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Abstract
Background Up to 30% of patients with knee osteoarthritis (KOA) have evidence of sensitization, with a similar proportion experiencing severe pain during procedures. Most patients with KOA are elderly and often develop side effects from intravenous sedation. Our study investigated the effectiveness of a methoxyflurane inhaler combined with local anesthesia in reducing procedural pain from genicular nerve block compared with local anesthesia alone.
Methods 42 adults with refractory KOA were randomized into two groups. Methoxyflurane group received a self-titrated methoxyflurane inhaler with local anesthesia whereas lidocaine group received local anesthesia only. The primary outcome was pain score on a 0–10 verbal numerical rating scale (VNRS) during the procedure. Secondary outcomes included changes in VNRS and behavioral pain scale (critical care pain observational tool) during the procedure, hemodynamic changes, anxiety level, sedation score, and adverse events.
Results 42 patients with a mean age of 66±12 years participated in this study. There were no significant baseline differences. During the procedure, the methoxyflurane group experienced a significantly greater VNRS pain reduction from baseline (2 (1, 4) vs −1 (−2, 0); p<0.01) and greater VNRS reduction over time (p=0.01) compared with the lidocaine group, with a higher sedation score (p<0.01). Immediately postprocedure, anxiety levels were lower in the methoxyflurane group compared with the lidocaine group (median State-Trait Anxiety Inventory score 21 (IQR 20, 24) vs 27 (23, 29); p=0.02), but the median reduction in anxiety level was not significant (6 (1, 12) vs 5 (0, 14); p=0.61). There were no differences in behavioral pain scores, hemodynamic parameters, recovery or discharge times, and adverse effects between the two groups.
Conclusion A methoxyflurane inhaler combined with local anesthesia provided better procedural pain control than local anesthesia alone with no observable differences in adverse effects. Future studies evaluating the impact of a methoxyflurane inhaler on different types of painful procedures are warranted.
- Ambulatory Care
- Analgesia
- Pharmacology
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Methoxyflurane is a short-acting inhaled anesthetic with analgesic and anxiolytic properties that is self-administered around the world for conscious trauma patients in out-of-hospital settings, and is increasingly used to provide sedation for invasive, painful procedures in hospital settings. It has not been studied in the context of procedure-related discomfort in a chronic pain setting.
WHAT THIS STUDY ADDS
In this randomized trial, a self-administered metered dose inhaler containing methoxyflurane significantly reduced pain and anxiety during genicular nerve block (GNB), a painful procedure performed for prognostic and therapeutic purposes.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Given the analgesic and anxiolytic effects identified in our study, methoxyflurane inhaler use may facilitate better outcomes when GNBs are used as a predictive tool before radiofrequency ablation. The use of a methoxyflurane inhaler should be considered as a viable alternative to parenteral sedation in settings where intravenous administration is not practical.
Introduction
In the past three decades, the incidence of knee osteoarthritis (KOA) has continued to surge secondary to rising life expectancies, obesity rates, and lifestyle changes such as an increase in sedentary behaviors and a high rate of injuries. KOA is associated with significant decrements in quality of life. Although arthroplasty can be effective for KOA, it is associated with a substantial failure rate and not everyone is a candidate, which makes seeking bridge therapies a high priority.1
Genicular nerve block (GNB) is commonly used for prognostic (before radiofrequency ablation, RFA) and therapeutic purposes.2 3 Up to 30% of KOA patients have central sensitization,4–6 with a similar proportion experiencing severe pain during GNB. Techniques to minimize procedural pain include local anesthetic cream and intravenous sedation. Yet, a recent study found that topical local anesthetic cream only reduced pain from skin infiltration,7 and intravenous sedation is associated with myriad adverse effects such as respiratory depression and vomiting, particularly in the elderly.8 In addition, intravenous sedation is associated with prolonged recovery time, increased costs, and a higher false-positive rate during diagnostic procedures stemming from residual analgesia and interference in the activities necessary for accurate evaluation of postprocedure pain relief.9 Hence, intravenous sedation can lead to lower success rates during therapeutic interventions, and is therefore not recommended during procedures with diagnostic and prognostic utility.10 11
