¹Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
²Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
³Division of Dermatology, University of Calgary, Calgary, AB, Canada
⁴Beacon Dermatology, Calgary, AB, Canada
⁵Toronto Dermatology Centre, Toronto, ON, Canada
⁶Division of Dermatology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
⁷Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB, Canada

Conflict of interest: Leah Johnston does not have any conflicts of interest to disclose. Benjamin Barankin has been an advisor and speaker for Paladin Labs.
Jaggi Rao has been an advisor and speaker for Paladin Labs. Andrei Metelitsa has been an advisor and speaker for Abbvie, Clarion, Galderma, Merz Pharma, Paladin Labs.
Susan Poelman has been an advisor and speaker for Abbvie, Galderma, Merz Pharma and Paladin Labs. Geeta Yadav has been an advisor and speaker for Paladin Labs.
Funding sources: None.

Abstract:
Pain management is an important aspect of dermatologic procedures, which are typically performed on awake patients in outpatient settings. The first-line modalities for procedural analgesia during most dermatologic procedures are topical and injectable local anesthetics, such as lidocaine. However, in some medical and cosmetic dermatologic procedures, pain cannot be effectively managed with local anesthetics due to procedure-specific lack of efficacy, large treatment surface areas, high dosage requirements, allergies, or other contraindications. In these circumstances, methoxyflurane inhalers may be highly beneficial. Methoxyflurane (Penthrox^®) has demonstrated efficacy for providing pain relief in randomized controlled trials in patients who presented to emergency departments with acute trauma-related pain, as well as in patients undergoing painful procedures for other medical indications. The limited side effect profile, ease of patient self-administration, rapid onset and quick resolution of central nervous system effects following cessation makes methoxyflurane an ideal choice for analgesia during outpatient dermatologic procedures. This review provides an overview of the supporting evidence for methoxyflurane inhalers and clinical commentary on potential indications for methoxyflurane use in dermatology.

Keywords: methoxyflurane, Penthrox, inhaled analgesia, pain control, dermatology

Introduction

Methoxyflurane is a volatile, halogenated hydrocarbon that can be vaporized and subsequently inhaled for analgesia at low doses and can also be used as an anesthetic agent at high concentrations.¹ Methoxyflurane was widely used as an inhaled anesthetic agent in the 1960s and in 1968, Abbott Laboratories developed the first low-dose methoxyflurane inhaler (Analgizer^®) for self-administration by patients.² However, in the 1970s, use of methoxyflurane as an anesthetic declined due to emerging reports of nephrotoxicity and hepatotoxicity and in 1999, Abbott Laboratories discontinued production and distribution of methoxyflurane inhalers in the United States and Canada.^1,3,4 In 2005, the United States Food and Drug Administration (FDA) responded to reports of methoxyflurane toxicity by formally withdrawing the license for methoxyflurane anesthetic agents, preventing future new drug applications in the United States.^3,4

Medical Developments International re-branded low dose methoxyflurane through the development of the Penthrox^® inhaler for analgesia in 2003. Since then, Penthrox^® has received health regulatory approval in Europe and Canada in 2015 and 2018, respectively. In 2018, the FDA lifted its previous clinical hold on methoxyflurane, allowing Penthrox^® to receive regulatory approval as a new investigational drug.³ This review provides an overview of the evidence on methoxyflurane for analgesia and clinical commentary on applications for its use in dermatology.

Mechanism of Action and Pharmacodynamics of Inhaled Methoxyflurane

Once inhaled into the lungs, methoxyflurane undergoes rapid absorption into the blood, allowing for a quick onset of action that starts after 30 seconds and can be detected by changes in pain scores within the first 2-5 minutes of inhalation.⁵ The exact mechanism of action of methoxyflurane in pain relief has not been fully delineated, but it is theorized to exert its analgesic effects by potentiating activation of gamma-aminobutyric acid (GABA) and glycine receptors in the central nervous system (CNS) and altering the immunoreactivity of substance P and beta-endorphin in the brain.^6-9 Methoxyflurane’s ability to provide analgesia at lower doses (3-6 mL), in addition to its use as an anesthetic at higher doses (40-60 mL), is unique among fluorinated anesthetic agents.^10-13

