Abstract
Study Design
A Randomized, Double-Blind, Controlled Trial.
Objective
Postoperative residual leg numbness is a common complication following decompressive and fusion lumbar spine surgery. Prostaglandin E1 derivatives, such as limaprost, have demonstrated efficacy in reducing leg numbness in non-surgical populations. However, evidence regarding the efficacy of limaprost in post-surgical patients remains limited. This randomized controlled trial aimed to compare patient-reported outcomes between postoperative limaprost and placebo treatment.
Methods
Sixty patients diagnosed with degenerative lumbar spine disease and undergoing one or two levels of decompressive and fusion lumbar spine surgery were randomized to receive either postoperative limaprost or placebo for 6 months. Primary outcome evaluation was leg numbness severity, as assessed using the Visual Analog Scale (VAS). Secondary outcomes included tingling sensation, back pain, leg pain, the Oswestry Disability Index (ODI), and the EuroQol-5D (EQ-5D).
Results
Baseline demographic characteristics and patient-reported outcomes were comparable between the two groups. Both groups exhibited significant reductions in leg numbness at all postoperative time points (P < 0.001). However, no significant difference in leg numbness scores was observed between limaprost and placebo groups (P = 0.5). Notably, patients in limaprost group exhibited significantly greater reductions in back pain compared to the placebo group over the entire follow-up period (P < 0.001). No clinically significant differences were observed between groups for other patient-reported outcomes.
Conclusion
Postoperative limaprost did not result in a significant reduction in leg numbness compared to placebo. Nevertheless, limaprost may offer potential benefits in alleviating back pain following decompressive and fusion lumbar spine surgery.
Introduction
Degenerative lumbar spine disease (DLSD) is a prevalent condition affecting approximately 3.63% of the global population. 1 It can manifest as a range of symptoms, including back and leg pain, weakness, and numbness, which can significantly diminish quality of life. Treatment options for DLSD encompass both medical and surgical interventions. Medical management often involves the use of non-steroidal anti-inflammatory drugs (NSAIDs), pregabalin, or prostaglandin E1 derivatives such as limaprost. Previous studies have demonstrated the efficacy of these medications in alleviating back and leg pain, as well as improving numbness and overall quality of life.2–5
For patients who do not respond adequately to conservative treatment or experience severe symptoms, surgical decompression and/or fusion may be considered. The primary objective of this procedure is to relieve neural compression and thereby improve pain and numbness. 6 A notable concern following decompressive and fusion spinal surgery is the persistence of postoperative leg numbness. While initial improvement may occur, subsequent changes are often minimal, contrasting with the significant pain reduction observed at each assessment.7–10 Residual leg numbness can increase the risk of falls, chronic wound development, and further deterioration of quality of life.11,12
Prostaglandin E1 derivatives, such as limaprost, have been shown to effectively reduce leg numbness in non-surgical patients.2,4 The mechanism of action of limaprost involves vasodilation, inhibition of platelet aggregation,13–16 and modulation of neurotrophic factors, including the inhibition of nerve growth factor (NGF) and the promotion of vascular endothelial growth factor (VEGF). 17 However, the efficacy of postoperative limaprost in improving leg numbness outcomes following spinal decompressive and fusion surgery remains unexplored. This study aims to compare patient-reported outcomes after decompressive and fusion procedure, specifically oblique lumbar interbody fusion (OLIF), utilizing its indirect decompressive properties and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF), utilizing its direct decompressive properties in patients treated with limaprost vs placebo. 18
Material and Methods
Study Design and Patient Population
This randomized, single-center, double-blind, controlled trial was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University IRB No.018/61 (COA No.0428/2023). All participants provided written informed consent prior to enrollment. The study was conducted at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, from April 2020 to December 2022. It aimed to compare patient-reported outcomes between postoperative administration of prostaglandin E1 derivative (Limaprost) and placebo in patients with degenerative lumbar spine disease.
Patients were eligible for inclusion in the study if they met the following criteria: a diagnosis of degenerative lumbar spine disease, undergoing one or two levels of decompressive and fusion lumbar spine surgery, exhibiting preoperative leg numbness confirmed by Semmes-Weinstein monofilament testing (a quantitative sensory test that assesses tactile perception by applying calibrated filaments to the skin), and being over 18 years of age. Patients were excluded if they had lumbar spine disease from causes other than degeneration, a history of previous lumbar spine surgery, diabetes mellitus with polyneuropathy or peripheral vascular disease, were pregnant or breastfeeding, or were unable to follow up regularly. Eligible patients were then randomly assigned to either the Limaprost or placebo group.