Methoxyflurane is an inhaled anesthetic agent that is self-administered through a hand-held inhaler with a rapid onset (within 1 min) and short duration (20–30 min) of action. The equianalgesic potency of inhaled methoxyflurane 3 mL is between 25 and 50 µg of intravenous fentanyl.12 Methoxyflurane has been widely used in Europe, parts of the Middle East and Asia, Canada, and in Australia and New Zealand for over 30 years to provide trauma-related pain management outside of hospitals in sports or trauma-related pain in hemodynamically stable patients with moderate to severe pain.13 14 The safety profile of methoxyflurane inhaler is favorable, being devoid of acute cardiorespiratory effects and end-organ toxicity; hence, it does not require an anesthesiologist for monitoring.15 Recently, its use has expanded to include procedural pain control in hospital settings such as during endoscopy, biopsies, burn care, and uncomplicated labor.16 In a small case series involving 15 patients undergoing repeated burn care, methoxyflurane resulted not only in significant pain reduction but also had an anxiolytic effect.17 Inhaled self-administration permits more precise titratability than oral medications, and obviates the need for an intravenous if not otherwise indicated.18 Whereas the pharmacokinetics of methoxyflurane theoretically make it an ideal medication to provide analgesia and anxiolysis during prognostic procedures in the elderly, it has never been studied in this context. The objectives of this pragmatic study were to investigate the effectiveness of methoxyflurane combined with local anesthesia versus local anesthetic only for procedural pain and anxiety in individuals undergoing GNB, and to determine whether better pain control during GNB results in intermediate-term benefit.
Patients and methods
Permission to conduct this randomized controlled trial was provided by the Ethic Committee of the Faculty of Medicine Ramathibodi Hospital (MURA2022/565), with subsequent registration on 30 September, 2022 (http://www.thaiclinicaltrials.org/show/TCTR20221231003). All patients were treated at the pain clinic in Ramathibodi Hospital between January 3, 2023 (the first patient enrollment) and June 30, 2023. The study was conducted in concordance with CONSORT guidelines and the Declaration of Helsinki, with all patients providing informed, written consent.
Participants
Adults aged 35–85 years with KOA (Kellgren-Lawrence grade III or IV) greater than 3 months in duration and a demonstrated ability to use the methoxyflurane inhaler were eligible for participation. Other inclusion criteria were at least moderate radiographic evidence of degeneration (Kellegren-Lawrence grade of III or IV) and failure to respond to previous conservative treatments including physical therapy and non-opioid analgesics. Exclusion criteria were body weight less than 45 kg, allergy to any study medication (eg, fluorinated anesthetics, amide local anesthetic or steroid), personal or family history of malignant hyperthermia, poorly controlled cardiorespiratory disease (eg, life-threatening arrhythmias, chronic lung disease, and uncontrolled asthma), hepatic or renal dysfunction, seizure disorder, uncontrolled bleeding disorder, and poorly controlled psychiatric condition including active substance use disorder and a personality disorder rendering the patient uncooperative. Patients who did not meet all selection criteria and/or met at least one exclusion criterion, as well as those wishing to withdraw before randomization, were deemed screen failures.
Randomization and blinding
Using a computer-generated randomization table, patients were randomized in blocks of six into two groups: a methoxyflurane (M)+lidocaine group, and a lidocaine-only (L) group. Allocation concealment was performed using sealed envelopes opened at the time of the procedure. Before starting the procedure, M-group patients were instructed on how to use the inhaler. Neither patients, the doctors performing the procedure, nor outcome assessors were blinded to treatment allocation.
Methoxyflurane and lidocaine-only treatments
All participants received local anesthesia infiltration at the three needle insertion sites with 5 mL of lidocaine 1%, with additional lidocaine provided on an “as needed” basis (eg, verbal or behavioral (grimacing, movement of the knee or squeamishness)) indications of severe discomfort, severe verbally reported pain (≥7/10 pain or pain greater than the “worst” preprocedural pain score). In addition to the baseline local anesthetic, the M-group also received 6–10 inhaled breathers of up to 3 mL of methoxyflurane (Penthrox, Medical Development International Limited, Australia) between 90 and 120 s prior to local infiltration, and again (1–10 breaths) as needed throughout the procedure. Those performing or overseeing the procedures were all board-certified pain specialists with extensive experience performing GNB.
