Current Medical Research & Opinion Vol. 28, No. 5, 2012, 847–857
0300-7995 Article ST-0468.R1/681035
doi:10.1185/03007995.2012.681035 All rights reserved: reproduction in whole or part not permitted
Original articleExtended-release tramadol/paracetamol inmoderate-to-severe pain: a randomized,placebo-controlled study in patients withacute low back pain
Ben LaskoMedical Director, Manna Research, Toronto, Ontario,
Canada
Randy J. LevittLabopharm Inc., Laval, Quebec, Canada
K.D. RainsfordEmeritus Professor of Biomedical Sciences, Sheffield
Hallam University, Sheffield, UK
Sylvie BouchardClinical Faculty Lecturer, Faculty of Medicine, McGill
University, and Emergency Physician at the Lakeshore
General Hospital, Montreal, Quebec, Canada
Anna RozovaSybil RobertsonLabopharm Inc., Laval, Quebec, Canada
Address for correspondence:Randy J. Levitt, PhD, Paladin Labs Inc., 100 Alexis
Accepted: 21 March 2012; published online: 25 April 2012
Citation: Curr Med Res Opin 2012; 28:847–57
Abstract
Objective:
Combinations of oral analgesics may offer several potential benefits compared with an individual agent. The
objective of this study was to investigate the efficacy and safety of an extended-release, twice-daily fixed
combination of 75 mg tramadol/650 mg paracetamol (DDS-06C) in the treatment of moderate-to-severe
pain, using acute low back pain as a model.
Research design and methods:
In this phase III study, 277 patients with moderate-to-severe acute low back pain were randomized to 1–2
tablets of DDS-06C or placebo every 10–12 h for 2.5 days during the double-blind phase. Following the
double-blind phase, patients had the option to continue for a 2.5-day open-label phase.
Clinical trial registration:
Clinicaltrials.gov (Identifier: NCT00643383)
Main outcome measures:
The primary end point was the sum of pain intensity differences (SPID) over the 50-h double-blind phase
(SPID50). Secondary end points included total pain relief score over the 50-h double-blind phase
(TOTPAR50), patient’s global impression of medication, and SPID over the first 4 h.
Results:
A statistically significant (p¼ 0.038) greater decrease in pain intensity was observed in the DDS-06C group
(median SPID50: �6.0) versus placebo (median SPID50: �4.0). Greater pain relief was also observed in
patients randomized to DDS-06C: the median TOTPAR50 was 13.0 for the DDS-06C group and 11.0 for
placebo (p¼ 0.026). DDS-06C demonstrated statistically significant superior efficacy compared with
placebo for the majority of the other secondary end points. Overall, 38% of patients treated with DDS-
06C experienced at least one adverse event; the intensity was mild-to-moderate in 81% of cases. The most
commonly reported adverse events (45% of patients receiving DDS-06C) were nausea, dizziness, vomiting,
and somnolence.
Conclusions:
Using acute low back pain, a model with a high degree of heterogeneity and intrinsic variability, DDS-06C
was superior to placebo on measures of pain intensity and relief, and was well-tolerated.
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Introduction
Combinations of oral analgesics may offer several potentialbenefits compared with an individual agent. Combininganalgesics into a single product may facilitate prescribingand compliance by reducing the number of medicationsthat patients use to manage pain. Combining productswith different mechanisms of action may provide multi-modal coverage of pain resulting from a broad spectrum ofpathologies, and the individual agents may act synergisti-cally1. Additionally, lower doses of the respective analge-sics used in the combination may result in a lowerincidence of adverse events (AEs). Given the multiplephysiological pathways involved in the perception ofpain, combination therapy has been recommended by var-ious pain management guidelines2.
Tramadol is an atypical weak opioid used for the treat-ment of moderate-to-severe pain3. It is comprised of twoenantiomers, (þ)-tramadol and (�)-tramadol, in a race-mic 1:1 mixture. Tramadol has a number of analgesiceffects in the central nervous system due to three comple-mentary mechanisms of action. First, (þ)-tramadol and itsmajor metabolite, (þ)-O-desmethyltramadol (M1), act asm-opioid receptor agonists in the spinal cord and brain4.The (þ)-M1 metabolite has a greater affinity for m-opioidreceptors than (þ)-tramadol, and is primarily responsiblefor the opioid action of tramadol5. Secondly, (þ)-tramadolblocks central pain pathways by inhibiting the reuptake ofserotonin, and thirdly, (�)-tramadol inhibits the reuptakeof norepinephrine4.
