A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement
- A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement
- Acute pain; Pain intensity; Pain relief; Post-operative pain
- Issue Date
- INFORMA HEALTHCARE
- CURRENT MEDICAL RESEARCH AND OPINION, v. 31, NO 1, Page. 75-84
To evaluate the relative efficacy and safety of extended-release tramadol HCl 75 mg/acetaminophen 650 mg
(TA-ER) and immediate-release tramadol HCl 37.5 mg/acetaminophen 325 mg (TA-IR) for the treatment of
moderate to severe acute pain following total knee replacement.
This phase III, double-blind, placebo-controlled, parallel-group study randomized 320 patients with
moderate to severe pain ( 4 intensity on an 11 point numeric rating scale) following total knee
replacement arthroplasty to receive oral TA-ER (every 12 hours) or TA-IR (every 6 hours) over a period of
48 hours. In the primary analysis, TA-ER was evaluated for efficacy non-inferior to that of TA-IR based on the
sum of pain intensity difference (SPID) at 48 hours after the first dose of study drug (SPID48). Secondary
endpoints included SPID at additional time points, total pain relief at all on-therapy time points (TOTPAR),
sum of SPID and TOTPAR at all on-therapy time points (SPIDþTOTPAR), use of rescue medication,
subjective pain assessment (PGIC, Patient Global Impression of Change), and adverse events (AEs).
Analysis of the primary efficacy endpoint (SPID48) could not establish the non-inferiority of TA-ER to TA-IR.
However, a post hoc analysis with a re-defined non-inferiority margin did demonstrate the non-inferiority of
TA-ER to TA-IR. No statistically significant difference in SPID at 6, 12, or 24 hours was observed between the
TA-ER and TA-IR groups. Similarly, analysis of TOTPAR showed that there were no significant differences
between groups at any on-therapy time point, and SPIDþTOTPAR at 6 and 48 hours were similar among
groups. There was no difference in the mean frequency or dosage of rescue medication required by both
groups, and the majority of patients in both the TA-ER and TA-IR groups rated their pain improvement as
‘much’ or ‘somewhat better’. The overall incidence of 1 AEs was similar among the TA-ER (88.8%) and
TA-IR (89.5%) groups. The most commonly reported AEs by patients treated with TA-ER and TA-IR included
nausea (49.7% vs 44.4%), vomiting (28.0% vs 24.2%), and decreased hemoglobin (23.6% vs 26.1%).
This study is limited by the lack of placebo control, and the invalidity of the initial non-inferiority margin.
This study demonstrated that the analgesic effect of TA-ER is non-inferior to TA-IR, and supports TA-ER as
an effective and safe treatment for moderate to severe acute pain post total knee replacement.
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