Genicular nerve block
The patients were positioned supine with their knees flexed and monitoring equipment such as non-invasive blood pressure, oxygen saturation, heart, and respiratory rates, was applied according to American Society of Anesthesiologists standards for minimal sedation by non-anesthesiologists. Sedation was overseen by a registered nurse working under the supervision of the anesthesiologist performing or supervising the procedure. Supplemental oxygen via nasal cannula was available and delivered on an “as needed” basis. Skin insertion sites for the three targeted nerves (superomedial, superolateral, and inferomedial genicular nerves) were identified, and after superficial anesthesia was applied as noted above, 25-gage Quincke spinal needles (Spinocan, B Braun, Germany) were inserted into previously described target points using ultrasound guidance19 with a high-frequency probe (Arietta 70, Hitachi Healthcare, Japan). For the superomedial and superolateral genicular nerves, these points were at the metaphyses (ie, the junction between the epiphysis and diaphysis) on the median and lateral sides of the femur, respectively, at a depth of between 70% and 90% across the width of the femur, just superficial to bone. For the inferomedial genicular nerve, the insertion point was at the metaphysis of tibia, at a depth 70%–90% across the width of the tibia, just superficial to bone. Once the metaphysis was identified in a longitudinal plane, the ultrasound probe was rotated 90° to obtain a cross-sectional view and confirm satisfactory placement. The injection was performed using an in-plane technique with a 2 mL solution consisting of 1.5 mL of preservative lidocaine 2% (The Thai Government Pharmaceutical Organization, Thailand) combined ½ mL of dexamethasone 5 mg/mL (Atlantic Laboratories Corporation, Thailand), administered around each nerve. When the procedure was completed, patients were encouraged to ambulate.
Data collection and outcomes
Baseline demographic and clinical data including age, sex, body weight and height, psychiatric comorbidities, and disorders associated with central sensitization (eg, fibromyalgia, irritable bowel syndrome, bladder pain syndrome, migraine headaches) were recorded at the time of randomization. Data collection was performed by a disinterested unblinded observer. Between the procedure and follow-up, no analgesic or non-analgesic pain interventions were permitted. The primary outcome measure was self-reported pain intensity during the procedure, recorded using a verbal numerical rating scale (VNRS) immediately after the procedure. Secondary outcomes included behavioral pain scale scores that consider facial expressions, body movements, and muscle tension using the critical care pain observational tool (CPOT), sedation scores using Pasero-sedation scale, anxiety levels using the validated Thai version of the State-Trait Anxiety Inventory (STAI) and adverse effects assessed using open-ended questions surveying symptoms such as dizziness, headache, nausea, and vomiting. Intraprocedural pain scores were recorded by averaging VRNS scores at various times during the procedure, while postprocedural pain and anxiety scores were recorded on arrival in the post-anesthetic care unit, which averaged less than 5 min from the procedure completion time. Additionally, procedural time (time from the start of sedation or local anesthetic to removal of the last needle) and recovery time (time from GNB completion to the patient being able to walk) were recorded. At 1-month follow-up, average VNRS pain over the past week and Patient Global Impression of Improvement (PGI-I) were recorded via in-person visits, or if not possible, telemedicine (by telephone or video call). A positive categorical outcome at 1 month was predefined as a reduction in VNRS pain score ≥ 2 points and a PGI-I score ≤3 (see appendix 1).
Supplemental material
Statistical analysis
Sample size calculation
Based on telephone interviews with seven patients who underwent GNB under local anesthesia at Ramathibodi Hospital, the mean baseline VNRS pain score was estimated to be 7.43, with the treatment group risk reduction assumed to be 0.3, for a small-to-moderate effect size. With 80% of power, type I error of 0.05, and an estimated 20% dropout rate, the required sample size was determined to be 21 in each group.