Paracetamol is an analgesic and antipyretic drug withweak anti-inflammatory properties. Its mechanism ofaction is suggested to be both central and peripheral.Proposed mechanisms include cyclooxygenase inhibition,nitric oxide synthesis blockade, and effects on several neu-rotransmitter systems, in particular the serotonergicsystem. Thus, paracetamol has been proposed to affectopioidergic, noradrenergic, serotonergic, and cholinergicsystems6,7.
Co-administering paracetamol with tramadol results insynergistic analgesia in both animal and human painmodels1,8. Furthermore, clinical studies have demon-strated the efficacy and tolerability of immediate-release(IR) tramadol/paracetamol (37.5 mg/325 mg) for a varietyof pain models, including acute nociceptive pain associ-ated with orthopedic surgery, osteoarthritis flare, and oralsurgery9–13. IR tramadol/paracetamol combinations aremarketed worldwide with a variety of indications in thetreatment of moderate-to-severe pain14–16.
A twice-a-day tramadol/paracetamol formulationwould be more convenient for patients than currently mar-keted IR formulations, which must be taken up to 4 times aday. DDS-06C is an extended-release, twice-daily fixed-combination formulation of 75 mg tramadol hydrochlorideand 650 mg paracetamol developed by Labopharm Inc
(Laval, QC, Canada). This formulation was designed toprovide effective analgesia for a full 12-h period. It wasdeveloped using hydroxypropyl distarch phosphate(Contramid�, Labopharm, Laval, Quebec, Canada), across-linked high amylose starch matrix that provides con-trolled release of the active ingredients over an extendedperiod17. In a multiple-dose comparative bioavailabilitystudy, equivalent total systemic exposure (based on areaunder the plasma time–concentration curve [AUC]) atsteady state was demonstrated for both active componentsof DDS-06C (2� 75 mg tramadol/650 mg paracetamolcontrolled-release tablets administered every 12 h) versusIR tramadol/paracetamol (2� 37.5 mg tramadol/325 mgparacetamol IR tablets administered every 6 h)18.
The objective of this randomized, double-blind, phaseIII study was to demonstrate the efficacy and safety ofDDS-06C versus placebo for the treatment of moderate-to-severe pain, using acute low back pain as a pain model.This condition is particularly complex and often presentswith intractable pain, so there is a therapeutic need foreffective and long-lasting treatment of pain in this state.
Patients and methods
Patient selection
Patients included in this study were selected from 31 activecenters: 14 from the USA and 17 from Canada. The cen-ters were comprised of walk-in clinics, clinical researchcenters (that received patients referred from pharmacies),and hospital emergency rooms. Patients included in thestudy were males or females in generally good health,18–80 years of age, with moderate-to-severe acute lowback pain. At baseline, included patients had a rating ofat least 2 on a 4-point categorical pain intensity ratingscale (0¼ none, 1¼mild, 2¼moderate, 3¼ severe), anda rating of at least 4 on the 11-point pain intensity numer-ical rating scale (PI-NRS) (ranges from 0 [no pain] to 10[worst pain]). The onset of the current acute low back painepisode was within 48 h prior to dosing.
Patients with a known history or symptoms suspiciousfor spinal fracture, cancer (i.e., constitutional symptomssuch as recent unexplained chills or weight loss), orspinal infection (e.g., IV drug abuse, immunosuppression)were excluded from the study. Also excluded were patientswith cauda equina syndrome, spina bifida, neurologicaldeficit (e.g., foot drop), spinal surgery within 1 year ofstudy entry, chronic low back pain, back pain radiatingbelow the knee, or more severe pain in a region otherthan the lower back. Other exclusion criteria were: treat-ment with non-pharmacological therapy (e.g., chiroprac-tic adjustment) within 3 weeks of entry to the study, use ofany sedative hypnotics, topical preparations/medicationsand anesthetics or muscle relaxants within 4 h prior to
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study entry, use of short-acting analgesics (e.g., paraceta-mol) within 4 h prior to study entry or use of other anal-gesics within 5 half lives prior to study entry, use of anopioid within the 14 days preceding randomization, treat-ment within the last 3 weeks with a drug that reduces sei-zure threshold, a chronic or acute painful condition otherthan the study indication which could have interfered withthe assessment of the efficacy of the study medication orany other condition that, in the opinion of the investiga-tor, could have adversely affected the patient’s ability tocomplete the study or its measures, patients who had ahistory of seizure disorder (other than infantile febrile sei-zures), bowel disease or postsurgical condition causing mal-absorption, significant renal or hepatic disease, or patientswho had ongoing or prior substance abuse or dependence(other than nicotine).