Based on estimates from disappearance curves, the apparent half-life of methoxyflurane is approximately 15-20 minutes.⁴ Methoxyflurane is highly lipid soluble and diffuses slowly from adipose tissue into the bloodstream, and approximately 50% is metabolized by multiple different cytochrome P450 (CYP450) enzymes in the liver.^4,14 Methoxyflurane undergoes the biochemical processes of oxidative demethylation and defluorination to form the following metabolites: fluoride, oxalic acid, dichloroacetic acid, and 2,2-difluoro-2-methoxyacetic acid.⁴ Methoxyflurane and its metabolites are renally excreted and methoxyflurane may also be metabolized by kidney microsomes, leading to intrarenal fluoride formation.¹⁵

The Penthrox^® Inhaler

In Canada, Penthrox^® is inhaled via an inhalation device (Figure 1).^4,16 Each inhaler device comes with a 3 mL bottle of methoxyflurane, which is poured into the base of the inhaler, as well as an activated carbon (AC) chamber that is attached to the top of the inhaler at the dilutor hole.¹⁶ Once the device is assembled, the patient can then inhale methoxyflurane from the mouthpiece.¹⁶ To minimize exposure of individuals in the surrounding environment to methoxyflurane, patients are instructed to exhale into the inhaler.¹⁶ The exhaled vapor passes through the AC chamber, allowing for adsorption of exhaled methoxyflurane.¹⁶ To provide a stronger dose of methoxyflurane with each inhalation, patients can cover the dilutor hole on the top of the AC chamber with their fingers.¹⁶ The estimated concentration of methoxyflurane provided with each inhalation is 0.2-0.4% with the dilutor hole uncovered and 0.5-0.7% when the dilutor hole is covered.¹² Approximately 6-10 initial breaths are needed to initiate adequate analgesia.¹⁶ The Penthrox^® inhaler can be used continuously for up to 25-30 minutes and, if needed, a second 3 mL inhaler can be utilized to provide ongoing analgesia for up to 54 minutes.^12,17 If used intermittently, a single inhaler may provide up to 1 hour of analgesia.¹⁷ The maximum recommended daily and weekly doses of methoxyflurane are 6 mL and 15 mL, respectively.⁴

Clinical Trials

A summary of randomized controlled trials (RCTs) that have been conducted in human participants using the Penthrox^® brand of methoxyflurane inhalers is provided in Table 1.

Initial studies on Penthrox^® focused on evaluating its use as a potential alternative treatment for procedures requiring sedation. A 2011 randomized, cross-over study conducted by Abdullah et al. investigated the use of methoxyflurane inhalation for conscious sedation and analgesia during third molar surgical extraction, in comparison to treatment with nitrous oxide.¹⁸ The study found that sedation was comparable between the two groups, though patient satisfaction scores demonstrated that methoxyflurane was preferred by patients over nitrous oxide (p<0.05) and had a more favorable side effect profile. In a 2013 study by Nguyen et al. in patients undergoing colonoscopies, methoxyflurane was compared to the standard of care, intravenous (IV) midazolam and fentanyl, for procedural sedation and analgesia.¹⁹ The study found that 92% of patients (n=115/125) in the methoxyflurane group received adequate procedural analgesia and sedation with methoxyflurane alone, and only 10 patients required additional IV sedation.¹⁹ Patients in the methoxyflurane group awoke sooner following the procedure and were also able to be discharged more quickly.¹⁹ In patients undergoing dressing changes following severe burns, a 2016 randomized, pilot cross-over study found that 63% (n=5/8) of patients preferred methoxyflurane inhalation over patient-controlled analgesia with IV 10 mg/mL ketamine and 0.5 mg/mL midazolam for pain control.²⁰

The ‘STOP!’ trial in the United Kingdom was a 2014 placebo-controlled, double-blind, RCT on methoxyflurane use in patients aged 12 years or older who presented to the emergency department with minor traumatic injuries.² A total of 300 patients, including 90 patients between the ages of 12 to 17 years, were enrolled in the study.^2,17,21 Methoxyflurane reduced Visual Analog Scale (VAS) pain severity ratings significantly more than placebo (p<0.0001) at 5, 10, 15 and 20 minutes, with the greatest improvement in pain (-18.5 mean change in VAS rating from baseline) observed at 15 minutes.² The median time to initial pain relief was 4 minutes, which occurred after 1-5 inhalations in 49.7% (n=74) and after 6-10 inhalations in 34.9% of participants (n=52).² Another 2014 placebo-controlled, double-blind, RCT demonstrated the efficacy of methoxyflurane in reducing pain in patients undergoing routine bone marrow biopsies.²²