Data presentation and comparisons
Study outcomes were analyzed using intention-to-treat. Continuous variables are presented as mean (SD), or median (IQR) as appropriate. Categorical data is presented as number (percentages). Comparisons between groups were conducted using t-tests or Man-Whitney U tests for continuous variables, and χ2 or Fisher’s exact tests for categorical data. Two-way analysis of variance was used to test effects between subjects, with treatment group and time as independent factors. SPSS for Windows V.21.0 (IBM, Armonk, NY, USA) was used. P values <0.05 were considered statistically significant.
Results
The Consolidated Standards of Reporting Trials flowchart for the study was shown in figure 1. Forty-two patients were enrolled, with no significant differences between the two groups in age, body mass index, pain characteristics, analgesics usage. However, there was a higher percentage of females in M group (90.5% vs 61.9%; p=0.03) (table 1). The average age of participants was 66±12 years, with the mean duration of pain being 5.1±3.4 years. 73% of patients were on either codeine or tramadol and 74% of subjects were obese according to the WHO-body mass index cut-off for Asian populations.20 The average baseline and worst pain scores were 6.0±2.6 and 9.1±2.5, respectively. In preprocedural period, the two groups had similar VNRS pain and anxiety scores (table 2).
Consolidated Standards of Reporting Trials patient flow diagram demonstrating study progression.
Baseline demographic data
Outcomes during and after GNB
Primary outcome and other pain measures
For the primary outcome measure, the intraprocedure pain score was lower in the M group than the L group (3 (0–5) vs 8 (6–10); p<0.001). The M group experienced significantly lower VNRS pain scores during and immediately after the GNB (p<0.001). The M group had significantly greater VNRS pain score reduction when comparing preprocedure versus intraprocedure scores (2 (1 to 4) vs −1 (−2 to 0); p<0.01) (figure 2). However, the VNRS pain score reduction from preprocedure to postprocedure pain did not significantly differ between groups. There was no significant difference in CPOT at any time point between two groups (table 2), but the M group had a lower maximum CPOT compared with the L group that fell shy of statistical significance (1 (1–5) vs 3 (3–7); p=0.06).
Violin plot demonstrating verbal numerical rating scale pain scores at each study time point. Violin plots are similar to box plots except that they demonstrate how frequently values occur. In the figure, the wider aspects of the density plot demonstrate more frequent occurrences of the specified pain scores.
Secondary outcomes
The maximal sedation score was significantly higher in the M than the L group, with 57% in the M group being fully awake versus 100% in the L group (p<0.01, table 2). The M group reported less postprocedural anxiety than the L group (21 (20–24) vs 7 (23–29); p=0.02). For adverse events, there was one patient who developed high blood pressure during the procedure in the L group, one patient who developed tachycardia during the procedure in the M group, and one patient in the M group experienced transient desaturation to 90% during the procedure which responded to verbal stimuli to take deep breaths. 30% of patients in the M group experienced dizziness compared with 10% of the L group (p=0.13). At 1-month follow-up, there were no significant differences in VNRS, PGI-I and binary positive outcome between the groups (table 2).
Discussion
This pragmatic study demonstrated that a low-dose (up to 3 mL) methoxyflurane inhaler combined with local anesthesia provided better procedural pain control for GNB than local anesthesia alone, with a higher level of sedation but no significant differences in adverse effects or anxiety.