Study design
This double-blind, randomized, placebo-controlled, two-arm, multicenter study (Labopharm protocol 06CCL3-001) evaluated the efficacy and safety of DDS-06Cversus placebo for the treatment of acute low back pain.The study was conducted from March 2008 to January2009. The protocol complied with the 1996International Conference on Harmonisation – GoodClinical Practice (ICH-GCP) guidelines and was con-ducted in compliance with the 2004 revision of theDeclaration of Helsinki (Tokyo). The trial was registeredon clinicaltrials.gov (Identifier: NCT00643383) on March20, 2008.
During the screening/baseline visit, patients providedinformed consent and underwent an initial screening forinclusion/exclusion. Laboratory evaluations, physicalexamination, medical history and vital signs (includingheight and weight) were performed. At the beginning ofthe double-blind phase, patients were randomized to DDS-06C or placebo. To maintain blinding, the active drug andplacebo were identical in appearance and taste. As a gen-eral rule, the patient received two tablets of DDS-06C orplacebo every 10–12 h without regard to meals. However,at the investigator’s discretion, he/she may have decided toinitiate treatment with one tablet of the study medicationbased on various clinical factors (e.g., level of pain, age,BMI, etc.). It was also possible to reduce the dose from twoto one tablet, and subsequently go back to two tablets,based on an individual patient’s tolerability and level ofpain relief.
Patients were required to remain in the study facility forthe first 4 h following the first dose of the study medication(on-site period). They were asked to maintain a standard-ized level of activity during the on-site period: standingand/or sitting (walking to the bathroom was permitted).After 4 h, patients left the clinic but were required to
perform the pain intensity and pain relief evaluations asdetailed below. Patients were informed of the importanceof closely adhering to the evaluation schedule andreminded that if treatment was stopped early, they mustreturn to the clinic for a discontinuation visit as soon aspossible and no later than 48 h after the last dose of studymedication. Patients were also advised to minimize theirlevel of physical activity (e.g., walking for a short distance,sitting, standing). Any intensive physical activity (e.g.,lifting or pushing weights exceeding 3 kg (6 lbs), jumping,jogging, gardening, shoveling, etc.) was prohibited for theduration of the double-blind phase.
The double-blind phase lasted for 2.5 days, with admin-istration of one to two tablets of DDS-06C or placebooccurring every 10–12 h. Remedication was only allowedon day 1, and consisted of one tablet of study medicationwhich could be taken at any time within 4–10 h after theinitial dose. No other rescue medication was allowed atany time during the study. The last visit of the double-blind phase was on day 3. Patients who required furtheranalgesia could continue into the open-label phase. Forthose patients who did not require further analgesia orwere not willing to continue participation in the study,day 3 was the patient’s final study visit. Patients thatagreed to continue to the open-label phase of the studyreceived one to two tablets of DDS-06C every 10–12 h foran additional 2.5 days. The last study visit for thesepatients was on day 6.
Study assessments
The primary end point was the sum of pain intensity dif-ferences over the 50-hour observation (SPID50).Secondary end points consisted of 9 measures: total painrelief score over the 50-hour observation (TOTPAR50),the sum of pain intensity differences over the first 4 h ofobservation (on-site period) (SPID4), the patient’s globalimpression of study medication, time to onset of meaning-ful pain relief, time to onset of perceptible pain relief, timeto remedication, weighted SPID50 (SPIDW50), weightedTOTPAR50 (TOTPARW50), and the change from base-line in pain intensity at the end of the open-label phase.
During the screening/baseline visit, patients rated theirpain intensity on a 4-point categorical scale (0¼ none,1¼mild, 2¼moderate, 3¼ severe). Randomized patientssubsequently rated their pain intensity (using the 4-pointscale) and pain relief (using a 5-point categorical scale:0¼ none [no relief], 1¼ a little, 2¼moderate, 3¼ a lot,4¼ complete) at the following 10 time points (relative tothe first dose): 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h (�30 min),26 h (�30 min), 30 h (�30 min), 34 h (�30 min), and50 h (�30 min). SPID50 and TOTPAR50 were computedas the sum of the differences between each post-baselinepain intensity and pain relief score, respectively, and the
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baseline score. SPIDW50 and TOTPARW50 were calcu-lated by multiplying these differences by the correspondingtime interval since the previous observation (adjusted ateach daily dosing), and summing these weighted values upto hour 50. SPID4 was computed as the sum of the differ-ences between each post-baseline pain intensity scoreduring the 4 h on-site period and the baseline score.
The patient’s global impression of study medication wasassessed at the end of the double-blind phase (or at studydiscontinuation) using a 4-point categorical scale(1¼ very effective, 2¼ effective, 3¼ somewhat effective,4¼ ineffective).
Time to onset of meaningful pain relief and time toonset of perceptible pain were measured on day 1 usingthe double stop-watch method. Perceptible pain reliefwas defined as the point at which the patient began toexperience any pain relief even though the pain was notcompletely relieved, and meaningful pain relief wasdefined as the point at which the patient felt a significantpain relief even though the pain may not have been com-pletely relieved. Time to remedication was defined as thetime of the rescue medication dose (which was onlyallowed 4–10 h post-initial dose) minus the time of theinitial dose.
