Introduction
Lumbar spinal stenosis (LSS) is a common degenerative spinal condition that affects up to 39% of the population [1]. LSS is characterized by spinal canal narrowing, thereby reducing the space for the cauda equina nerve roots [2]. Neurologic intermittent claudication (NIC), a hallmark symptom of LSS, causes leg pain or weakness associated with prolonged standing or walking [3], resulting in a significant decline in patients’ quality of life [4]. Conservative treatment, including physical therapy and pharmacological interventions, remains the first-line approach, with over half of the patients exhibiting symptom improvement [5].
In recent years, due to their targeted action on neuropathic pain pathways by binding to the α2δ subunit of the voltage-gated calcium channels, the use of gabapentin (GBA) and pregabalin (PGB) as pharmacologic options for managing LSS symptoms has been investigated [6]. GBA, an analog of γ-aminobutyric acid, improves pain scores and increases walking distance in patients with LSS. Hence, it can have potential benefits in managing LSS symptoms [7]. PGB is a newer generation of gabapentinoid that has enhanced potency and a higher bioavailability and that exhibits linear predictable absorption [8]. Previous studies have shown that PGB is effective in reducing radicular pain and delaying the need for surgery in patients with LSS [9,10].
However, the use of gabapentinoid for treating LSS has remained controversial. GBA and PGB are commonly prescribed for LSS. However, two placebo-controlled studies on patients with LSS did not show significant differences in terms of symptom relief between GBA and PGB compared with a placebo [11,12]. To date, only a few studies have compared the efficacy of GBA and PGB or their benefits over placebo in patients with LSS. Therefore, the current study assessed the efficacy of GBA and PGB for treating LSS compared with a placebo, focusing on their impact on NIC symptoms, walking distance, and health-related quality of life.
Materials and Methods
Ethics statement
This was a prospective, parallel-arm, double-blind, placebo-controlled randomized trial conducted at a single-center tertiary care hospital from February 2018 to October 2023. The Institutional Review Board approved the study protocol (certificate of approval no., 585/2014) prior to patient enrollment. The trial was registered with the Thai Clinical Trial Registry (TCTR20250116002). All participants received a detailed study information and provided a written informed consent before inclusion.
Study population
The participants with clinically suspected LSS visiting the outpatient orthopedic clinic were referred to one of the four senior spine specialists for evaluation. Comprehensive history taking and neurological examination, peripheral vascular assessment, and the ankle-brachial index (ABI) test were performed. Each patient underwent conventional radiography and magnetic resonance imaging (MRI) of the lumbar spine. A senior orthopedist initially reviewed the MRI findings and confirmed them with the attending neuroradiologist’s report. Participants who met all of the following criteria were included: (1) a clinical history of predominant NIC symptoms [3,13], which include pain, fatigue, heaviness and/or numbness in the lower extremities associated with prolonged standing or walking that is relieved by sitting or forward flexing of the spine, with or without low-back pain; (2) persistent NIC symptoms for >3 months prior to inclusion; (3) MRI-confirmed LSS, including central stenosis or lateral recess stenosis, with or without concomitant lumbar spondylosis or low-grade degenerative spondylolisthesis (grade I or II); (4) no previous pharmacologic treatment for LSS symptoms, including nonsteroidal anti-inflammatory drugs, gabapentinoid, and oral prostaglandin E1 analogs within 3 months. The exclusion criteria were as follows: (1) patients with peripheral arterial occlusive diseases, defined as an ABI of <0.9, (2) pregnant or breastfeeding women, (3) those with epilepsy, (4) those with chronic kidney disease with a creatinine clearance of <60 mL/min, (5) those with liver cirrhosis, (6) those with previous spinal surgery or epidural steroid injection, (7) those with cauda equina syndrome or muscle weakness with a motor power grade 3 or less according to the Medical Research Council scale, (8) those with other spinal pathologies, including spondylodiscitis and primary or metastatic spinal tumors, (9) those who cannot complete questionnaires or follow-ups due to cognitive disorders or lack of cooperation, and (10) those with allergy to paracetamol, GBA, and/or PGB.
Randomization and blinding
The participants who met the eligibility criteria were enrolled by an independent clinical trial manager and were randomly assigned to one of three treatment groups (GBA, PGB, or a placebo) in a 1:1:1 ratio. Randomization was conducted using a computer-generated sequence with various block sizes to ensure a balanced group distribution. Allocation concealment was conducted using opaque, sealed envelopes. Each patient was assigned with a code based on the randomization list. The envelopes were opened by the pharmacists, who were not involved in patient care and outcome measurement, before dispensing the assigned treatment. Hence, both participants and outcome assessors remained blinded to the treatment allocation.
