This study is to assess the non-inferiority of using inhaled methoxyflurane (MOF) versus intravenous conscious sedation with fentanyl and midazolam on women's perception of pain, during hysteroscopy and/or polypectomy in an outpatient setting. The researchers will determine whether the participants receiving the inhaled MOF (experimental group) achieve similar clinical effects in reduction of pain and ability to complete the procedure. Women's perception of pain will be recorded on a scale from 0 to 10 using the numeric rating scale (NRS).

Methoxyflurane (MOF) is a halogenated hydrocarbon volatile general anesthetic that was discontinued in the 1960s due to potential nephrotoxicity. It was subsequently found that at sub-anesthetic doses, it was safe, with no risk of renal impairment, and provided excellent procedural analgesia. The mechanism of action for the analgesic effect is unclear, although it may be related to an effect on substance P and beta-endorphin levels. It is indicated for use for the short-term relief of moderate to severe pain associated with procedures in adults and may be safely used in the geriatric population (>65 years). It has a rapid onset and short half-life, so the effects rapid resolve following procedures (1).

MOF is indicated for self-administration under the supervision of medical personnel for procedural pain and has been safely used in over 5 million patients (2). The use of MOF for procedural analgesia does not affect systemic blood pressure, respiratory rate, or consciousness (2, 3, 4). The most common adverse effects include dizziness, confusion, feeling intoxicated, nausea, and a bad taste. A number of studies have shown no serious adverse events during usage for various procedures (4, 5, 6, 7). It should be avoided in patients with significant renal disease, a history of impaired hepatic function after the use of halogenated anesthetic agents, malignant hyperthermia, and clinically evident hemodynamic or respiratory depression. It should also be avoided in patients using opiates, sedatives, hypnotics, phenothiazines, tranquilizers, skeletal muscle relaxants, alcohol, and potentially nephrotoxic medications.

MOF is self-administered under the supervision of a health care professional using an inhaler (green whistle) that is loaded with 3 cc of 99.9% methoxyflurane. The inhalation device includes an activated carbon chamber that absorbs the exhaled MOF to avoid anesthetic pollution of the procedure room (1). The effects of the medication on psychomotor function return to baseline levels when compared to placebo in a number of tests, including auditory reaction time, hand-eye coordination, and logical reasoning (8). This would allow the patient to return to highly skilled activities such as work or driving on the day of the procedure.

Hysteroscopy is one of the most commonly performed procedures in gynecology (9). Relocating gynecologic procedures such as hysteroscopy from the operating room to an ambulatory setting improves resource allocation and access to the OR for other patients while also improving the patient experience (9). In some centers, this move encounters a significant barrier in providing adequate analgesia. Ineffective analgesia can lead to incomplete or suboptimal assessment and management of pathology (10, 11). The large variance in analgesic options, ranging from oral non-steroidal anti-inflammatories or opiates to intravenous opiates, suggests that there is no single best option.

Sairally et al. (2024) reported that up to a third of patients undergoing hysteroscopy experience severe pain, which may result in procedures being completed in an operating room setting. This can be overcome with intravenous sedation rather than oral analgesia or nitrous oxide; however, access to nurse-administered intravenous (IV) sedation may be limited, and removing an anesthetist from the operating room limits case numbers that can be done there.

The current standard for ambulatory analgesia in most Canadian centers is intravenous sedation with fentanyl and midazolam. This is an effective option, but it requires intravenous access and monitoring of vital signs during and after the procedure. Both opiate and benzodiazepine medications have well-known potential risks, including hypotension, hypoxia, and somnolence. There is often a need for prolonged post-procedure monitoring, especially in the older age groups, which can limit the number of procedures completed in a given amount of time.

The use of inhaled methoxyflurane (Penthrox) has been shown to provide appropriate and effective analgesia for ambulatory care settings with less need for prolonged post-procedure monitoring with quicker recovery and discharge from care. Several studies have examined the effectiveness of methoxyflurane (MOF) use during orthopedic, general surgery, and urological day procedures and with brachytherapy (3, 7, 9, 12, 13, 14, 15, 16, 17). One recent study (9) demonstrated that the use of MOF during hysteroscopy and/or polypectomy and other ambulatory gynecologic procedures was effective, well tolerated with no serious adverse effects. Twidale et al (2022) noted that using MOF during hysteroscopy significantly reduced pain for patients compared to inhaled nitrous oxide.