Safety data collected consisted of AEs, laboratory eval-uations (biochemistry, hematology, urinalysis), physicalexamination findings, vital signs (blood pressure, heartrate, respiratory rate and body temperature), and concom-itant medications. AEs were monitored from the time ofthe first study medication dose until the end of the study oruntil discontinuation. AEs were recorded as serious AEs(SAEs) if they met applicable criteria (based on ICH-GCPguidelines). All SAEs that occurred during the study andfor 30 days after the patient’s last dose of study medicationwere documented. All AEs and SAEs were followed toresolution, until the condition stabilized, or until thepatient was lost to follow-up
Statistical analyses
The primary population for efficacy analyses was theintent-to-treat (ITT) population, which was defined asall randomized patients who received at least one dose ofthe double-blinded study medication (during the double-blind phase), regardless of the status of the post-dosingassessment. In the sensitivity analysis, efficacy parameterswere also analyzed for the per protocol (PP) population,which was defined as all randomized patients who com-pleted the double-blind phase of the study without majorprotocol deviations. Safety analyses were performed on thesafety population, which was defined as all patients whoreceived at least one dose of the study medication (double-blind and/or open-label phase).
For the efficacy analyses, missing data during thedouble-blind phase of the study were handled using thebaseline observation carried forward (BOCF)/last observa-tion carried forward (LOCF) method of imputation asfollows: (1) for patients who discontinued during thedouble-blind phase due to AEs, BOCF was used (the base-line value for the pain intensity parameter was substituted,and the rating of 0¼ none was substituted for the painrelief parameter); (2) for patients who discontinuedduring the double-blind phase due to reasons other thanAEs, LOCF was used (the last post-baseline value of therespective efficacy parameter was substituted); (3) forpatients who completed the double-blind phase but weremissing data values due to missed visits or windowing,LOCF was used (in cases where no post-baseline data wasavailable, BOCF was used). Exploratory supportive efficacyanalyses were performed using LOCF as the method ofimputation for all patients. For all missing data duringthe open-label phase of the study, LOCF was used.
To achieve 90% power to detect an effect size of 0.45 forthe primary end point (SPID50), a sample size of 105patients in each treatment group was needed to completethe study; this assumed a 1:1 randomization ratio and atwo-group two-tailed t-test with significance set ata¼ 0.05. Assuming a discontinuation rate of 30%, anenrollment of 135 patients in each treatment group wasrequired.
For the analysis of SPID50, residual diagnostics (nor-mality and homogeneity of variance assessments) wereperformed to verify if an analysis of covariance(ANCOVA) could be considered robust. The normalityof the residuals from the ANCOVA model were tested andfound to be non-normally distributed using Shapiro-Wilk(and confirmed with a variety of other statistical tests).Furthermore, the distribution of SPID50 values usingBOCF/LOCF as the method of imputation is both bimodaland highly skewed (Figure 1), rendering methodologybased on a normal distribution (ANCOVA) inappropri-ate. Therefore, a non-parametric approach (Wilcoxonrank-sum test) was used as the primary basis for comparisonof the two treatment groups.
To be consistent with the primary end-point analysis,the normality of the residuals from the ANCOVA modelfor TOTPAR50, SPID4, SPIDW50, and TOTPARW50were tested and found to be non-normally distributed.Therefore, analysis of these end points was performedusing a non-parametric method (Wilcoxon rank-sumtest). For the patient’s global impression of study medica-tion, frequency counts were compared based on theCochran–Mantel–Haenszel (CMH) mean score statisticusing modified ridit scores, stratified by pooled center.Time to onset of meaningful pain relief, time to onset ofperceptible pain relief, and time to remedication weresummarized using Kaplan–Meier curves, and a Cox pro-portional hazards regression model stratified by
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investigative site was used to compare between treatmentgroups. Pain intensity at the end of the open-label phasewas analyzed using descriptive statistical methods.
Safety data were analyzed using descriptive statistics onAEs, concomitant medications, physical examination, lab-oratory evaluations, and vital signs.