Intervention
All participants received the same standard conservative management. The therapy included back exercise education (avoiding excessive lumbar flexion and extension, lifting heavy objects, and strengthening abdominal muscles), physical therapy with pelvic traction, lumbosacral corset support, and pharmacologic treatment with a nonsteroidal anti-inflammatory (NSAID) drug (250 mg of naproxen, taken orally twice daily). Each group received additional treatment drugs according to each medication’s standard effective dose titration. The GBA group received oral GBA 3 times daily, starting at a dose of 300 mg/day for the first week. The dose was titrated to 900 mg/day on day 7 and up to 1,800 mg/day on day 14. The PGB group received oral PGB, starting at a dose of 75 mg/day, and the dose was titrated to 150 mg/day (75 mg twice daily) on day 7, with increments up to 300 mg/day (150 mg twice daily) on day 14. The placebo group received a placebo 3 times daily. The placebo was manufactured by our pharmacology unit according to a standardized protocol to match the GBA tablets in terms of size and weight. After titration to the therapeutic dose within 14 days, treatment with the target dose was continued throughout the remainder of the study period. All participants were informed about the possible common side effects of gabapentinoids, including dizziness, somnolence, drowsiness, headache, nausea and vomiting, and edema. Participants who developed side effects were advised to rest in bed, and their oral fluid intake was increased. If a patient could still not tolerate the side effects, the intervention was discontinued. Then, the patient was withdrawn from the study. In addition, no other pain interventions or medications were allowed during the study.
Data collection and study outcome
All outcome measures were assessed at baseline and monthly until the 4-month follow-up. Two well-trained research assistants who were blinded to the treatment allocation performed data collection. The primary outcome of the study was the Visual Analog Scale (VAS)-assessed NIC pain. The secondary outcomes included the Swiss Spinal Stenosis (SSS) score, Self-Paced Shuttle Walk Test score, time to onset of claudication symptoms, Euro-QoL Group’s 5-Dimension, 5-Level (EQ-5D-5L), and side effects and adverse events (AEs) of the treatment. The open-ended question “Have you experienced any changes after receiving the study drug within the last 4 weeks?” was used to evaluate the possible AE of the treatment during each follow-up.
Visual Analog Scale for Pain
The VAS was used to assess pain intensity for NIC in patients with LSS. The VAS is a 10-cm straight line with two labels: “no pain” and “worst possible pain” at each end [14]. The patients were instructed to draw a vertical mark on the line to indicate the level of pain that best reflected the intensity of their leg pain or NIC symptoms.
Swiss Spinal Stenosis score
The SSS score is a self-administered questionnaire that is used to measure disability in patients with spinal stenosis [15]. It comprises 18 items with the following three domains: symptom severity (seven questions, each scored 1–5), physical functional disability (five questions, each scored 1–4), and patient satisfaction related to spinal stenosis disease (six questions, each scored 1–4). A higher score indicated greater severity and disability [16].
Self-paced walking test
The self-paced walking test (SPWT) measures walking ability by recording the total distance a patient can walk continuously on a level surface at their self-paced pace, stopping either when patients develop LSS systems or after 30 minutes [17]. The test exhibited a strong reliability in patients with LSS [18]. In addition, the time to onset of claudication symptoms was recorded during the SPWT.
EuroQoL 5-Dimension 5-Level
EQ-5D-5L is a patient-reported instrument utilized to evaluate health-related quality of life, and it has been widely used in patients with LSS. It assesses five dimensions: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. The scores range from 0 to 1, with higher scores indicating a better health status [19].
Statistical analysis
All data were examined via a prespecified analysis. The primary analysis followed the modified intention-to-treat analysis, which included all randomized participants with at least one postbaseline assessment. Demographic and baseline data were summarized using descriptive statistics (i.e., mean±standard deviation [SD], median [IQR], and number [%] as appropriate). Data were examined using generalized estimating equations. The correlation structure among the repeated outcomes was assessed using the corrected quasi-likelihood and resulted in an exchangeable correlation structure. For each outcome, the generalized estimating equations model of the outcome after treatment (at 1, 2, 3, and 4 months) was fitted with the independent variables of the outcome at baseline, treatment (placebo, GBA, and PGB), follow-up time (as a factor), treatment-by-time interaction, and duration of symptoms. Bonferroni’s adjustment was applied for between-group and within-group comparisons. A p-value of <0.05 indicated statistically significant differences. All analyses were conducted using the IBM SPSS software ver. 29.0 (IBM Corp., Armonk, NY, USA).