Safety Profile and Precautions for Use

Cardiorespiratory Depression

Methoxyflurane is contraindicated in individuals with hemodynamic instability and/or respiratory compromise.¹⁶ However, methoxyflurane use may be safe in the context of stable chronic respiratory conditions and it has been safely used in patients with obesity, obstructive sleep apnea, and asthma.^33-36

Nephrotoxicity

Nephrotoxicity has occurred in patients treated with anesthetic doses of methoxyflurane when plasma fluoride ion concentrations exceeded 50 μmol/L.¹⁵ However, nephrotoxicity is not commonly observed in patients treated with sevoflurane, another halogenated inhalational anesthetic, when plasma fluoride ion concentrations surpass a similar threshold.¹⁵ Sevoflurane defluorination by kidney microsomes occurs at a lower rate compared to methoxyflurane, suggesting that the renal toxicity observed with high doses of methoxyflurane may be attributable to increased intrarenal fluoride production during methoxyflurane elimination.¹⁵ In clinical studies that used the Penthrox^® inhaler, participants’ serum fluoride levels remained under 10 μmol/L after inhalation of 3 mL of methoxyflurane and no studies have reported nephrotoxicity from Penthrox^® use.¹⁶ A large retrospective post-authorization study found that Penthrox^® provided a reduced risk of nephrotoxicity compared to other commonly used analgesic agents.³⁴ These studies suggest that with the lower methoxyflurane dose used in the Penthrox^® inhaler, serum methoxyflurane levels and subsequent intrarenal fluoride production remain well below the nephrotoxicity threshold.

Hepatotoxicity

Hepatotoxicity is an established risk that occurs with anesthetic doses of methoxyflurane and previous reports include some fatal cases of methoxyflurane-induced hepatic dysfunction.¹⁶ Penthrox^® has not been associated with an increased risk of hepatotoxicity compared to other analgesic agents in post-authorization studies, however, there have been some cases published in the last 40 years on methoxyflurane-associated hepatitis that occurred following treatment with analgesic doses of methoxyflurane.^16,34 Methoxyflurane should be avoided in patients with evidence of underlying hepatic dysfunction and patients who have had previous hepatic damage following the use of methoxyflurane or other halogenated hydrocarbon anesthesics.¹⁶

Malignant Hyperthermia

A previous personal or family history of malignant hyperthermia in response to methoxyflurane or other halogenated anesthetics is a contraindication to methoxyflurane use.¹⁶

Central Nervous System, Psychomotor and Cognitive Effects

Methoxyflurane may cause transient dizziness, headache, muscle relaxation and sometimes drowsiness following inhalation.¹⁶ Methoxyflurane is contraindicated in individuals with an altered level of consciousness.¹⁶ A 2016 placebo-controlled RCT investigated the psychomotor and cognitive effects following 15 minutes of inhalation of a 3 mL methoxyflurane inhaler.³³ This study found that impairments in psychomotor and cognitive performance, including cognition, hand-eye coordination, and auditory reaction time resolved within 30 minutes of cessation of methoxyflurane inhalation.³³ This finding supports the claim that most patients should be able to safely drive and can return to work on the same day following procedures that use methoxyflurane inhalation for analgesia.³³ However, it is recommended that patients wait for up to 30 minutes after discontinuing methoxyflurane inhalation before driving.³³

Abuse Potential

The CNS side effect of euphoria with methoxyflurane use can be a risk factor for potential misuse and there have been very rare post-marketing reports of abuse related to anesthetic use.¹⁶ However, in comparison to many other analgesics, such as opioids, methoxyflurane has a significantly lower potential for abuse when treating acute pain.²⁵

Pregnancy and Breastfeeding

The potential for long-term effects of fluoride exposure during pregnancy and breastfeeding on offspring development has not been fully delineated.¹⁶ In studies that investigated the use of methoxyflurane during labor, elevated fetal serum and urine fluoride levels were measured post-delivery, though these levels were sub-nephrotoxic and no clinical signs of nephrotoxicity were observed.^37-39 Additionally, a retrospective study in females who received methoxyflurane during pregnancy found that there were no significant differences in maternal and fetal outcomes and rates of congenital abnormalities compared to patients who received fentanyl or no analgesia.⁴⁰ In the perinatal period, methoxyflurane use during labor was associated with reduced perinatal mortality rates and a reduced incidence of fetal distress, compared to cases where no analgesia was administered.⁴⁰

