Evidence Mounting for the Green Whistle

Figure: green whistle, pain management, EMS, ED, pain killer, inhaler, Penthrox, intramuscular injection, methoxyflurane, analgesics, tramadol, morphine, fentanyl, InMEDIATE study, ketoprofen, opioids, RAMPED study, nausea, dizzinessFigureFigureFigureImagine you fall and injure your ankle; you are in excruciating pain and can't stand. The paramedics arrive, and you ask for a strong painkiller, but instead they provide you with a handheld inhaler known as the green whistle. You inhale the medicine in the device for a few seconds, and your pain improves to a more tolerable level. This scenario, in which rapid, effective, and noninvasive inhalation-based pain management is administered throughout much of the resource-abundant world, is unfortunately not yet available in the United States. The reluctance and reasons underlying the lack of regulatory buy-in here for approving the green whistle, more formally known as Penthrox (inhaled methoxyflurane), remain unclear, although Asia, New Zealand, and countries in Europe and Asia have employed this novel and safe approach for decades. Canada too has used it since 2018. Simply put, treating pain effectively and rapidly is a priority. This applies universally, but particularly for acute traumatic painful (fractures, dislocations, and others) and nontraumatic (biliary colic, renal colic, etc.) conditions in the emergency department and the field. Timely pain relief, however, is possible before an intramuscular injection of pain medicine takes effect and well before an intravenous catheter can be placed, just not in the United States. Regulatory issues surrounding the review and approval of inhaled methoxyflurane in the United States are based on misconceptions about the established safety record of subanesthetic doses of Penthrox that has been demonstrated in numerous clinical trials and real-world use, with millions of children and adults successfully treated throughout Australia, New Zealand, Europe, and Canada. (Adv Ther. 2016;33[11]:2012; https://tinyurl.com/4r7d3a58.) The availability of Penthrox is possible due to the advent of inhalation-based delivery methods of the volatile anesthetic contained in the green whistle. The safety and efficacy have been demonstrated in multiple well-designed trials over the past several years. (Acad Emerg Med. 2021;28[2]:164; https://tinyurl.com/4vyecntn; J Pain Res. 2020;13:1777; https://tinyurl.com/42fj6eez.) Additional trials support the effectiveness of using such an approach for rapid and effective pain relief. (Adv Ther. 2016;33[11]:2012; https://tinyurl.com/4r7d3a58; Ann Emerg Med. 2020;75[3]:315; https://tinyurl.com/3bn59sre.) Comparative Effectiveness Inhaled methoxyflurane has been compared with various analgesics in prehospital settings and EDs. The evidence suggests that methoxyflurane offers several advantages, particularly in rapid onset of action and ease of administration. A study comparing methoxyflurane to intramuscular tramadol in the prehospital setting found that methoxyflurane had a faster onset of action and higher patient and paramedic satisfaction scores. (Singapore Med J. 2021;62[6]:281; https://tinyurl.com/yf58az5h.) Another study demonstrated that methoxyflurane was less effective than intravenous morphine and intranasal fentanyl but still provided effective analgesia in most patients. (Prehosp Emerg Care. 2010;14[4]:439.) Methoxyflurane was also found to be less effective than morphine and fentanyl in pediatric patients but still provided significant pain relief. The InMEDIATE study showed that methoxyflurane provided greater analgesia and a faster onset of action in the ED compared with standard analgesic treatments, which included IV opioids and nonopioid analgesics. (Ann Emerg Med. 2020;75[3]:31; https://tinyurl.com/3bn59sre.) The MEDITA trial in Italy also demonstrated that methoxyflurane was superior to standard analgesic treatment (including IV morphine, paracetamol, and ketoprofen) in pain relief and speed of onset. (Adv Ther. 2019;36[11]:3030; https://tinyurl.com/5da2bxtm.) The RAMPED study also found that methoxyflurane was associated with clinically significant lower pain scores at multiple time points though it did not achieve a substantial reduction in pain compared with standard care. (Acad Emerg Med. 2021;28[2]:164; https://tinyurl.com/4vyecntn.) A systemic review and meta-analysis of four randomized controlled trials with 536 patients comparing the efficacy and safety of low-dose methoxyflurane with standard-of-care analgesics in adults with trauma-related pain demonstrated analgesic superiority of methoxyflurane at five to 30 minutes post-medication administration, a larger number of patients treated with methoxyflurane achieving pain intensity of 30 mm or less on a visual analog scale, relative reductions in pain intensity of 30 percent or more and 50 percent or more, and shorter median time to pain relief with methoxyflurane. (J Pain Res. 2021;14:93; https://tinyurl.com/2fa8yfzh.) Overall, methoxyflurane is a viable option for acute pain management in prehospital settings and EDs, particularly when rapid onset and ease of administration are a priority. It may be less effective than IV opioids like morphine and IN fentanyl in some scenarios in the prehospital arena. Harms and Benefits Inhaled methoxyflurane has several benefits and risks compared with current practices of acute pain management in the emergency department, particularly considering its rapid onset of action and ease of administration. Potential benefits include: Rapid Onset of Action: Methoxyflurane provides faster pain relief compared with standard analgesics. The InMEDIATE study demonstrated a median time to first pain relief of three minutes for methoxyflurane versus 10 minutes for standard analgesic treatment. Similarly, the MEDITA trial reported a median onset of pain relief of nine minutes for methoxyflurane compared with 15 minutes for standard analgesic treatment. Ease of Administration: Methoxyflurane is self-administered via a handheld inhaler, which simplifies its use in the ED. (Br J Anaesth. 