Sample size calculation
The sample size was calculated using a one-way analysis of variance, aiming for a power of 80% and a significance level of 0.05. Based on the study by Yaksi et al. [7], the expected VAS scores were 2.9 in the treatment group and 4.7 in the control group, with an effect size of 0.125 and a pooled SD of 2.4. A minimum of 27 participants per group was required to detect this difference. To allow for a potential 10% drop-out rate, the total sample size was increased to 90 participants.
Results
Of the 113 eligible participants, 23 were excluded. Ninety participants were enrolled and randomly assigned to three groups (Fig. 1). The baseline demographic and clinical characteristics of the participants were comparable (Table 1). Most participants were female, with a mean age±SD of 63.14±9.70 years. The mean symptom duration±SD was 19.38±4.11 months, and most participants exhibited 1–2 levels of stenosis on MRI.
In terms of primary outcome, all participants exhibited a significant improvement in VAS pain at the 4-month follow-up. However, the placebo, GBA, and PGB groups did not significantly differ in terms of VAS pain. All participants exhibited significant improvements in the overall SSS scores and in the symptom severity and satisfaction domains. However, only the GBA group presented with significant improvement in the physical function domain at the 4-month follow-up compared with the 1-month follow-up. There were no significant differences between the groups in terms of overall scores or any domain (Tables 2, 3, Fig. 2).
Supplement 1 and Fig. 3 show the distance and the time to the first onset of symptoms assessed using the SPWT. All participants exhibited significant improvements in both parameters throughout the follow-up. However, the groups did not significantly differ in terms of the distance and the time to the first onset of symptoms (Supplement 2). In addition, all participants had significant improvement in the EQ-5D-5L scores during the follow-up period. The PGB group had a greater improvement in the EQ-5D-5L scores compared with the GBA group at the 1- and 2-month follow-ups, with a mean difference of 0.07 (95% confidence interval [CI], 0.00 to 0.14; p=0.045) and 0.08 (95% CI, 0.03 to 0.13; p=0.001), respectively. However, there were no significant differences in terms of the EQ-5D-5L scores at later the follow-ups. Further, the PGB and GBA groups did not significantly differ from the placebo group in terms of the EQ-5D-5L scores.
AEs were recorded throughout the follow-up period. The GBA and PGB groups had a higher overall frequency of AEs than the placebo group (p=0.001) (Table 4). The most commonly reported AEs were dizziness, followed by sedation, both of which primarily occurred after the initial dose increment. The incidence of dizziness and drowsiness/sedation was significantly higher in the GBA and PGB groups than in the placebo group (p<0.001 and p<0.001, respectively). However, there were no significant differences between the GBA and PGB groups in terms of the frequency of AEs (p=1.000). All AEs were tolerable, and all participants continued the treatment until the study was completed. None of the participants withdrew from the study because of AEs. Two participants in the GBA group and one in the PGB group reported an unsteady gait; however, this symptom resolved during follow-up.
Discussion
To the best of our knowledge, this is the first double-blind randomized control trial (RCT) to compare the efficacy of GBA, PGB, and placebo in patients with LSS. Results showed no significant improvement in VAS pain, walking distance, time to onset of NIC, or EQ-5D-5L scores between these two classes of gabapentinoid and the placebo, which were administered along with physical therapy and NSAIDs. However, both GBA and PGB were associated with a significantly higher incidence of AEs, including dizziness and drowsiness.
Although oral gabapentinoid is widely used for the conservative treatment of LSS, high-quality evidence supporting its efficacy remains limited [20]. Previous literature on GBA and PGB in LSS has contrasting findings. Further, most studies primarily focused on sciatica and radicular pain [21,22], and only a few examined NIC symptoms. Our results are in accordance with existing evidence. Haddadi et al. [12] showed that adjunctive GBA (900 mg/day) was not associated with significant differences in Oswestry Disability Index or satisfaction regarding pain reduction and functional performance compared with placebo after a 3-month period in patients with LSS. Moreover, GBA was significantly less effective than nasal calcitonin in this context. Similarly, Markman et al. [11] conducted a double-blind, active-placebo-controlled crossover RCT. They reported that PGB was not superior to diphenhydramine in reducing time to moderate symptoms, pain intensity, or self-reported functional outcomes, including Oswestry Disability Index and SSS. However, the treatment duration in their study was only 10 days, which may have been insufficient to achieve the maximum therapeutic effect.