A study in Sprague-Dawley rats also did not demonstrate a teratogenic effect of methoxyflurane when used in pregnancy.⁴¹ However, daily 8-hour methoxyflurane exposure at a concentration of 0.08% for the full 21-day gestational period was associated with a 9% reduction in birth weight compared to the control group, while in the 50% nitrous oxide group, a 21% reduction in birth weight was observed.⁴¹ In Swiss/ICR mice, 4-hour daily exposure to methoxyflurane at trace (2 parts per million [ppm]) and subanesthetic (60 ppm) concentrations for 10 days was not associated with adverse effects but at anesthetic concentrations of 2000 ppm, reductions in birth weight, skeletal ossification, and renal maturation, as well as an increased incidence of minor skeletal abnormalities, were observed.⁴²

Based on the current literature, limited methoxyflurane use at analgesic doses during pregnancy does not appear to be associated with an increased risk of maternal or fetal adverse outcomes. However, the long-term effects on offspring development are unknown and therefore methoxyflurane is currently classified as a Pregnancy Category C drug by the FDA, indicating that it is not recommended for use during pregnancy and breastfeeding unless benefits are expected to outweigh potential risks.^16,40

Combination Analgesia and Potential Drug Interactions

Methoxyflurane has been used safely in combination with other analgesic agents, including topical and injectable local anesthetics, acetaminophen, IV morphine and IV fentanyl.^29,43-45 However, methoxyflurane should be used with caution in patients undergoing concomitant treatment with other CNS depressants, such as opioids, sedatives, muscle relaxants, and sedating antihistamines, due to the potential for transient drowsiness and alterations in psychomotor function.¹⁶

Methoxyflurane use should be avoided in individuals who are taking other medications with a potential risk of nephrotoxicity, including contrast dyes, gentamicin, tetracycline, colistin, polymyxin B and amphotericin B, and should be used with caution in patients who are concurrently taking non-steroidal anti-inflammatory drugs.¹⁶ Drugs that induce the activity of CYP2E1 and/or CYP2A6, which are the CYP450 enzyme subtypes that predominantly metabolize methoxyflurane, can also increase the risk of methoxyfluraneinduced nephrotoxicity.¹⁶ These drugs include alcohol, isoniazid, phenobarbital, and rifampicin.¹⁶

Vital Signs

Clinically significant changes in vital sign parameters, including blood pressure, pulse rate, respiratory rate, and peripheral capillary oxygen saturation, have not been observed with Penthrox^® use in clinical trials.^2,19,36 Continuous monitoring of vital signs during and after Penthrox^® use is not required in healthy patients who do not have major comorbidities.^16,23,28,44 However, some healthcare providers may recommend that patients remain in clinic for observation for 10-15 minutes after finishing methoxyflurane inhalation.

Storage, Handling and Preparation

Penthrox^® inhalers have a shelf-life of approximately 36 months, should be stored at temperatures between 5° and 30° Celsius and can be discarded with normal waste disposal.¹⁶ Contact precautions are not required when handling the inhalers. Penthrox^® inhalers may be stored in a clinic setting or patients may obtain their inhalers from a pharmacy prior to appointments. A major advantage of the Penthrox^® inhaler over other methods of analgesia is that minimal preparation of the inhaler device is needed before use. The first step for setting up the inhaler is to insert the AC chamber into the dilutor hole on the top of the inhaler.¹⁶ Administration of Penthrox^® without the AC chamber should be avoided, as this can significantly increase occupational exposure to methoxyflurane.¹⁶ Once the inhaler is assembled, liquid from the Penthrox^® bottle can be poured into the inhaler base, and it is recommended that subsequent use of the inhaler occur shortly after this step.¹⁶ If the inhaler is not used immediately and is stored under open conditions, approximately 50% of methoxyflurane will be lost after 5 hours.⁴⁶ Placement of an assembled inhaler into a low-density polyethylene bag within the inhaler’s original packaging can limit major losses of methoxyflurane for up to 3 days.⁴⁶