Results
Patient characteristics
In this study, 277 patients met the eligibility criteria andwere randomized to receive either DDS-06C (n¼ 141) orplacebo (n¼ 136). As seen in Figure 2, 26 of 277 patients(9.4%; DDS-06C, n¼ 19; placebo, n¼ 7) prematurely dis-continued the study during the double-blind phase. Themost frequently indicated reason for discontinuation,regardless of treatment group, was AEs (DDS-06C,n¼ 17; placebo, n¼ 3). A total of 219 patients enteredthe open-label phase (109 patients from the DDS-06Cgroup continued on active treatment and 110 patientsfrom the placebo group switched to DDS-06C treatment).There were ten patients (4.6%) that discontinued duringthe open-label phase; all ten patients were randomized toplacebo during the double-blind phase. The most fre-quently indicated reason for discontinuation during theopen-label phase was AEs (n¼ 7). The ITT populationcontained all 277 patients that comprised the safety pop-ulation. The PP population contained a total of 226patients (DDS-06C, n¼ 111; placebo, n¼ 115).
Baseline characteristics are presented in Table 1. Themean age of the ITT population was 42.2 (SD: 13.0) years;145 of 277 (52.3%) were female, and 156 of 277 (56.3%)were Caucasian. There were no statistically significant
differences between treatment groups with regard to age,gender, or race. At baseline, the mean patient rating ofpain intensity score was 2.3 for the DDS-06C group, and2.2 for the placebo group (difference between groups wasnot statistically significant; p¼ 0.0701). The majority ofthe patients in both treatment groups (66.0% in the DDS-06C group and 75.7% in the placebo group) had a score of2 (moderate pain). As seen in Table 2, there was no sta-tistically significant difference between groups with regardto acute low back pain history. The majority of patients(54.9%) had an onset of pain 2 days prior torandomization.
The treatment groups were comparable with regard topast and current medical conditions, and prior and con-comitant medications. Overall, 110 of the 277 randomizedpatients (39.7%) reported use of medications within the 30days prior to taking the study medication that were dis-continued before study initiation, and 114 patients(41.2%) took medications concomitantly with the studymedication. The most commonly used class of medicationsthat were discontinued before study initiation were otheranalgesics and antipyretics (51/277 patients, 18.4%), andthe most commonly used class of concomitant medicationswere lipid modifying agents (19 patients; 6.9%).
Dosing and exposure
Overall, 251 patients were exposed to DDS-06C duringthis study (141 patients treated with DDS-06C duringthe double-blind phase, and 110 patients treated with pla-cebo during the double-blind phase who were switched toDDS-06C during the open-label phase). The mediannumber of days of therapy for all patients exposed toDDS-06C was 3 days.
SPID50 BOCF/LOCF score-20 -15 -10 -5 0 5 10
Num
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0
10
20
30
40
50
60
Figure 1. Distribution of SPID50 values. Histogram of the distribution of SPID50 values for the 277 patients in the ITT population (method of imputation:BOCF/LOCF).
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During the double-blind phase, 27.7% of patients in theDDS-06C group always took one tablet of study medica-tion, 44.0% of patients always took two tablets, and 28.4%of patients switched between one or two tablets. In theplacebo group, 19.9% of patients always took one tablet,47.1% of patients always took two tablets, and 33.1% ofpatients switched between one or two tablets. Dosingduring the open-label phase was similar to the double-blind phase: 31.1% of patients always took one tablet,48.6% of patients always took two tablets, and 20.3% ofpatients switched between one or two tablets.
Analgesic efficacy
Results from the primary and secondary efficacy end pointsare summarized in Table 3. For the primary end point(SPID50), using BOCF/LOCF as the method of
imputation, a greater reduction in pain intensity wasobserved in the DDS-06C group (median score: �6.0)compared to the placebo group (median score: �4.0).This difference was found to be statistically significantusing the Wilcoxon rank-sum z-test (p¼ 0.038). A statis-tically significant difference in favor of the DDS-06Cgroup was confirmed using two other nonparametric anal-yses: the Wilcoxon rank-sum t-test (p¼ 0.039) and theKruskal–Wallis test (p¼ 0.038). An exploratory analysisusing a less conservative method of imputation (LOCF forall patients) also demonstrated a statistically significantdifference in favor of the DDS-06C group (�6.0 vs.�4.0, p¼ 0.012).
Greater pain relief was also observed in patients ran-domized to DDS-06C compared with those randomized toplacebo: the median TOTPAR50 score was 13.0 for theDDS-06C group and 11.0 for the placebo group. Thisdifference was statistically significant (p¼ 0.026).
Assessed for eligibility n = 325
Randomized n = 277
DDS-06C Allocated to intervention: 141
Received allocated intervention: 141
Placebo Allocated to intervention: 136 Received allocated intervention: 136
Figure 2. Study flowchart. Disposition of the 277 patients that met the eligibility criteria for this study. Eligible patients were randomized to receive eitherDDS-06C (n¼ 141) or placebo (n¼ 136). *Patient requests included reasons for discontinuation other than adverse events or lack of efficacy.
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A statistically significant difference in TOTPAR50 wasalso demonstrated using LOCF as the method of imputa-tion (p¼ 0.008).
