Double-blind, randomized, double-dummy clinical trial comparing the efficacy of ketorolac trometamol and naproxen for acute low back pain

The study postulates that Ketorolac trometamol is not inferior to Naproxen in efficacy, provides faster pain relief, and is a safe acute treatment option for acute pain relief.

Low back pain (LBP) significantly affects the quality of life of patients and is the major reason for workplace absenteeism. Mechanical LBP can be secondary to lumbar strain or sprain (70% of all reported cases), age-related degenerative changes (10%), herniated disks (4%), osteoporotic fractures (4%), or spinal stenosis (3%), with all other causes accounting for <1% of cases. The best approach to treat LBP seems to be a combination of pharmacological and non-pharmacological strategies. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common type of medication used in the treatment of acute pain, exerting their effect by interfering in the inflammatory response. They inhibit the cyclooxygenase (COX) enzyme, reducing the synthesis of prostaglandins. The traditional NSAIDs inhibit both COX-1 and COX-2, and inhibiting COX-1 decreases platelet aggregation, irritates the gastric mucosa, and alters renal flow. Ketorolac trometamol (KT) is an NSAID, which inhibits COX that results in reduced synthesis of prostaglandins, thromboxanes, and prostacyclin as well as diminished platelet aggregation. Compared with aspirin, which produces prolonged and irreversible antiplatelet effects that persist beyond drug administration, the antiplatelet activity of KT is not apparent after elimination from the plasma and is reversible. In addition, the platelet effects of KT are not related to dose. The effectiveness, safety, and analgesic efficacy and potency of KT are considered higher than those of ketoprofen in postoperative ear–nose–throat and dental surgeries. The study aimed to test the hypothesis that KT is not inferior to naproxen (NA) in its analgesic efficacy and incidence of adverse effects for the treatment of moderate to-severe acute LBP.

Rationale behind research:

Previous studies have reported the efficacy of UC-II in the treatment of arthritis. The current study was conducted so as to further explore the efficacy of UC-II in treating knee OA and also comparing it with placebo and glucosamine hydrochloride plus chondroitin sulfate (GC)

Objective:

To compare the efficacy of KT and naproxen (NA) in the treatment of acute low back pain (LBP) of moderate-to-severe intensity.

Study outcomes

Primary endpoint: The primary end point was the rate of pain relief (RPR) calculated by the following formula:

RPR =VAS(vi)-VAS(vf)/ VAS (vf)

where VAS(vi) is the VAS on V0 (before taking the drug) and VAS(vf) is the VAS on V0–60 or V1 or V2 .

Secondary endpoint: The secondary end point was RPR1 and was calculated for each of the three drug administrations on each day as follows:

RPR1=VAS(vi)-VAS(vf) / VAS(vf)

where VAS(vi) is the VAS 1 hour before the administration of medication and VAS(vf) is the VAS 1 hour after the administration of medication. Participants were instructed to record adverse events in a diary. The investigators checked the diary on every visit. Adverse effects occurring up to 10 days after V0 (V3 ) were also included in the study.

Time Points: On the first treatment day (Vo), at 2 days (V1 ) and 4 days (V2) and at Ten days (V3)

Outcomes

• Baseline: Both sample groups were clinically homogeneous, and there was no significant difference between them at the baseline
• Primary Outcomes: Comparison of the RPR between V0 and V0–60 showed a 5.6% gain in the RPR for KT compared with NA, which was below the 10% limit and within the noninferiority margin. Comparing the RPR for V1 and V0 , and for V2 and V0 , the upper limit of the 95% CI was >10%.
• Secondary Outcomes: The secondary end point showed that KT was not inferior to NA on day 1 for the first and third administrations of the drug, on day 2 for the second and third administrations, on days 3 and 4 for the first three administrations, and on day 5 for the first and third administrations. A post hoc analysis was prformed using Likert scale scores of the investigators’ global assessment of efficacy on reducing the participants’ pain as the end point. On V1, participants in the KT group had 193.1% higher odds of pain reduction compared with those in the NA group, controlling for age. However, this was not observed on V2, at which no statistically significant difference in pain improvement was detected between the two treatment groups. However, the percentage of participants who reported an improvement in pain relief at V0–60 was higher in the KT group (24.2%) than in the NA group (6.5%; P=0.049). The percentage of participants rated as excellent, very good, or good by the investigator for the KT treatment group (66.7%) was much higher than that for the NA group (40.0%), with 95% CIs for the differences of −0.493 and −0.041. These results indicated that, compared with the NA treatment, the KT treatment had a margin of superiority equal to 4.1%

Adverse Events: There were 35 adverse events in the study population treated with NA and 42 in the population treated with KT. The main adverse effects were diarrhea, stomach pain, drowsiness, nausea, and vomiting. The frequency of occurrence of each event between the two treatments was not statistically significant.

Figure 1: RPR as assessed using VAS scores

This study showed that the efficacy of KT was not inferior to that of NA in the treatment of acute LBP of moderate-to-severe intensity, with no significant differences in the occurrence of adverse effects between the two treatment groups. However, participants who received KT exhibited a higher percentage of response after the initial administration and had higher odds of responding according to the investigator’s assessment at the first visit, suggesting a faster pain relief in the KT group. The rate of pain relief should always be considered when choosing an analgesic in order to improve the quality of life for patients.

Only two studies have evaluated KT for the treatment of acute LBP, and both studies used opioids as comparators. In both studies, KT had comparable efficacy and fewer side effects. The current study is the first to compare KT to another NSAID in the management of acute LBP. The results of our study comparing KT with the gold standard NSAID NA indicated that KT is a valid option for the treatment of LBP.