Occupational Exposure

The maximum exposure level for methoxyflurane is approximately 15 ppm.^45,47 In Canada, provincial legal limits for methoxyflurane exposure range from 2 ppm per day to 2 ppm over the course of 1 week.³⁷ While occupational exposure to methoxyflurane from patients’ exhalations is a theoretical health risk for healthcare providers, the real-world observed exposure level following 8-hour shifts is much lower than the legal exposure limits, ranging between 0.008 and 0.736 ppm in nurses who supervised methoxyflurane use.⁴⁸ Additionally, serum fluoride levels measured in ambulance paramedics were not significantly elevated above healthy reference ranges.⁴⁹ Typical exposure to methoxyflurane results in serum fluoride level increases that are nearly 50-fold lower than the thresholds that have been associated with nephrotoxicity, suggesting that methoxyflurane exposure has a low risk of negative health effects for healthcare providers when used in well-ventilated environments.^16,47,48 In a study that monitored ambient air in emergency department triage rooms, methoxyflurane concentrations ranged from 0.002 to 0.024 ppm, suggesting that exposure is very low for healthcare providers who work in adjacent rooms.⁴⁸

The long-term risks of methoxyflurane exposure in pregnant healthcare workers who supervise methoxyflurane use have not been studied.³⁷ Currently, it is recommended that pregnant or breastfeeding healthcare workers limit their exposure to methoxyflurane by avoiding direct supervision of Penthrox^® use.³⁷

Environmental Impact and Cost-Effectiveness

In a study that compared the climate change impact of Penthrox^® inhalers to nitrous oxide in terms of all materials and processes involved in manufacturing, clinical use, and disposal, Penthrox^® was found to have a lower environmental impact than nitrous oxide.⁵⁰ The current market cost of Penthrox^® in Canada is $55 per 3 mL inhaler, making it more expensive than the estimated costs per treatment session of IV acetaminophen, opioid analgesics, and nitrous oxide.^51-53 However, although the estimated cost during dermatologic procedures for nitrous oxide use is $20 per session, this estimate does not account for the expensive initial cost of purchasing a nitrous oxide delivery system, which can cost approximately $8,000-$12,000.^52,54,55 Nitrous oxide machines can also take up a significant amount of space in clinic rooms, which is not an issue with methoxyflurane given the small size of the inhaler device. Overall, the favorable efficacy, safety profile, and lower environmental impact of Penthrox^®, in addition to the lack of requirement for an expensive initial purchase of space-occuping equipment to administer Penthrox^®, makes it worth the slightly higher material cost per treatment session (Table 2).^50-53

Applications in Dermatology and Real-World Commentary

Pre-procedural evaluation for pain control is essential prior to the start of dermatologic procedures.⁵⁶ While injections of local anesthetic agents can effectively manage pain during many dermatologic procedures, such as simple punch or shave biopsies, some procedures may require additional interventions to optimize patient comfort. It is important to take into consideration both patient and procedure-specific factors. Pediatric patients, patients with chronic pain, and patients with procedural anxiety are more likely to experience higher levels of pain during and after dermatologic procedures.^57,58 Additionally, procedures where pain cannot be effectively managed with local anesthetic infiltration due to demonstrated lack of efficacy, large treatment surface areas, high dosage requirements or other contraindications, including allergies to local anesthetics, may warrant consideration of alternative analgesic methods. Given the demonstrated efficacy, limited side effect profile, rapid onset, and complete resolution of CNS effects within 30 minutes of cessation, methoxyflurane is an ideal choice for analgesia during many procedures that are performed in outpatient dermatology settings. Presently, no studies have been published on methoxyflurane use during dermatologic procedures. Based on the real-world clinical experience of the authors of this article, we propose that methoxyflurane inhalers are a useful tool to consider for pain relief during a variety of dermatologic procedures.

Potential Indications for Methoxyflurane in Medical Dermatology

Platelet-Rich Plasma and Intralesional Corticosteroid Injections for Hair Loss Disorders

Intradermal injections into the scalp with either intralesional corticosteroids and/or platelet-rich plasma (PRP) are a mainstay of treatment for many hair loss disorders, including alopecia areata, androgenetic alopecia and scarring alopecias. However, the abundance of pain sensory receptors in the scalp contributes to high levels of pain that many patients experience during scalp injections.⁵⁹ Pain, as well as interference of local anesthetics with platelet functionality, limits their use during PRP sessions.⁵⁹ Methoxyflurane may be useful in reducing pain during scalp injections and it does not carry the same risk of local interactions with intradermally-injected therapies.

Botulinum Toxin Injections

Methoxyflurane may also be beneficial for analgesia during botulinum toxin (BTX) injections. Common medical indications for BTX include axillary and palmoplantar hyperhidrosis as well as chronic migraines, which can be treated with a series of standardized injections into sites on the head and neck. BTX treatment sites, especially the palms and soles, can be highly sensitive during BTX injections.⁶⁰ Methoxyflurane inhalation may help to minimize discomfort during BTX injection sessions.