The median SPID4 score was �2.0 for the DDS-06Cgroup and�1.0 for the placebo group. Consistent with theSPID50 results, this difference was statistically significant(p¼ 0.024). Since only one patient (randomized to pla-cebo) had data imputed using BOCF during the first 4 h, anexploratory analysis using LOCF as the method of impu-tation yielded identical results (p¼ 0.024).
For the patient’s global impression of study medication,there was a statistically significant difference betweentreatment groups in favor of DDS-06C (p¼ 0.005).There were 120 patients (86.3%) in the DDS-06C groupwho reported effectiveness (somewhat effective, effective,or very effective) versus 94 patients (69.6%) randomized toplacebo. Conversely, 30.4% of patients in the placebogroup reported that the drug was ineffective, comparedto only 13.7% of patients in the DDS-06C group.
Regarding time to onset of meaningful pain relief, therewas a significant difference between treatment groups in
favor of DDS-06C (hazard ratio: 1.565, p¼ 0.027).Furthermore, there were significantly more patients thatreached meaningful pain relief within the first 4 h post-dosing in the DDS-06C group than in the placebo group(43.3% vs. 31.1%, p¼ 0.019).
Regarding time to onset of perceptible pain relief, theresults favored a faster onset of DDS-06C versus placebo(hazard ratio: 1.219); however, the difference was not sta-tistically significant (p¼ 0.166). There were 108 patientsin the DDS-06C (76.6%) and 95 patients in the placebogroup (70.4%) who reached perceptible pain relief withinthe first 4 h post-dosing (p¼ 0.170).
Although patients were allowed to remedicate with thestudy medication once on day 1 (between 4 and 10 h afterthe initial dose), there were very few patients who reme-dicated: 18 patients (12.8%) in the DDS-06C group and 17patients (12.5%) in the placebo group (p¼ 0.959).Overall, there was no significant difference betweengroups (hazard ratio: 0.93, p¼ 0.828).
The median SPIDW50 score was �20.0 for theDDS-06C group and �15.3 for the placebo group.
Table 1. Baseline characteristics of randomized patients (ITT population).
*Pain intensity numeric rating scale: ranges from 0 (no pain) to 10 (worst pain) (randomized patients had to have a score of at least 4).yPain intensity scale: none¼ 0; mild¼ 1; moderate¼ 2; severe¼ 3 (randomized patients had to have a score of at least 2).
Table 2. Onset of the current episode of acute low back pain (ITT population).
Number of patients (%) DDS-06Cn¼ 141
Placebon¼ 136
Overalln¼ 277
Onset on the day of randomization 6 (4.3%) 4 (2.9%) 10 (3.6%)Onset of 1 day prior to the randomization date 51 (36.2%) 57 (41.9%) 108 (39.0%)Onset of 2 days prior to the randomization date 80 (56.7%) 72 (52.9%) 152 (54.9%)Onset of 3 days prior to the randomization date 4 (2.8%) 3 (2.2%) 7 (2.5%)
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This difference was not found to be statistically significant(p¼ 0.162). However, an exploratory analysis using LOCFas the method of imputation demonstrated a statisticallysignificant difference in favor of the DDS-06C group(�22.0 vs. �17.3, p¼ 0.024).
The median TOTPARW50 score was 43.0 for theDDS-06C group and 30.5 for the placebo group. This dif-ference was not statistically significant (p¼ 0.066).However, an exploratory analysis using LOCF as themethod of imputation demonstrated a statistically signifi-cant difference in favor of the DDS-06C group (46.5 vs.31.8, p¼ 0.007).
The mean change from baseline in pain intensity for allpatients who had a pain intensity measurement on the day5 visit (211 patients) was �1.3� 0.8. This represents a60% decrease in the pain intensity rating from baseline.
Safety and tolerability
As seen in Figure 2, the primary reason for discontinuationin patients receiving active treatment was AEs: there were17 of 141 patients (12.1%) in the DDS-06C group andthree of 136 patients (2.2%) in the placebo group whodiscontinued due to AEs during the double-blind phase(Figure 2). The most commonly reported reason for
discontinuation due to AEs in the DDS-06C group wasvomiting (nine patients). There were seven of 219 patients(3.2%) who discontinued due to AEs during the open-label phase (Figure 2). The most commonly reportedreason was dizziness (five patients).
Overall, 95 of the 251 patients exposed to DDS-06C(37.8%) experienced at least one AE while being treatedwith active drug. The intensity was mild-to-moderate inthe majority (77 of 95; 81.0%) of cases. During the double-blind phase, 59 of 141 patients in the DDS-06C group(41.8%) and 17 of 126 patients in the placebo group(12.5%) reported at least one AE. During the open-labelphase, 48 of 219 patients (21.9%) reported at least one AE.