Analgesic efficacy and safety
Although the primary outcome measure, VNRS, was significantly lower in the M group compared with the L group, there was no significant difference in change for CPOT, which relies on clinician observation of behavioral variables (eg, facial expressions, body movements) associated with pain. In the M group, 86% of participants were awake or only slightly drowsy and hence could reliably self-report pain intensity or VNRS, the gold standard for pain assessment. Studies have been mixed regarding the correlation between behavioral (more multidimensional) and self-reported pain scores, with one study finding patients preferred the latter.21 22 Factors that can adversely affect the correlation between self-reported and behavioral pain scores include delirium (or excessive sedation), analgesic usage (both prescribed and administered), catastrophization and other psychiatric morbidities, and secondary gain.22 23
Similar to previous studies evaluating up to 6 mL (two inhalers) for minor surgeries (n=173) and radiological procedures (n=123),16 we found that methoxyflurane can be used safely and effectively for ambulatory pain procedures. Since methoxyflurane has a rapid onset, it can be useful when rapid analgesia is required such during a perineural injection or RFA.24 Moreover, unlike other inhaled anesthetics commonly used for anesthesia such as sevoflurane and isoflurane, methoxyflurane possesses independent analgesic effects by virtue of reduced junctional conductance and modification of several ion channels such as calcium-dependent ATPase (though the precise mechanisms are still being elucidated), demonstrating superiority to opioids in one randomized phase 3 study conducted in severe trauma-related pain.13 25
Our study demonstrated effective pain control and safety during GNB in elderly patients, which represents a population at high-risk for adverse events from parenteral analgesics and anxiolytics. There are few studies evaluating methoxyflurane in the elderly and none specifically for procedural pain, though one subgroup analysis explored its effects on the elderly suffering from trauma-related pain, finding non-inferiority to standard analgesic therapy including opioids for severe pain and only minor, temporary adverse events.26 In our study, methoxyflurane provided lower immediate postprocedural pain scores, which might facilitate discharge as evidenced by our finding of no significant differences in recovery time between, and also prevent the need for postprocedure opioids. Since methoxyflurane’s duration of analgesic effect is less than 30 min, it should theoretically have minimal effect on the false-positive rate of diagnostic blocks, especially when a longer-acting local anesthetic such as bupivacaine is used. Randomized and retrospective studies found a significant increase in the false-positive rate of diagnostic blocks when the longer-acting agents fentanyl and midazolam were administered during sympathetic blocks and sacroiliac joint injections, while a retrospective study found a higher failure rate for neurolysis when intravenous sedation was used for prognostic celiac plexus blocks.10 27 Reasons why sedation can increase the false-positive rate of diagnostic or prognostic injections include residual pain relief, prolonged anxiolysis (particularly in those with a high affective component to their pain), and interference with the daily activities necessary to accurately interpret postblock pain relief.
As noted earlier, a concern about using methoxyflurane inhalers in the elderly is the possibility of adverse effects such as cardiorespiratory depression. In a large multi-center study, Mercadante et al reported a 17% rate of side effects, all non-serious, in patients treated with the same dose of methoxyflurane versus 3% in those treated with other forms of analgesia including intravenous opioids.28 In our study, 14% (3/21, sedation score=3) of participants who received methoxyflurane developed somnolence, but there was no respiratory depression requiring treatment. Other side effects included dizziness (33% vs 10% in the control group) and dry mouth (5% vs 0%). The advanced age of participants might explain the relatively high incidence of side effects observed, even in the control group. Although methoxyflurane did result in sedation, all patients were able to respond to verbal commands (eg, report pain scores), suggesting it may a useful adjunct for painful diagnostic or prognostic procedures such as GNB.29 There were no differences compared with the control group regarding delayed recovery and home discharge; most participants could walk on their own within approximately 10 min of completing the nerve block. Since methoxyflurane is self-administered through an inhaler and accurately titratable to individual requirements (ie, personalized medicine), it can be used safely in outpatient procedures.
Anxiolysis
Previous studies have found that the anxiolytic effects of methoxyflurane, which stem in part from activation of gamma-aminobutyric acid (GABA) receptors and favorable alterations in ionic conductance, can enhance patients’ comfort, which is an ideal quality when selecting an agent for poorly tolerated diagnostic blocks that are contingent on isolating the pain-alleviating effects of the injection only.10 11 30 31 In our study, patients who used methoxyflurane reported less anxiety immediately after the procedure. However, there was no statistically significant difference in the change in anxiety level when compared with the control group. Future studies with appropriate sample sizes are needed to explore the anxiolytic effects of methoxyflurane, including its duration of action.