Debuka et al (2023) showed that removal of orthopaedic external fixator hardware could be completed using methoxyflurane (MOF) rather than the usual general anesthetic or regional block. The average mean visual analogue score (VAS) was 3.9, and patient satisfaction with the level of analgesia was >95%. The authors estimated that relocating these procedures to an ambulatory setting freed up about 80 hours of operating room time a year in their center and reduced the cost per hour from 283 pounds to 24 pounds. The included ages of participants were 19 to 85 years of age, which would be comparable to those undergoing hysteroscopy.

Locke et al (2024) found that replacing intravesical lidocaine with inhaled MOF for cystoscopic procedures was efficacious, had high levels of patient satisfaction and was associated with a VAS score of 4 +/- SD 2.6. Elterman et al (2022) found that using MOF during rigid cystoscopy and water vapour therapy for benign prostatic enlargement in a population with a mean age of 72 resulted in VAS scores of zero. Stewart et al (2023) found that using MOF during cervical brachytherapy applicator removal significantly reduced median pain scores for both retrospective recall and prospective evaluation.

In a randomized, multicentre, non-blinded randomized control trial, Nguyen et al. (2013) compared IV fentanyl and midazolam versus MOF use during colonoscopies and noted no difference in VAS scores before, during, and after the procedure. The procedure preparation time, total time in the room, and procedure success (including polyp detection and removal) were no different between IV sedation and MOF. The MOF group had no reported oxygen desaturations, awoke quicker, and were ready for discharge sooner than the IV sedation group. Ninety-seven percent of the patients said they would use MOF again for colonoscopy.

Nguyen et al (2015) used the same protocol for colonoscopy on patients who were morbidly obese or had sleep apnea. The patients did report more pain in the MOF group but noted this pain was tolerable, and there was no difference in pain scores following the procedure. The preparation time, total time in the room, and procedural success were again similar in the two groups. The MOF group experienced less respiratory depression, hypotension, and tachycardia. This group had a shorter time to be fully awake and were ready for discharge sooner than the intravenous sedation group.

Hayne et al (2022) noted in a multicenter, randomized double-blind placebo-controlled trial in men undergoing their first TRUS-guided prostate biopsy that there were lower scores for pain (mean 2.51 MOF VS. 2.82 PLA; 95% CI -0.75-0.14; p=0.18) and an improved patient experience in the MOF group. There were no adverse events reported, and after 15 minutes, there was no difference in the discomfort in the two groups. Copping et al (2024), in a randomized double-blind placebo-controlled study, found that the use of MOF during portacath insertion and removal and solid organ biopsy resulted in reduced pain scores, lower patient anxiety, and no serious adverse events.

Spruyt et al (2014) completed a single site randomized double-blind placebo-controlled study for bone marrow biopsy showing significant reduction in the worst pain scores in the MOF group compared to placebo (3.3 ±2.0 vs 5.0 ±2.4, p<0.001) (17). The reported adverse events were minor, including dizziness, euphoria, and flushing. Significantly more patients rated the procedure experience as very good to excellent in the MOF group (63% vs 50%).

Although there is somewhat limited evidence for the use of MOF for procedural analgesia in the literature (21, 22), there are a number of quality studies that have demonstrated the safety and efficacy of MOF. There are no reported serious adverse events. The minor complications, including dizziness, nausea, flushing, and drowsiness, all resolve quickly. None of the trials reported hypotension, respiratory depression, or significant cardiac issues. Since MOF has been an effective analgesic for several ambulatory procedures, it has excellent potential to provide a safe, reproducible, and effective analgesia for ambulatory hysteroscopy and/or polypectomy.