The most common AEs (reported by45% of patientstreated with DDS-06C) during the double-blind and open-label phases are presented in Table 4. Overall, the mostcommonly reported AEs were nausea, dizziness, vomiting,and somnolence. With the exception of one case of vom-iting during the double-blind phase (experienced by apatient in DDS-06C group), all incidences of the mostcommonly occurring AEs were considered at least possiblyrelated to treatment. During the double-blind phase, themean time to onset of the most common AEs in patientstreated with DDS-06C was between 1.3 and 1.4 days (sim-ilar time to onset in the placebo group), and mean
Table 3. Summary of efficacy results – ITT population (n¼ 277).
Change in pain intensity from baseline to the end of theopen-label phase (n¼ 219) [mean (standard deviation)]
�1.3 (0.8) –
*Performed as supportive efficacy analyses.BOCF, baseline observation carried forward; LOCF, last observation carried forward.1Wilcoxon rank-sum; 2Cochran–Mantel–Haenszel; 3Cox proportional hazards regression.
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durations ranged from 1.1 days (vomiting) to 2.9 days(somnolence). During the open-label phase, mean dura-tions of the most common AEs were 2.0 days for dizzinessand 2.3 days for nausea. There were no notable changes invital signs (blood pressure, heart rate, respiratory rate, andbody temperature) for any patient during the double-blindphase or open-label phase.
Only one SAE occurred during the study: a patient inthe DDS-06C group experienced exacerbation of backpain requiring hospitalization during the double-blindphase. The SAE was considered severe and not related tothe study medication. The patient completely recovered.
Discussion
This randomized, multicenter, placebo-controlled studydemonstrates the efficacy and safety of DDS-06Cversus placebo for the treatment of moderate-to-severe pain, using acute low back pain as a painmodel. To date, this is the only phase III study thathas been conducted with DDS-06C. One of the lim-itations of this study is that low back pain is a modelwith a high degree of heterogeneity and intrinsic var-iability. However, this model is representative of thepatient population which currently uses immediate-release combination treatment with tramadol and para-cetamol (27% of prescriptions for branded tramadol/paracetamol combination products in Europe are forlow back pain; 2008 IMS MIDAS Prescribing Insight
Medical Database). Furthermore, low back pain affectsmore than 80% of the population worldwide at somepoint in their lifespan19, and is difficult to treat20.Another limitation of this study is that due to theallowance for dosing with one or two tablets, patientswill have variations in exposure to the drug. Althoughthis dosing regimen considers an individual’s clinicalneeds, it does not allow for any conclusions to bedrawn regarding dose-dependent effects of DDS-06C.
In this study, the superior analgesic efficacy of DDS-06C versus placebo was confirmed for the primary efficacyend point of SPID50, using both BOCF/LOCF and LOCFas the method of imputation. Although SPID has beenused as an end point in various pain studies, there is onlyone published back pain study which used SPID, and it wascalculated after 3 and 6 hours of treatment21. Therefore,this study is the first to use SPID as an end point overseveral days of treatment for back pain. DDS-06C alsodemonstrated a statistically significant difference from pla-cebo on the following secondary end points: TOTPAR50,SPID4, patient’s global impression of study medication,and time to onset of meaningful pain relief.
In terms of the clinical significance of these results,Farrar et al. have suggested that a 33% reduction frombaseline in percent SPID (SPID/maximum possibleSPID) or percent TOTPAR (TOTPAR/maximum pos-sible TOTPAR) represents a clinically relevantresponse22. This classification was based on clinicaldata using LOCF as the method of imputation23.Examining the SPID results from the current study,39 patients (27.7%) in the DDS-06C group and 27patients (19.9%) in the placebo group experienced aclinically significant response when using BOCF/LOCFas the method of imputation (7.8% absolute differencebetween groups) (Table 5). The difference betweengroups is even more apparent when using LOCF (44patients [31.2%] in the DDS-06C group vs. 27 patients[19.9%] in the placebo group; absolute difference:11.3%). Examining TOTPAR, 78 patients (55.3%) inthe DDS-06C group and 60 patients (44.1%) in theplacebo group experienced a clinically significantresponse using BOCF/LOCF (11.2% absolute differencebetween groups) (Table 5). The difference between
Table 5. Percentage of patients with a clinically significant SPID50 orTOTPAR50 score – ITT population.
