in the active treatment arm. Moreover, the median time to response was similar among patients who received either Tramadol Contramid OAD 200 mg or Tramadol Contramid OAD 300 mg, thus suggesting the contribution of the two dose levels to the overall reduction in time to achieve that level of response. The overall test for comparison of the Patient Global Impression of Change achieved statistical significance between Tramadol Contramid OAD and placebo. Eighty percent (80%) of the patients indicated that their pain symptoms had improved with Tramadol Contramid OAD, whereas 69% of patients indicated that improvement had occurred with placebo. These results were confirmed with the Physician Global Impression of Change and indicate an overall high level of satisfaction with the analgesic effects of Tramadol Contramid OAD. Sixty-six percent (66%) of patients in the open-label phase and 59% of the patients randomized to Tramadol Contramid OAD experienced an AE of which 59% and 43%,
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respectively, were considered to be at least possibly related to Tramadol Contramid OAD. This is comparable to the frequencies of AEs, between 45% and 79%, that have been reported in the literature for other marketed formulations of tramadol.6,21,23 Eighty-eight percent (88%) of the AEs reported by patients randomized to Tramadol Contramid OAD were mild to moderate. The discontinuation rates during the doubleblind phase of the study were low in both the active (25%) and placebo (23%) arms and are comparable to discontinuation rates from other studies involving titration to optimum dose of once-daily formulations of tramadol.21,24 In a recent 12-week fixed dose study of another extended-release formulation of tramadol, 100 mg to 400 mg once a day versus placebo, between 71% and 84% of patients in the active treatment group experienced an AE regardless of the relationship to study treatment. Discontinuations due to AEs in that study were in the order of 20% to 30%, higher than for the treatment group reported herein.25 The AEs reported by at least 5% of the patients dosed with Tramadol Contramid OAD during the double-blind phase were nausea (15%), constipation (14%), dizziness/vertigo (10%), and somnolence (7%). No new or unexpected AEs were reported. Following treatment for up to 90 days with Ultram, nausea, constipation, dizziness/vertigo, and somnolence occurred in more than 20% of patients, and vomiting affected 17% of patients.26 A criticism of enrichment designs, such as the one used in this study, is that they may lack generalizability. In a disease state such as pain, the balance between efficacy and tolerability is an important consideration in the selection of the pharmacological treatment. In this case, an enrichment design may be used to identify the population of patients who, based upon efficacy and tolerability, are most appropriately treated with a particular drug and, therefore, are most representative of the patient population who will eventually use it. Effective blinding was ensured in the trial through the use of indistinguishable placebo and active treatments. Furthermore, a sevenday washout period between the open-label and double-blind treatments was included. Another approach to maintaining the blind would have been to use an active placebo so
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that patients in the placebo arm would have experienced similar AEs to those experienced by patients in the active arm. Although this approach may provide added assurance that the blind is maintained, it is controversial in that it involves exposing patients to an active substance and its associated risks without any anticipated benefit.27 Tramadol Contramid OAD is the only analgesic developed with the Contramid delivery system, and combines both immediate and extended release of tramadol over 24-hours for consistent relief of persistent pain. It is, therefore, possible that, as a result of the reduction in peak and trough plasma concentrations, more consistent pain relief throughout the entire dosing interval can be achieved. The analgesic efficacy of Tramadol Contramid OAD 100 mg to 400 mg was established in a previous optimal-dose non-inferiority study.20 Tramadol Contramid OAD demonstrated a statistically significant greater average reduction in the PI-NRS score compared to placebo over the entire treatment period. The responder analysis showed that consistent analgesia is provided over the spectrum of pain intensities with Tramadol Contramid OAD. The Global Impressions of Change indicate a high level of satisfaction with the analgesic effect among both patients and their physicians. The relatively low incidence of the most common AEs reported during the double-blind phase and their generally low intensity support the safety of Tramadol Contramid OAD. This study has shown that, with once-daily administration, Tramadol Contramid OAD provides efficacious analgesia and has a relatively good safety profile. Thus, Tramadol Contramid OAD could be an acceptable alternative for management of pain.
Acknowledgments The authors would like to acknowledge the following practitioners for their participation in the study: Serban Stroescu, MD, Phyllis Troia, MD, Leah Schmidt, DO, Mark Shirley, DO, Charles Larrison, MD, Darren Pearson, MD, Allan Soo, MD, John Crane, MD, Douglas Haselwood, MD, Rashid Khairi, MD, Lisa Cohen, DO, James Farrell, DO, Paul Pickrell, MD, Clara Garcia, MD, Frederick Murphy,
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MD, Adesh Jain, MD, Edward Portnoy, MD, and Chae Haen, MD, and John L. Moore for his contribution to the preparation of this manuscript.
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