Intervention
All participants underwent one or two levels of decompressive and fusion lumbar spine surgery, specifically oblique lumbar interbody fusion (OLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF), performed by an experienced spine surgeon (WL) at King Chulalongkorn Memorial Hospital. Participants were randomly assigned to receive either 15 μg of limaprost (Opalmon®) three times daily or a placebo.
Randomization was performed using a blocked design. The allocation sequence was concealed until after participant enrollment. This was a double-blind study. The placebo pills, composed of sterile cellulose powder, were designed to match the size and shape of the Limaprost pills.
In addition to the experimental treatment, all participants received standard postoperative pain management medications which included Celecoxib 200 mg orally twice daily, Pregabalin 25 mg orally after meals in the morning and 75 mg orally before bedtime, and Paracetamol 500 mg orally every 6 hours. Intravenous Morphine was prescribed only while admitted as needed but Oral morphine was not prescribed. The duration of treatment for both groups was 6 months.
Outcome Assessment and Evaluation
Baseline patient characteristics including age, sex, body weight, height, body mass index (BMI), comorbidities, surgical procedure, and surgical level were collected. The primary outcome was the Visual Analog Scale (VAS) score for leg numbness. Secondary outcomes included VAS scores for leg tingling sensation, leg pain, and back pain, the Oswestry Disability Index (ODI), and the EuroQol-5D-5L (EQ-5D-5L). VAS scores were rated on a 10-point scale, where 0 represented no symptoms and 10 represented the worst possible symptoms. ODI scores were rated on a 0-100 scale. EQ-5D-5L scores were rated on a 1-5 scale for each dimension and converted to a utility score adjusted for the Thai population. All outcome measures were assessed at five time points: baseline, immediately postoperatively, and at 1, 3, and 6 months postoperatively. Adverse events were monitored and recorded at each follow-up visit.
Statistical Analysis
The sample size was determined based on the following assumptions: a minimum clinically important difference of 2 points in VAS leg numbness scores, a common standard deviation of 2.5, 8 and an assumed within-subject correlation of 0.7. Under these assumptions, a total of 25 participants per group would yield 90% power to detect this difference at a two-sided significance level of 5%. To account for a potential 10% loss to follow-up, the sample size was increased to 60 participants per group.
Statistical analyses were performed using Stata 17 (Statacorp LLC, College Station, Texas, USA). Baseline participant characteristics are reported as mean (standard deviation) for continuous variables and frequency (percentage) for categorical variables.
To assess changes in primary and secondary outcomes, a mixed-effects model with a random intercept and random slope was employed. This model adjusted for baseline scores and included an interaction term for treatment and time. Predicted mean scores and differences in scores between the limaprost and placebo groups were derived from this model.
Results
A total of 66 participants were screened for eligibility, of whom 6 were excluded. Sixty participants were enrolled and randomized to either the limaprost or placebo group (30 participants per group). Data from all 60 participants were collected and analyzed (Figure 1). Flow diagram of participants throughout the study.
Participant Characteristics at Baseline. Data are Presented as Mean (SD) and Frequency (%).
Primary Outcome
At baseline, the mean Visual Analog Scale (VAS) leg numbness scores were 5.57 (95% CI 5.25-5.89) in the placebo group and 5.70 (95% CI 5.38-6.02) in the limaprost group. Both groups exhibited a significant decrease in VAS scores over time, with the most substantial reduction observed between the preoperative and immediate postoperative periods (Figure 2A). At the 6-month follow-up, the predicted mean VAS leg numbness scores were 1.90 (95% CI 1.13-2.67) in the placebo group and 1.56 (95% CI 0.79-2.34) in the limaprost group. The mean difference in VAS leg numbness scores between the limaprost and placebo groups over the entire follow-up period was −0.16 (95% CI -0.71 to 0.38; P = 0.59). Predicted mean of patient-reported outcome scores at each timepoint.
Secondary Outcomes
At baseline, the mean VAS leg tingling sensation scores were 1.72 (95% CI 1.50-1.94) in the placebo group and 1.40 (95% CI 1.18-1.63) in the limaprost group. The most significant change in scores occurred between baseline and the immediate postoperative period (Figure 2B). Over the entire follow-up period, the mean difference in scores between the limaprost and placebo groups was negligible (−0.03, 95% CI −0.18 to 0.13; P = 0.72).
The mean VAS back pain scores at baseline were 5.13 (95% CI 4.65-5.61) in the placebo group and 5.57 (95% CI 5.09-6.05) in the limaprost group. Both groups exhibited a decrease in VAS back pain scores from baseline, but the reduction was more pronounced in the limaprost group at all subsequent time points, with the maximum difference observed at 3 months postoperatively (mean scores of 3.36 [95% CI 2.61-4.11] vs 1.44 [95% CI 0.69-2.19], respectively; Figure 2C). Over the entire follow-up period, VAS back pain scores were significantly lower in the limaprost group compared to the placebo group (mean difference = −1.10, 95% CI −1.74 to −0.45; P = 0.001).
