Efficacy and Safety Assessment of a Novel Once-Daily Tablet Formulation of Tramadol

Gérald Mongin; Vladimir Yakusevich; Adorjan Köpe; Nadezhda Shostak; Eduard Pikhlak; Laszlo Popdán; Judit Simon; Catherine Navarro; Louise Fortier; Sybil Robertson; Sylvie Bouchard


Clin Drug Invest. 2004;24(9) 

In This Article


A total of 431 patients from 21 centres in four European countries were randomised. 430 patients took at least one dose of randomised study medication (safety population) and had at least one post-baseline assessment (ITT population). Seventy patients (16%) in the ITT population discontinued the study prior to week 12 (Figure 2). Of these, a total of 41 patients discontinued due to adverse events (titration phase 21; maintenance phase 20). The reasons for premature discontinuation in the ITT population are listed in Figure 2.

Patient populations and dispositions. Safety population: received at least one dose of study medication; intention-to-treat population: received at least one dose of medication and had at least one post-baseline assessment; per-protocol (PP) population: completed the study or received study medication for at least 2 weeks during the maintenance phase, had efficacy assessments within 2 days of the last dose and had no major protocol violations. BID = twice daily; OAD = once daily. 1, Patients who discontinued early were still considered part of the PP population if they met all of the criteria. 2, 67-year-old female, ischaemic stroke, considered 'not related' to study medication. 3, Patients who were excluded may have been excluded for more than one reason and may therefore be recorded more than once. 4, Final visit: week 12 or discontinuation.

Fifty-four tramadol OAD patients and 62 tramadol BID patients were excluded from the ITT population. The PP population consisted of the 314 patients who remained after the exclusion of major protocol violators from the ITT population (Figure 2). The most frequent reasons for exclusion were: no WOMAC pain score at baseline or final visit, whether that was week 12 or an early discontinuation (41 in each treatment group); intake of prohibited prior or concomitant medications (tramadol OAD 7, tramadol BID 15); major violation of eligibility criteria (tramadol OAD 7, tramadol BID 5); incorrect intake of study medication (tramadol OAD 2, tramadol BID 5); and treatment duration out of the allowed window (12 weeks ± 10 days of the scheduled treatment duration) [tramadol OAD 4, tramadol BID 5]. Patients who were excluded may have been excluded for more than one reason and therefore could be listed more than once. The two treatment groups in the PP population were similar with no statistically significant differences regarding diagnosis, sex distribution, age, mean BMI and mean pain at baseline (WOMAC pain subscale score) [ Table I ].

Ninety-nine percent of the patients presented at study entry with concurrent illnesses. Other than musculoskeletal diseases, vascular (66%), cardiac (25%), GI (24%) and ocular (21%) disorders were reported most often. The frequency of each concurrent illness was similar in both treatment groups.

Use of analgesics (other than the study medication), sedative hypnotics, anaesthetics and muscle relaxants were not permitted during the trial. These medications had to be washed out for five half-lives prior to randomisation.

Ninety percent of the patients in the OAD group and 92% of those in the BID group were treated with one or more medications prior to the start of the study. The most commonly reported prior medications were taken for pain or cardiac disorders. The two treatment groups were similar with regard to the use of analgesics prior to the start of the study (salicylate derivatives and related substances: tramadol OAD 37%, tramadol BID 38%; opioids: tramadol OAD 13%, tramadol BID 11%).

Patients were permitted to continue treatment with all other medications with the exception of monoamine oxidase inhibitors, tricyclic antidepressants, antipsychotics, selective serotonin reuptake inhibitors or other drugs that reduce seizure threshold. The two groups were similar with regard to the use of ACE inhibitors (tramadol OAD 30%, tramadol BID 33%) and organic nitrates (tramadol OAD 14%, tramadol BID 12%). However, more patients took dihydropyridine derivatives in the tramadol BID group (tramadol OAD 7%, tramadol BID 13%), whereas more patients took ß-blocking agents (tramadol OAD 19%, tramadol BID 12%) in the tramadol OAD group.

Treatment for adverse events was allowed, as necessary, in order to permit patients to continue in the study. The adverse events most often requiring treatment with concomitant medications were constipation (18% of patients) and nausea (6% of patients).

The median optimal daily dose received was 200mg in both treatment groups. Only 34% of the tramadol OAD patients and 37% of the tramadol BID patients required doses of tramadol higher than 200mg ( Table II ). Compliance was within the range defined as 'acceptable' (80-120%) for all patients but one. The mean exposure to study medication was similar between the two groups (82 days; range 3-121 days), with the majority of patients (79%) being dosed for 84 days or more.

Both the primary endpoint (percentage change in WOMAC pain subscale) and all secondary efficacy endpoints were successfully achieved (VAS pain ratings over the 24 hours prior to visits; Likert-scale rating of pain at the end of the dosing interval; remaining WOMAC scores: stiffness, physical function and global; and patient and investigator overall ratings of pain).

An immediate and significant improvement in the mean WOMAC pain score was seen during the titration phase for both treatments (tramadol OAD 43%, tramadol BID 40%). Furthermore, improvement continued throughout the maintenance phase when patients were receiving their fixed optimum dose (tramadol OAD 58%, tramadol BID 59%) [Figure 3].

Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale score in the per-protocol population (composite of five visual analogue scale ratings [100mm each]: min. = 0mm; max. = 500mm). Improvement from baseline to last visit: tramadol OAD 58.3% (n = 161); tramadol BID 58.7% (n = 153). BID = twice daily; last visit = week 12 or premature discontinuation; OAD = once daily.

The percentage improvement in WOMAC pain score from baseline to week 12 was similar in both groups. Non-inferiority of tramadol OAD versus tramadol BID with respect to the WOMAC pain subscale score was demonstrated. More precisely, the 95% CI for the difference in improvement between treatments, estimated as (-7.67, 3.82), demonstrated the non-inferiority of tramadol OAD compared with tramadol BID since its lower bound, corresponding to the lower limit of the 97.5% CI, was greater than -15% (Figure 3, Table III ).

The comparison of VAS pain ratings over a 24-hour period showed similar significant improvement throughout the study ( Table IV ).

Both tramadol OAD taken once every 24 hours and tramadol BID taken every 12 hours demonstrated similar efficacy at the end of the respective dosing intervals. In fact, in daily ratings, 73% of all patients indicated that their pain was mild/barely noticeable or absent at the end of the dosing interval (tramadol OAD 72.3%, tramadol BID 71.3%) [Figure 4].

Daily rating of pain at the end of the dosing interval in the per-protocol population (24-hour efficacy) as rated on a 4-point Likert scale (none, mild/barely noticeable, moderate or severe) at week 12. BID = twice daily; OAD = once daily.

Each WOMAC secondary efficacy endpoint showed an improvement from baseline similar to that of the WOMAC pain subscale in both groups with no significant difference between them (stiffness: tramadol OAD 49.1%, tramadol BID 49.3%; physical function: tramadol OAD 51.7%, tramadol BID 50.1% and global: tramadol OAD 53.6%, tramadol BID 51.9%). The trend for a marked decrease in pain during the titration phase with a continued decrease throughout the maintenance phase was sustained for all three of these secondary efficacy measures (WOMAC stiffness, physical function and global scores).

The majority of patients in both groups (84%) gave an overall rating of the study medication as effective or very effective (tramadol OAD 82.6%, tramadol BID 83.0%). No statistically significant differences were noted between the treatment groups (Figure 5).

Patient overall rating of efficacy at the last visit in the per-protocol population (week 12 or premature discontinuation). BID = twice daily; OAD = once daily.

The majority of investigators (86%) also rated the overall efficacy of analgesia in both groups as very effective or effective (Figure 6).

Physician overall rating of efficacy at the last visit in the per-protocol population (week 12 or premature discontinuation). BID = twice daily; OAD = once daily.

Safety data are reported for the safety population (n = 215 in each treatment group). A similar percentage of patients in each group reported at least one adverse event (tramadol OAD 81%, tramadol BID 79%). The most common adverse events were GI and central nervous system (CNS) related. A greater percentage of tramadol BID patients reported dizziness/vertigo (tramadol OAD 26%, tramadol BID 37%), vomiting (tramadol OAD 8%, tramadol BID 14%) and headache (tramadol OAD 13%, tramadol BID 18%), while more tramadol OAD patients reported somnolence (tramadol OAD 30%, tramadol BID 21%) [ Table V , Figure 7]. Furthermore, the episodes of vomiting or dizziness/vertigo reported by the patients in the tramadol BID group were more severe than those reported in the tramadol OAD group (vomiting: tramadol OAD 6% severe vs tramadol BID 23% severe; dizziness/vertigo: tramadol OAD 2% severe vs tramadol BID 13% severe). Similar occurrences of nausea, constipation and weakness were noted in each of the treatment groups ( Table V , Figure 7). Most of these adverse events were rated as mild or moderate (tramadol OAD 67%, tramadol BID 64%).

Adverse events experienced by at least 10% of the patients in at least one of the treatment groups in the safety population. BID = twice daily; OAD = once daily.

The mean time of onset of the most common adverse events and their median duration was similar in the two groups (median onset between 3 and 13 days, and duration between 2 and 18 days depending upon the adverse event) [ Table VI ].

The incidence of headache, vomiting and weakness stabilised after 7 days, whereas dizziness/vertigo, nausea and somnolence required 30 days to stabilise. Reports of constipation continued to increase throughout the study in both groups. A similar number of patients in each group (19 in the tramadol OAD group and 22 in the tramadol BID group) withdrew from treatment because of adverse events.

Eleven serious treatment-emergent adverse events (SAEs) occurred in 11 patients (three in the tramadol OAD group, eight in the tramadol BID group; p = 0.2205) [ Table VII ]. Three of these (cerebrovascular disorder, chest pain and bladder neoplasm) were considered by the investigator to be 'possibly related' to the study medication. All SAEs resolved during the study, except for a cerebral ischaemic stroke that occurred in a 67-year-old woman and resulted in her death. The investigator determined this event to be 'not related' to the study medication ( Table VII ).


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