Introduction
Chronic low back pain due to radiculopathy, including conditions such as lumbar spinal stenosis or herniated disc [1], is managed using various treatment modalities. These include anti-inflammatory medications, physical therapy, transforaminal epidural steroid injection (TFESI) for lumbar radiculopathy [2], and surgical intervention.
TFESI is a widely used, minimally invasive procedure for managing pain associated with nerve root inflammation or compression. It involves the targeted delivery of corticosteroids into the epidural space adjacent to the affected nerve root to reduce inflammation and alleviate neuropathic pain. Fluoroscopic guidance is employed to ensure accurate needle placement and optimal drug delivery [3]. While TFESI is generally well tolerated, some patients may experience discomfort from needle insertion or transient nerve root irritation. Local anesthetics administered at the injection site may not always provide adequate analgesia during the procedure. Therefore, additional medications have been explored to improve intraprocedural pain control.
Methoxyflurane is an inhalable analgesic that offers a non-invasive alternative to conventional pain management methods. It has been widely used for over 4 decades, particularly in pre-hospital emergency settings such as ambulance services and initial trauma management before hospital admission [4]. Methoxyflurane can be self-administered by patients, provides rapid analgesia, and has a well-established safety profile. More recently, its use has been extended to various medical and surgical procedures [5].
Spruyt et al. [6] evaluated the efficacy of inhaled methoxyflurane in patients undergoing bone marrow aspiration for hematological malignancies and reported a statistically significant reduction in pain compared to placebo. These findings support its potential as a viable alternative for patients seeking to avoid conscious sedation. Similarly, Sawang et al. [7] conducted a randomized controlled trial demonstrating that methoxyflurane, when combined with local anesthesia, significantly improved pain relief during genicular nerve block in patients with knee osteoarthritis. Participants receiving methoxyflurane reported lower intraprocedural pain and anxiety levels, while maintaining a safety profile comparable to the control group.
To date, no study has specifically investigated the efficacy of inhaled methoxyflurane during TFESI. In light of previous findings, the present study aimed to evaluate the efficacy and safety of inhaled methoxyflurane, compared to a placebo, in providing pain relief and improving patient outcomes during TFESI for lumbar radiculopathy.
Materials and Methods
This randomized, double-blind, placebo-controlled study was conducted in Thammasat University Hospital between January 2021 and December 2022. The study was registered with the Thai Clinical Trials Registry (TCTR20220706001) and approved by the Institutional Humen Research Ethics Committee of Thammasat University (MTU-EC-OT-6-196/64). Written informed consent was obtained from all participants before enrolment. We hypothesized that inhaled methoxyflurane would significantly reduce procedural pain during TFESI in patients with lumbar radiculopathy compared to placebo.
Participants
Patients diagnosed with lumbar spinal stenosis or lumbar disc herniation presenting with symptoms of lumbar radiculopathy at our institution were considered for inclusion. Participants were required to be 18 years or older, have radiculopathy due to lumbar disc herniation or lumbar spinal stenosis involving no more than three spinal levels, and exhibit symptoms persisting for at least 3 months without improvement following conservative treatment. Additional inclusion criteria included the ability to understand the study protocol, provide voluntary written informed consent, and participate fully in outcome assessments without restrictions.
Exclusion criteria included individuals with traumatic back pain, prior spinal surgery, severe degenerative spinal conditions, or skin infection at the injection site. Pregnant or lactating women, patients who had known allergies to study medications, or those unable to discontinue anticoagulant or antiplatelet therapy were also excluded. Additional exclusions included uncontrolled underlying medical conditions, severe kidney disease, a history of cardiac, pulmonary, or hepatic disease, and a known risk of malignant hyperthermia based on personal or family history.
Randomization
Sixty-five patients were randomized in a 1:1 ratio to either the inhaled methoxyflurane group or the inhaled placebo group. Block randomization (block size of four) was performed using a computer-generated randomization list. Treatment allocation was concealed in sealed, opaque envelopes, which were opened by an investigator (W.P.), not involved in outcome assessment, immediately prior to the patient entering the intervention room.