2018;120[5]:1040; https://tinyurl.com/2cnjf9xd.) This can be particularly advantageous in busy or resource-limited environments where rapid and straightforward analgesic options are needed. Patient and Physician Satisfaction: Studies have shown high satisfaction rates among patients and physicians. The MEDITA trial reported that 90 percent of physicians rated the practicality of methoxyflurane treatment as excellent, very good, or good compared with 64 percent for standard analgesic treatment. Controlled by the Patient: The fact that Penthrox can be self-administered allows patients to control their pain relief by inhaling as needed, providing a sense of control and potentially reducing anxiety. Minimal Impact on Respiratory and Cardiovascular Systems: Methoxyflurane has minimal respiratory depressant effects and little impact on the cardiovascular system at therapeutic doses for pain relief, making it safe for use in many patients, including those with underlying health issues. Versatility: It can be used in various settings, including prehospital care by first responders (paramedics and firefighters) and in the emergency department. Psychological Benefits: The rapid onset of pain relief combined with patient control can also reduce patient anxiety and improve overall satisfaction with care. Potential harms include: Adverse Effects: Methoxyflurane is associated with a higher incidence of minor adverse effects such as dizziness and headache. The STOP! trial reported treatment-related adverse events in 42.2 percent of patients receiving methoxyflurane compared with 14.9 percent receiving placebo. (Adv Ther. 2016;33[11]:2012; https://tinyurl.com/4r7d3a58.) These adverse effects were generally mild and transient. Efficacy Compared with Opioids: Methoxyflurane provides effective analgesia, but it may be less effective than intravenous opioids like morphine and intranasal fentanyl. The RAMPED study found that methoxyflurane did not achieve a substantial reduction in pain compared with standard care, although it was associated with clinically significant lower pain scores at multiple time points. Environmental Impact: The environmental impact of using inhaled methoxyflurane is an important consideration and has been evaluated in comparison with other commonly used analgesics such as nitrous oxide. It also has a lower climate impact compared with nitrous oxide, according to a life cycle impact assessment study. Specifically, the study found that methoxyflurane has a climate effect of 0.84 kg carbon dioxide equivalent, which is 117.7 times less than that of Entonox (a mixture of nitrous oxide and oxygen). The primary contributors to the environmental impact of methoxyflurane are the raw materials and production process, which account for 34.4 percent of its total climate impact. The overall environmental footprint of methoxyflurane is considerably smaller than that of nitrous oxide despite this, making it a more environmentally friendly option for analgesia in the emergency department. Overall, inhaled methoxyflurane offers a lower environmental impact compared with nitrous oxide, primarily due to its reduced greenhouse gas emissions. This makes it a more sustainable choice for acute pain management in clinical settings aiming to reduce their carbon footprint. There has been an emphasis to shift to dry powder inhalers, which have 20 times less of an impact on greenhouse gas emissions compared with the environmental impact of standard metered-dose inhalers that contain hydroxyfluoroalkanes. Risk to Physicians: The Penthrox inhaler includes an activated charcoal filter, which absorbs any exhaled methoxyflurane and reduces environmental exposure and minimizes the inhalation of rebreathed drugs, which can minimize the potential harm to those providing the analgesia in a closed space like an ambulance. Cost: It's difficult to estimate and establish a cost per administration because inhaled methoxyflurane is not commercially available in the United States. Data from the United Kingdom cites the cost of a Penthrox inhaler at about $23 US per vial. Looking to the Future Concerns raised by critics of Penthrox's safety largely involve data finding that anesthetic doses—as opposed to subanesthetic doses administered using the Penthrox device—generate fluoride ions (from metabolism in the liver), leading to kidney damage or toxicity. (Hum Exp Toxicol. 2016;35[1]:91; https://tinyurl.com/54fadjvd.) This toxicity, however, was only seen at much higher doses of methoxyflurane used in the operating room, not the doses used in the Penthrox inhaler. This misinterpretation about the toxic effects of methoxyflurane at high concentrations has resulted in confusion and a misunderstanding about the effectiveness of low-dose Penthrox and its short duration in real-world use. The efficacy of Penthrox in acute care settings and its ability to help children and adults is well established. Its safety record is supported by the fact that millions of people have received the medication safely without major adverse effects such as nausea, dizziness, and somnolence (although self-limited). Overcoming regulatory hurdles will require randomized clinical trials conducted in the United States to determine the ability of Penthrox to provide safe, rapid, and effective pain relief. We urge the Food and Drug Administration to reconsider its position and offer Americans the opportunity to gain access to a drug with established benefits that vastly exceed the potential harms. DR. GLATTER is an assistant professor of emergency medicine at Lenox Hill Hospital, Northwell Health, in New York City. Follow him on X @DrRobertGlatter. DR. MOTOV is the research director in the department of emergency medicine at Maimonides Medical Center and a professor of emergency medicine at SUNY Downstate Medical College in New York City. Follow him on X @painfreeED. DR. MILNE is an associate professor of medicine at Schulich School of Medicine and Dentistry, Western University, in London, Ontario, Canada. Follow him on X @TheSGEM. Share this article on X and Facebook. Access the links in EMN by reading this on our website: www.EM-News.com. Comments? Write to us at [email protected].

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