References

1. Penthrox product monograph. Paladin Labs Inc, 100 Alexis-Nihon Blvd, Suite 600, St-Laurent, Quebec, Canada.
2. Jephcott, C, J Grummet, N. Nguyen, O. Spruyt. 2018. A review of the safety and efficacy of inhaled methoxyflurane as an analgesic for outpatient procedures. British Journal of Anaesthesia 120:1040-1048.
3. Debuka E, P Birkenhead, S Shah, B Narayan, N Giotakis, P Thorpe, SM Graham, BE Fischer, N Peterson. 2023. Penthrox (methoxyflurane) as an analgesic for removal of circular external fixators and minor procedures during the COVID-19 pandemic. Strategies in Trauma and Limb Reconstruction 18:82-86.
4. Trimmel H, A Egger, R Doppler, M Pimiskern, WG Voelckel. 2022. Usability and effectiveness of inhaled methoxyflurane for prehospital analgesia - a prospective, observational study. BMC Emergency Medicine 22:8-17.
5. Mercadante S, A. Voza, S Serra, F Ruggiano, F Carpinteri, G Gangitano, F Intelligente, E Bonafede, A Sblendido, A Farina, A Soldi, A Fabbri. 2019. Analgesic efficacy, practicality and safety of inhaled methoxyflurane versus standard analgesic treatment for acute trauma pain in the emergency setting: a randomised, open-label, active controlled, multicentre trial in Italy (MEDITA). 2019. Advanced Therapeutics 36:3030-3046.
6. Locke JA, S Neu, J Lawrence, S Herschorn. Pilot study to assess the feasibility of self-administered, low dose methoxyflurane for cystoscopic procedures. 2024. Canadian Urology Association Journal 18:251-254.
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9. Sairally BZF, PP Smith, PM De Silva, S O'Connor, C Yates and TJ Clark. 2024. Inhaled methoxyflurane (Penthrox) as a novel pain relief for outpatient hysteroscopy and other gynaecological procedures. 2024. 302:206-210.
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11. De Silva P, Mahmud A, Smith PP and Clark TJ. 2020. Analgesia for office hysteroscopy: A systematic revierw and meta-analysis. Journal of Minimally Invasive Gynecology 27:1034-1047.
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14. Wong KY, JS Ki Lau, AY Chung Siu, PG Kan. A randomized non-inferiority pilot study on the use of methoxyflurane (Penthrox) for pain control in the emergency department. Hong Kong Journal of Emergency Medicine 29:203-211.
15. Elterman DS, KC Zorn, N Bhojani, B Chughtai. 2022. Efficacy and safety of methoxyflurane (Penthrox) for pain control during water vapor thermal therapy (Rezun) for benign prostatic enlargement. Canadian Journal of Urology 29:11355-11360.
16. Twidale EK, Neutens S, Hynt L, Dudley N, Streeton C. 2024. Methoxyflurane analgesia for outpatient hysteroscopy: a double-blind, randomised, controlled trial. Australian New Zealand Journal of Obstetrics and Gynecology DOI; 10.111/ajo.13861.
17. Stewart AJ, C Brookr, G Vose, K Redmond, A Williams, N Pankhania, H Dommett, J Kirk-Bayley, AP Franklin, B Morrison. 2023. Pain and symptom relief using inhaled methoxyflurane for gynecologic brachytherapy applicator removal. Journal of Contemporary Brachytherapy 15:37-42.
18. Hayne D, J Grummet, D Espinoza, SP McCombie, V Chalasani, KS Ford, M Frydenberg, P Gilling, B Goreon, C Hawks, A Konstantatos, AJ Martin, A Nixon, C O'Brien, MI Patel, S Sengupta, S Shahbaz, S Subramaniam, S Williams, HH Woo, MR Stockler, ID Davis, N Buchan. 2022. Pain-free TRUS B': a phase 3 double-blind placebo-controlled randomized trial lof methoxyflurane with periprostatic local anaesthesia to reduce the discomfort of transrectal ultrasonography-guided prostate biopsy (ANZUP 1501). BJU International 129:591-600.
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Inclusion Criteria:

Abnormal uterine Bleeding requiring hysteroscopy Postmenopausal bleeding requiring hysteroscopy

Exclusion Criteria:

Uterine or patient characteristics that preclude hysteroscopy Submucosal fibroids requiring myomectomy Past allergic reaction to fentanyl or midazolam BMI > 42 Contraindications precluding use of intravenous sedation (sleep apnea) Lack of patient consent History of malignant hyperthermia History of significant renal or hepatic disease

After the interventions are assigned, an unblinded nurse will prepare the study medications according to each participant's identification number and treatment allocation group. Nursing staff in these clinics would normally prepare procedural medications. The nurse will prepare identical syringes filled with either fentanyl, midazolam, or normal saline, label the syringes with the participant identification number, and deliver them to the procedure room at the time of the scheduled hysteroscopy, confirming the patient's identity with the procedure team. They will also provide the Green Whistle and a vial of the methoxyflurane or saline. The physician, assisting nurses, and the participant will all be blinded to the identity of the medication in the syringe and the green whistle.