Pre-intervention
Before the procedure, the investigator (W.P.) prepared the inhaled methoxyflurane or inhaled placebo. For patients assigned to the inhaled methoxyflurane group, 3 mL of 99.9% methoxyflurane solution was added to the inhaler, which is the standard concentration for inhalation. In the placebo group, no substance was added; instead, a training inhaler identical in appearance to the methoxyflurane inhaler was used to maintain blinding. Standardized instructions on inhaler use were provided to all patients. Inhalation commenced 4 minutes before the procedure and continued throughout its duration. Pre-intervention data collection included demographic information (age, sex) and diagnosis. Baseline pain was assessed using the Visual Analog Scale (VAS) by the evaluator (T.T.), who remained blinded to group allocation throughout the study.
Study interventions and drug protocol
All TFESI procedures were performed by a single orthopedic spine surgeon (T.S.), who remained blinded to group allocation throughout the study. Patients were placed in the prone position on a radiolucent table. Each patient was instructed to begin using inhaled methoxyflurane or inhaled placebo 4 minutes prior to the commencement of the procedure (Fig. 1).
After standard sterile preparation, the procedure was performed under uniplanar fluoroscopic guidance to ensure accurate needle placement just inferior to the pedicle at the target level. Local anesthesia was administered with 1 mL of 1% lidocaine. A 9 cm, 23G Quincke spinal needle (Becton Dickinson S.A., Madrid, Spain) was then inserted vertically toward the pedicle, targeting the safe triangle on the anteroposterior view. This region is located above the intervertebral neural foramen or beneath the pedicle on the lateral view. Once the needle was appropriately positioned, 0.5 to 1 mL of Iohexol (300 g/mL, Omnipaque; Patheon Italia S.p.A., Monza E Brianza, Italy) was injected. Fluoroscopic anteroposterior and lateral images were obtained to confirm correct epidural needle placement. Upon confirmation, 2 mL of a mixture containing triamcinolone acetonide (40 mg/mL) and 1% lidocaine was slowly injected. This process was repeated at each planned injection level.
Following the procedure, all patients received the same standardized pain management regimen. This included oral paracetamol (325 mg) combined with tramadol hydrochloride (37.5 mg) every 8 hours for pain relief, and oral naproxen sodium (250 mg) every 12 hours as needed, for the first 24 hours. Patients were instructed to record any post-procedural complications at home. A follow-up visit was scheduled 2 weeks later to assess laboratory parameters (serum creatinine, aspartate aminotransferase [AST], and alanine aminotransferase [ALT]) and to document any adverse events or complications.
Assessment and outcome measurement
All study data were collected by a single evaluator (T.T.), who was blinded to treatment allocation to minimize bias. Pain intensity was recorded intra-procedurally at each lumbar level, with the assessment repeated for all planned injection sites. Post-procedural pain was assessed at 0, 30, 60, 90, and 120 minutes following TFESI.
The primary outcome was procedural pain intensity, assessed using the VAS (0–10). Secondary outcomes included post-procedural pain intensity (VAS), patient and physician satisfaction, incidence of adverse effects, and comparison of renal and liver function parameters before and 2 weeks after TFESI.
Statistical analysis
Sample size estimation was based on the difference in the mean pain scores between the inhaled methoxyflurane and placebo groups, as reported by Spruyt et al. [6]. The mean VAS pain score was 3.3±2 in the inhaled methoxyflurane group and 5±2.4 in the placebo group. A two-sided test with a 5% significance level (α=0.05) and 80% power was used, with a 1:1 allocation ratio. Using Stata ver. 17.0 (Stata Corp., College Station, TX, USA), the required sample size was calculated to be 54 participants (27 per group). To account for potential dropouts, an additional 10% was added, resulting in a final sample size of 60 participants (30 per group).