The mean VAS leg pain scores at baseline were 6.18 (95% CI 5.81-6.55) in the placebo group and 5.99 (95% CI 5.62-6.36) in the limaprost group. The most significant change in scores occurred between baseline and the immediate postoperative visit (Figure 2D). Over the entire follow-up period, the mean difference in VAS leg pain scores between the limaprost and placebo groups was negligible (0.22, 95% CI −0.43 to 0.86; P = 0.51).
The mean ODI scores at baseline were 47.79 (95% CI 45.89-49.68) in the placebo group and 47.57 (95% CI 45.67-49.47) in the limaprost group (Figure 2E). Over the entire follow-up period, the mean difference in ODI scores between the limaprost and placebo groups was negligible (−1.12, 95% CI −4.26 to 2.01; P = 0.48).
The mean EQ-5D-5L scores at baseline were 49.67 (95% CI 46.92-52.41) in both the placebo and limaprost groups. The most significant change in scores occurred between baseline and the 1-month follow-up visit (Figure 2F). Over the entire follow-up period, the mean difference in EQ-5D-5L scores between the limaprost and placebo groups was negligible (−0.19, 95% CI −3.03 to 2.65; P = 0.89).
Discussion
Our study found no statistically significant difference in the improvement of VAS leg numbness scores between the randomized groups over the entire follow-up period. Similarly, secondary outcomes such as VAS tingling sensation, VAS leg pain, ODI, and EQ-5D-5L did not show significant differences between groups. However, the limaprost group exhibited a statistically significant greater improvement in VAS back pain scores compared to the placebo group both overall and at each postoperative visit.
While previous studies have demonstrated the efficacy of limaprost in improving leg numbness in non-surgical patients due to its potent vasodilator and platelet aggregation inhibition effects, which can increase blood flow to peripheral arteries at compressed neural elements,13,19 ours is the first to assess its efficacy post-decompressive spinal surgery. Our findings suggest that postoperative limaprost does not significantly improve VAS leg numbness or tingling sensation compared to placebo. This lack of improvement may be attributed to two factors: 1. Decompression Effect: Decompressive surgery itself may alleviate neural compression, potentially reducing the additional benefit of vasodilation from limaprost. 2. Severity of Compression: The extent and duration of nerve root compression may influence the responsiveness to vasodilators like limaprost, as suggested by previous research.
13
Consistent with the findings for leg numbness and tingling sensation, no significant difference in leg pain was observed between the groups. This is likely due to the primary role of surgical decompression in alleviating radicular pain caused by nerve root compression.
Interestingly, the limaprost group exhibited significant reductions in VAS back pain compared to placebo. This finding aligns with previous research suggesting that limaprost may have a role in reducing low back pain, potentially through mechanisms involving inflammatory mediators or extracellular signal-regulated protein kinase inhibition.20,21
While both groups showed significant improvements in ODI and EQ-5D-5L scores, there was no significant difference between the groups. This indicates that surgical intervention, regardless of additional drug therapy, led to similar improvements in disability and quality of life.
Our study has several limitations. First, the lack of a true placebo group, with all participants receiving standard postoperative medications, may have confounded the results, particularly for numbness outcomes. Due to ethical considerations, withholding all pain medication was not a feasible option. We aimed to balance scientific rigor with patient well-being within these constraints. Second, the relatively small sample size, powered primarily for leg numbness, may have limited our ability to detect differences in other outcomes. We had performed a subgroup analysis for each procedure (OLIF and MIS-TLIF). However, due to the limited sample size within each subgroup, it was not powered to examine the differences between each subgroup. Further study with larger sample size to explore these is required. Third, the 6-month follow-up period may be insufficient to assess long-term differences between groups. Additionally, as the primary outcome focused on numbness, morphine consumption data were not collected. Finally, our findings may not be generalizable to patients with conditions other than degenerative spine disease.
Conclusion
Our findings indicate that postoperative limaprost did not significantly improve leg numbness or other patient-reported outcomes, such as leg pain, disability, and quality of life, compared to placebo. However, a significant reduction in back pain was observed in the limaprost group compared to the placebo group. These results suggest that limaprost may be a valuable adjunct therapy for reducing back pain following decompressive and fusion lumbar spine surgery.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research received funding from Ratchadapiseksompotch fund, graduate affairs, faculty of medicine, Chulalongkorn university (Grant No. GA 64/06).