DDS-06C(n¼ 141)
Placebo(n¼ 136)
Absolute differencebetween groups
Number of patients with SPID50 score of �10 or less, n (%)BOCF/LOCF 39 (27.7%) 27 (19.9%) 7.8%LOCF 44 (31.2%) 27 (19.9%) 11.3%
Number of patients with TOTPAR50 score of 13 or more, n (%)BOCF/LOCF 78 (55.3%) 60 (44.1%) 11.2%LOCF 81 (57.4%) 61 (44.9%) 12.5%
Table 4. Incidence of treatment emergent adverse events reported by45%of patients treated with DDS-06C [n (%)].
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groups is also more apparent when using LOCF (81patients [57.4%] in the DDS-06C group vs. 61 patients[44.9%] in the placebo group; absolute difference:12.5%).
The fact that more patients experienced clinically sig-nificant pain relief than a decrease in pain intensity isexpected, since pain relief scales are perceived as moresensitive than pain intensity scales24. This may be due tothe fact that all patients begin with the same baseline painrelief (that of no relief), while patients start with differentlevels of pain intensity. The relatively high responseobserved in the placebo group for both SPID andTOTPAR is consistent with the well-characterized ‘pla-cebo response’ observed in other pain studies25–27. It is wellrecognized that there are neuro-psychological componentsto the placebo response25–27, and these would appear to beprominent in this study.
This study clearly demonstrated the safety and tol-erability of DDS-06C. The majority of AEs reportedby patients treated with DDS-06C were mild-to-mod-erate in intensity, and there was a low rate of discon-tinuation due to AEs in DDS-06C-treated patients inboth the double-blind and open-label phases (12% and3%, respectively). The most commonly reported AEs(reported by 45% of patients receiving DDS-06C)were nausea, dizziness, vomiting, and somnolenceduring the double-blind phase, and nausea and dizzi-ness during the open-label phase. Based on the well-known safety profile of the two active components(both separately and in combination), these AEswere expected, and are typical of other tramadol/para-cetamol formulations14–16. Furthermore, treatment withDDS-06C did not result in any SAEs that were con-sidered related to treatment.
Conclusion
DDS-06C is a twice-a-day tramadol/paracetamol formu-lation which has been previously demonstrated to haveequivalent systemic exposure to IR tramadol/paraceta-mol tablets administered every 6 h18. In this study withpatients with acute low back pain, a model which isrepresentative of the patient population that currentlyuses IR tramadol/paracetamol, the superior analgesicefficacy of DDS-06C versus placebo was confirmedfor the primary end point (SPID50). Results from sec-ondary end points provided additional confirmationregarding the efficacy of DDS-06C. Furthermore,DDS-06C was well-tolerated; the most common AEswere typical of other tramadol/paracetamol formula-tions, and tramadol and paracetamol used separately.Therefore, this twice-daily formulation of tramadol/paracetamol offers a convenient therapeutic optionfor patients with moderate-to-severe pain.
TransparencyDeclaration of fundingThis study was supported by Labopharm Inc.
Declaration of financial/other relationshipsB.L. was an investigator for this study. R.J.L. is an employee ofLabopharm Inc. K.D.R. was a consultant for Labopharm Inc.S.B. is a former employee of Labopharm Inc. and consultant onthis study. A.R. and S.R. were employees at Labopharm Inc. atthe time that this study was conducted.
CMRO peer reviewers may have received honoraria for theirreview work. The peer reviewers on this manuscript have dis-closed that they have no relevant financial relationships.
AcknowledgmentsThe authors wish to convey our deepest thanks to the patientswho participated in this clinical study. We also thank INCResearch, Inc. for their implementation of the study protocoland Peter Treasure, PhD, CStat (Peter Treasure StatisticalServices Ltd, King’s Lynn, UK) for his statistical expertise.Thanks also to Nancy Vermette for her assistance in creatingtables and figures for this publication.
We are grateful for the hard work and dedication of the fol-lowing principal investigators and their staff: Pierre Arsenault,MD; Armen Arslanian, MD; Richard L. Beasley, MD; StephanieBerg, MD; Guy Chouinard, MD; Shane Christensen, MD; LisaCohen, DO; David Damian, MD; Pierre Dauth, MD; WaymonDrummond, MD; Didier Fay, MD; Benoit Gervais, MD; AnilGupta, MD; Sam Henein, MD; Dan C. Henry, MD; LouiseLaberge, MD; Ken Lai, MD; Ben Lasko, MD; Vaughn H.Mancha, MD; Pierre Martin, MD; Giuseppe Mazza, MD; JamesMiner, MD; Dennis O’Keefe, MD; Michael O’Mahony, MD;Armando Perez, MD; Alan Reichman, MD; Paul Rheault, MD;John Sutherland, MD; Guy Tellier, MD; Anthony Wade,MD; Daniel Whittington, MD.
This article was previously presented as a poster at the 13thWorld Congress on Pain (Montreal, Canada; August 29 –September 2, 2010).
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