Categorical variables were summarized as percentages and compared using Fisher’s exact test. Continuous variables were reported as mean±standard deviation for normally distributed data and compared using Student t-test, or as median with interquartile range (IQR1–IQR3) for non-normally distributed data and compared using the Mann-Whitney U test. For paired comparisons, the paired t-test was used for normally distributed data, while the Wilcoxon signed-rank test was applied for non-normally distributed data.
Repeated-measures analysis of variance was used to compare changes in mean VAS scores at 0, 60, 90, and 120 minutes post-procedure, based on an intention-to-treat analysis. Bonferroni adjustment was applied for multiple comparisons. All p-values <0.05 were considered indicative of statistical significance.
Results
A total of 65 patients were assessed for eligibility. Five patients were excluded based on predefined exclusion criteria: prior spinal surgery (n=1), severe degenerative spine disease (n=2), severe renal or hepatic disease (n=1), and allergy to the study drug (n=1). The remaining 60 patients were randomized equally into two groups: the methoxyflurane group (n=30) and the placebo group (n=30). All randomized patients received the assigned intervention, with no discontinuations or loss to follow-up. All 60 patients were included in both efficacy and safety analyses. No exclusions were made from the final analysis, as depicted in the CONSORT (Consolidated Standards of Reporting Trials) diagram (Fig. 2). All participants completed follow-up assessments as scheduled, ensuring comprehensive data collection for statistical evaluation.
Baseline demographic data
The study population was predominantly female, comprising 60% of the placebo group and 53.33% of the methoxyflurane group, with no statistically significant difference (p=0.60). Mean age was comparable between groups, at 63.3±13.28 years in the placebo group and 63.73±13.22 years in the methoxyflurane group (p=0.89). Other baseline characteristics, including initial pain scores (p=0.06) and diagnostic categories (p=0.40), were also comparable between groups. In terms of procedural details, the most common approach was a two-level, two-attempt TFESI, performed in 53.33% of patients in the placebo group and 26.6% in the methoxyflurane group (Table 1). The average inhalation time for methoxyflurane was 20.23±3.6 minutes.
Efficacy of methoxyflurane
The efficacy of inhaled methoxyflurane during TFESI for lumbar radiculopathy was evaluated by comparing procedural pain scores against a placebo. A significant reduction in pain scores was observed in the methoxyflurane group across several procedural scenarios, including one-level, one-attempt (7.0±1.0 vs. 3.66±0.57, p=0.002), one-level, two-attempt (6.25±1.76 vs. 2.58±0.80, p=0.004), two-level, two-attempt (5.43±1.03 vs. 3.81±0.45, p<0.001), and two-level, four-attempt (5.85±0.96 vs. 3.28±1.50, p<0.001). No statistically significant difference was observed for three-level, three-attempt procedures (3.83±0.70 vs. 3.33±0.00, p=0.27). Overall, the methoxyflurane group demonstrated a significantly greater reduction in pain scores compared to the placebo group, with a mean difference of 2.37 (95% confidence interval, 1.85–2.89; p<0.01) (Table 2).
The methoxyflurane group demonstrated a consistently greater reduction in pain intensity compared to the placebo group at all post-procedural time points (Fig. 3). The mean reductions in pain scores were −2.03, −2.76, −3.36, and −3.93 at successive intervals. This reduction was evident across both moderate and severe pain subgroups. In the moderate pain subgroup, mean reductions were −3.87, −3.87, −4.12, and −4.12, while in the severe pain subgroup, reductions were −3.94, −4.84, −5.66, and −5.73 at the corresponding time intervals (Table 3).
Safety and satisfaction
Adverse events were reported in three patients in the methoxyflurane group (10%). Specifically, one patient experienced dizziness, one patient reported nausea/vomiting, and one reported dry mouth, with each event occurring in 3.33% of the group. No adverse events were observed in the placebo group. At the 2-week follow-up, renal and hepatic function parameters remained within normal limits in both groups. There were no significant changes in serum creatinine levels before and after the procedure in either group (placebo: p=0.24; methoxyflurane: p=0.25). Similarly, liver function tests, including AST and ALT levels, showed no statistically significant changes from baseline to follow-up in either group (AST: p=0.46 for placebo, p=0.37 for methoxyflurane; ALT: p=0.41 for placebo, p=0.08 for methoxyflurane) (Table 4).