Limitations and future research
There are several limitations to our study that warrant mentioning. First, the study was not double-blinded, though the potent odor of methoxyflurane would likely render this difficult. Since subjective outcome measures such as pain and anxiety are associated with prodigious placebo effects which are amplified with procedures, one cannot discount this as contributing to the anxiolysis and reduction of pain in the M-group.32 One method to overcome this obstacle could include lacing a saline inhaler with a very small, subtherapeutic dose of methoxyflurane to replicate the smell. Second, we performed GNB by targeting only three nerves whereas more recent literature shows greater effectiveness when five or more nerves are treated.33 A longer procedure might have required a higher dose of methoxyflurane, and resulted in more pronounced after-effects. Future research should consider targeting more nerves. Third, although we did record pain and sedation scores immediately postprocedure, the prognostic value of GNBs should be measured (ie, via a pain diary) over the duration of action for the local anesthetic (>90 min), which was not done. Ideally, when patients require sedation, a long-acting local anesthetic such as bupivacaine should be used to ensure any residual analgesic effects have worn off while the block is still active, though some randomized trials have used lidocaine.29 Fourth, because of the high cost of the methoxyflurane inhaler in Thailand, we suggest investigating the cost-effectiveness and comparative effectiveness (which would require an active comparator) of using methoxyflurane in same-day procedures. Fifth, since superficial anesthesia is a potential cause of false-positive blocks, future research might consider a direct comparison between methoxyflurane only and local anesthesia to determine the diagnostic validity based on postprocedure pain diaries and subsequent RFA outcomes.34 Finally, as alluded to above, the sample size was too small to detect differences in many secondary outcomes, including side effects. Future studies should examine the effect on a larger sample size evaluating different types of ambulatory procedures to confirm these findings.
Conclusions
The addition of methoxyflurane through a metered dose inhaler is a well-tolerated supplement to local anesthesia for procedural pain control, with no observable differences in adverse effects or a prolonged recovery time. Importantly for its prognostic and diagnostic value, the low dose administered does not appear to affect pain outcomes, either immediately postprocedure or at intermediate-term follow-up. Thus, a methoxyflurane inhaler could play an important role in procedural pain control in ambulatory settings, particularly in an elderly or debilitated population. Future studies performed with sham inhalers that evaluate its effect on diagnostic validity and subsequent RFA outcomes, as well as in different types of outpatient procedures, are warranted.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and the permission to conduct this randomized controlled trial was approved by Ethics Committees of Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (COA. MURA2022/565) on September 30, 2022 (https://www.thaiclinicaltrials.org/show/TCTR20221231003, as shown in online supplemental file). The study was conducted in concordance with Consolidated Standards of Reporting Trials guidelines and the Declaration of Helsinki, with all patients providing informed, written consent.
Acknowledgments
The authors gratefully acknowledge Ms Supak Ukritchon and Mr Witthawin Sae-Lee's assistance in the statistical analysis. We also want to thank the pain nurses at the Ramathibodi Hospital Pain Clinic for their dedicated work.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors PK, WI, SS, NT, RS, and KP contributed to the conception and design of the study. PK, SS, NT, SL, RS, and KP were involved in data acquisition. NT, SS, PK, WI, RS, KP, and SPC analyzed and interpreted data, drafting the article, and revising it critically for important intellectual content. The guarantor was NT. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the integrity of any part of the work were appropriately investigated and resolved.
Funding Internal funding was used to conduct this study. SPC receives funding from the US Department of Defense (MIRROR, HU0001-15-2-0003; Congressionally Directed Medical Research Program, 105637007) and National Institutes of Health (GR101558, R01DA048206-01, U24NS115708, 1UH3135804).
Competing interests SPC is a consultant for Avanos, SPR Therapeutics, Persica, and SWORD, and has previously served as a consultant for Clearing and Scilex in the past 3 years. Currently, SPC is the editorial board member of RAPM. SS, PK, WI, NT, SL, RS, and KP have no conflicts of interest to declare.
Provenance and peer review Not commissioned; externally peer reviewed.
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