In contrast to our findings, Yaksi et al. [7] conducted an unblinded RCT that supported the efficacy of GBA (900 mg/day, titrated weekly by 300 mg to a maximum of 2,400 mg/day). This study showed improvements in walking distance and greater pain reduction at 4 months when GBA was combined with standard conservative treatment compared with standard treatment alone. A possible explanation for the discrepancy in results could be differences in the age of participants. Yaksi et al. [7] predominantly included younger participants, with none of them older than 65 years. In addition, the GBA dose used in their study was relatively higher. Moreover, the placebo effect might occur due to its open-label design. In addition, their study used a composite pain score in both leg pain and low-back pain. Notably, previous studies have found that gabapentinoid was effective against chronic low-back pain, which may not be directly extrapolated or combined with NIC symptoms. Takahashi et al. [10] reported that combination therapy with PGB (with doses titrated to 300 mg/day) and NSAIDs was more effective in reducing leg pain than NSAID monotherapy. In particular, it improves the Roland-Morris Disability Questionnaire scores and lowers the incidence of spinal surgery at the 1-year follow-up. However, this was a retrospective study. Hence, a risk of selection bias might have been introduced. Other published studies have primarily compared PGB with limaprost or its combination [23–25]. To the best of our knowledge, only Markman et al. [11] directly compared PGB with a placebo.
Regarding the common AEs, the GBA and PGB groups had a significantly higher incidence of AEs than the placebo group. This finding is consistent with that of previous studies, which that have reported that the use of GBA is associated with AEs such as dizziness, somnolence, and nausea or vomiting [26]. Moreover, our analysis did not show significant difference in the AE incidence between the PGB and GBA groups, similar to the findings reported in previous studies [27,28]. This finding indicated a comparable safety profile between the two agents. In the placebo group, the overall incidence of AEs was 26.67%, with dizziness and headache being the most frequently reported symptoms. We hypothesized that this could be attributed to the nocebo effect [29], particularly influenced by the precounseling of potential AEs prior to treatment initiation. The anticipation of side effects may have led participants in the placebo group to report symptoms they perceived to be treatment-related.
Our findings are in accordance with various clinical guidelines that do not recommend GBA and PGB for the nonoperative treatment of LSS [17,30]. The possible explanations for our findings might lie in the pathomechanism of NIC, which is primarily caused by the mechanical compression of the cauda equina and nerve roots, leading to inflammatory responses, venous stasis, and disrupted blood flow to the nerve roots. Unlike other neuropathic pain conditions, such as postherpetic neuralgia [31], diabetic neuropathy [32], or sciatica, which is predominantly caused by nerve sensitization and ectopic discharges, the pain associated with NIC is multifactorial, which involves nociceptive, neuropathic, and mechanical pain pathways. GBA and PGB primarily target neuropathic components, which may not be the dominant mechanism. Thus, their efficacy may be limited in patients with predominant NIC. Further, in this study, the potential effects of gabapentinoid may have been masked by the benefit of naproxen. Nevertheless, future studies should be conducted to evaluate the efficacy of GBA and PGB as monotherapies.
This study has several limitations. First, although the GBA and PGB dosages were titrated to their effective levels, the maximum recommended doses were not achieved. The dosage differed from that used in previous studies [7,33]. Thus, the differences in the dosages could partly explain the discrepancies in the results. However, the targeted doses were selected because they were well-tolerated in actual clinical practice and still within the effective dose range, particularly in adult patients with LSS who are predominantly older. This is because advanced age is a common risk factor for somnolence and dizziness in those taking gabapentinoid [34]. These target dose ranges are effective in managing peripheral neuropathic pain [31,32] and central neuropathic pain in patients with spinal cord injury [35]. Second, the relatively small sample size, which was primarily powered to detect differences in VAS pain scores, might have limited the interpretation of other outcomes. Finally, the 4-month follow-up period might only reflect short- to midterm outcomes. Nevertheless, the time to an effective GBA and PGB dose is typically 7–14 days [36], with therapeutic effects plateauing at approximately 4 weeks [37]. Moreover, in neuropathic pain, the placebo response was more likely to stabilize at approximately 8 weeks [37]. Therefore, a 4-month follow-up was adequate for evaluating the treatment outcomes. To the best of our knowledge, this is the longest follow-up period reported in a prospective trial assessing the use of gabapentinoids in patients with LSS.
Conclusions
GBA and PGB did not exhibit superiority over a placebo in managing NIC and improving functional outcomes or quality of life. Further, they were associated with a higher incidence of AEs. These findings indicate that adjunctive treatment with GBA or PGB does not provide additional benefits beyond those of the standard conservative management for LSS.
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