Patient satisfaction levels were significantly higher in the methoxyflurane group, with 40% rating their experience as “excellent,” 53.33% as “very good,” and 6.67% as “good”; none of the patients rated their experience as “fair.” In contrast, the placebo group reported lower satisfaction, with only 10% rating their experience as “excellent,” 3.33% as “very good,” 53.33% as “good,” and 33.33% as “fair.” The difference in patient satisfaction between groups was statistically significant (p<0.01). Similarly, physician satisfaction was significantly higher in the methoxyflurane group, with 66.67% rating their experience as “excellent,” 26.67% as “very good,” and 6.67% as “good.” In the placebo group, only 6.67% rated the experience as “excellent,” 33.33% as “very good,” and 60% as “good.” This difference in physician satisfaction was also statistically significant (p<0.01) (Fig. 4).
Discussion
Methoxyflurane is a volatile fluorinated hydrocarbon that functions as an inhalational analgesic at subanesthetic doses. Its analgesic effects are primarily mediated through modulation of neuronal ion channels—enhancing inhibitory GABA-A receptor activity and attenuating excitatory NMDA receptor signaling within the central nervous system [8,9]. This dual mechanism reduces neuronal excitability and nociceptive signal transmission, thereby producing analgesia. Additionally, methoxyflurane influences voltage-gated calcium and potassium channels, further contributing to its analgesic and mild sedative effects [8,10]. Notably, at the low doses used for analgesia (e.g., 3 mL via inhaler), methoxyflurane has a favorable safety profile, with minimal hemodynamic or respiratory depression and relatively low risk of dependence compared to opioid analgesics [5,8].
The findings of this study confirm that inhaled methoxyflurane is an effective analgesic for procedural pain relief, showing significantly lower pain scores compared to placebo (p<0.01). Although no significant differences were observed in the three-level, three-attempt and three-level, six-attempt subgroups, this may be attributed to the small sample sizes or increased procedural complexity associated with these cases, which may inherently cause greater pain. Despite these exceptions, methoxyflurane consistently provided superior pain control overall, supporting its utility as a viable option for procedural analgesia.
Methoxyflurane’s rapid onset of action and ease of use contribute to its effectiveness in clinical settings. Previous studies, such as the STOP! Trial by Coffey et al. [10], have demonstrated its efficacy in emergency pain management. Similarly, Mercadante et al. [4] reported strong analgesic effects for acute pain, supporting the present study’s findings. Additionally, Nguyen et al. [11] highlighted methoxyflurane’s usefulness in procedural sedation, particularly during colonoscopy, where it provided effective analgesia with minimal adverse effects. While some variability in pain reduction was observed across different procedural levels in the present study, this may reflect the influence of procedural complexity on analgesic efficacy. Nevertheless, the consistent reduction in pain scores across most procedural categories supports methoxyflurane as a reliable and effective agent for procedural pain management. Its non-opioid nature, ease of administration, and strong analgesic properties make it a valuable alternative for patients undergoing TFESI.
The evaluation of pain scores across all recorded time points demonstrated a statistically significant reduction in the methoxyflurane group compared to the placebo group. Patients with moderate to severe pain experienced a substantial decrease in pain intensity within the first 30 minutes in both groups. Pain levels continued to decline between 30 and 60 minutes before reaching a stable plateau. Notably, in patients with severe pain, this reduction extended beyond 60 minutes, suggesting prolonged analgesic benefits. Recent studies support methoxyflurane’s efficacy across various clinical contexts, particularly in terms of its duration of analgesia. Sawang et al. [7] reported effective analgesia lasting approximately 60 minutes following genicular nerve block procedures for knee osteoarthritis. Similarly, Creutzburg et al. [12] demonstrated its utility in managing pain during burn dressing changes, with effects persisting up to 60 minutes post-administration. Babl et al. [13] reported successful pain control in pediatric emergency procedures, with analgesic effects sustained for 45 to 60 minutes. Additionally, the RAMPED trial found that methoxyflurane provided an average of 50 to 60 minutes of effective analgesia in emergency department settings [14]. Collectively, these findings highlight methoxyflurane’s value as a short-term analgesic, offering reliable and sustained pain relief for up to 60 minutes, thereby supporting its use in procedural analgesia.
In our study, three patients (10.0%) in the methoxyflurane group reported mild adverse events, including dizziness, nausea, vomiting, and dry mouth. These events were self-limiting and resolved without intervention. No adverse events were reported in the placebo group, though the between-group difference was not statistically significant (p=0.23). At the 2-week follow-up, renal and hepatic function parameters remained within normal limits in both groups, with no significant changes in creatinine levels pre- and post-procedure. These results align with prior research, demonstrating that low-dose methoxyflurane does not increase the risk of nephrotoxicity or hepatotoxicity. A post-authorization safety study reported no increased risk of hepatic or renal toxicity compared to other analgesics [15], and a systematic review concluded that methoxyflurane-related adverse effects are typically mild and self-limiting [4]. Historically, high-dose methoxyflurane—previously used as a general anesthetic—was associated with nephrotoxicity and hepatotoxicity due to its dose-dependent toxicity and prolonged exposure [16]. However, contemporary studies evaluating low-dose methoxyflurane for analgesia have not demonstrated comparable risks. A randomized controlled trial further substantiated its favorable safety profile [14], reporting no significant adverse events when administered within recommended dosage limits.
In our study, patient satisfaction in the methoxyflurane group was notably high, with reported levels ranging from 40% to 96.67%. Physician satisfaction reached 66.67%, reflecting substantial confidence in methoxyflurane’s analgesic efficacy. These findings are consistent with previous studies that have reported high patient satisfaction with methoxyflurane, often exceeding 90%. The consistently elevated satisfaction rates observed across studies may be attributed to methoxyflurane’s rapid onset of analgesia, ease of administration, and overall effectiveness in alleviating procedural pain [4,7,13,17].
The strengths of this study include its randomized, double-blind, placebo-controlled design, which minimizes bias and enhances the reliability of the findings. Blinding of both the proceduralist and outcome assessor ensured objective evaluation of analgesic efficacy. Pain intensity was assessed at multiple time points during and after the procedure, providing a comprehensive profile of methoxyflurane’s temporal analgesic effects. Safety monitoring included a 2-week follow-up to assess renal and hepatic functions, ensuring a thorough evaluation of methoxyflurane’s safety profile. Notably, this is the first study to investigate the use of inhaled methoxyflurane during TFESI, contributing novel insights to inform procedural pain management strategies.
However, certain limitations should be acknowledged. The relatively small sample size, especially within certain procedural subgroups, may limit the statistical power to detect subgroup-specific differences. Additionally, the lack of an active comparator limits the ability to assess the relative efficacy and safety of methoxyflurane compared to other commonly used analgesics. Furthermore, this study did not evaluate cost-effectiveness, an important consideration given methoxyflurane’s higher cost compared to conventional analgesics. Future studies incorporating larger sample sizes, active comparators, and economic analyses are warranted to further define methoxyflurane’s role in clinical practice.
Conclusions
This study demonstrates that inhaled methoxyflurane is an effective and well-tolerated analgesic for pain management during TFESI in patients with lumbar radiculopathy. It provided significant procedural pain relief with minimal, self-limiting side effects and no adverse impact on renal or hepatic function at 2-week follow-up. These findings suggest the use of inhaled methoxyflurane as a safe and efficacious analgesic option in the context of lumbar TFESI.
Key Points
Inhaled methoxyflurane significantly reduced pain during transforaminal epidural steroid injection, with effects lasting up to 60 minutes post-procedure.
It showed a favorable safety profile, with only mild, self-limiting adverse events and no significant alterations in renal or hepatic function.
Patient (96.67%) and physician satisfaction were higher compared to placebo.
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