Photodynamic Therapy

Photodynamic therapy (PDT) is commonly used to treat patients with field cancerization and superficial non-melanoma skin cancers, which often occur in sun-exposed areas on the face and scalp. PDT can be painful and previous studies have demonstrated a lack of efficacy of topical anesthetic agents in controlling pain during PDT sessions.⁶¹ One study that used inhaled nitrous oxide during PDT sessions found that it provided a statistically significant reduction in pain levels compared to the control group.⁶² Methoxyflurane inhalation may be similarly beneficial in reducing pain during PDT treatments.

Deroofing Surgery for Hidradenitis Suppurativa

While intraoperative pain during deroofing procedures for hidradenitis suppurativa (HS) can be effectively managed with infiltration of local anesthetic agents, the process of injecting local anesthetics can be very painful given the relatively high levels of pain that HS patients experience from inflamed HS lesions, in addition to the skin sensitivity in the intertriginous areas where HS lesions typically arise.⁶³ Methoxyflurane inhalers may help to provide pain relief during this first step of deroofing surgeries if inhalation is initiated a few minutes prior to and during injections of local anesthetic agents.

Other Minor Surgical Procedures

Depending on provider and patient preferences, methoxyflurane inhalation may be beneficial as an adjuvant to local injectable anesthesia or may be used alone during minor surgical procedures of short duration, including removal of syringomas, skin tags, extensive dermatosis papulosa nigra, and surgical subcision of acne scars. In the pediatric population, methoxyflurane inhalation may be useful during wart removal with liquid nitrogen cryotherapy and laser treatment sessions, as well as prior to local anesthetic injections in individuals with needle phobias.

Potential Indications for Methoxyflurane in Cosmetic Dermatology

Anxiety about pain is a major barrier to patients choosing to undergo cosmetic dermatologic procedures.⁶⁴ Thus, it is important to be able to provide patients with effective options to alleviate procedural pain and discomfort. While pre-treatment application of ice, topical anesthetic creams and injections of local anesthetics can be used for pain management, these modalities often have limited efficacy, and in the case of local anesthetic injections, may require higher than the maximum safe doses to provide adequate analgesia to an entire area.

Methoxyflurane may be useful in many cosmetic procedures, as it can effectively provide widespread analgesia during procedures involving large body surface areas, such as the full face and/or neck. The hand-held inhaler design of Penthrox^® makes it preferable to other delivery methods for inhaled analgesia due to the lack of bulky tubing and masks, which can block treatment sites on the face. Another benefit is that methoxyflurane is relatively less cumbersome for patients to use compared to holding ice packs at treatment sites for several minutes or applying topical anesthetic creams, which often require occlusion to achieve maximal efficacy.⁶⁵ Additionally, methoxyflurane is non-flammable, making it a safe choice for use during cosmetic dermatologic procedures that involve the use of lasers and energy-based devices.¹⁶ Potential procedural indications for methoxyflurane in cosmetic dermatology may include full-face ablative and non-ablative fractional laser resurfacing, laser tattoo removal, laser hair removal, radiofrequency microneedling, radiofrequency and ultrasound skin tightening procedures, sclerotherapy, and dermal filler injections.

Conclusion

In summary, methoxyflurane is an inhaled fluorinated analgesic agent that has demonstrated efficacy in managing pain in RCTs for a variety of different painful medical procedures. It is a compelling choice for analgesia in outpatient dermatology settings given its high efficacy, limited side effect profile, ease of patient self-administration, rapid onset, quick resolution of CNS effects following discontinuation, cost-effectiveness, and lower environmental impact compared to other inhaled analgesics.

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Schulich School of Medicine and Dentistry, Western University, Windsor, ON, Canada

Conflict of interest: Karen Michael has no conflicts. Jerry Tan is an advisor, consultant, speaker and/or trialist for Bausch, Cipher, Cutera, Galderma and Sun Pharma. Funding sources: None.

Abstract:
Oral isotretinoin continues to be unsurpassed in efficacy for acne. However, it is associated with potential adverse events including risk of fetal defects, necessitating appropriate mitigation strategies. Furthermore, the variance in bioavailability of the original formulation when ingested in fed versus fasted conditions can lead to differences in daily dosing and duration of exposure. Advances in formulation, with lidose encapsulation and subsequently with micronization, have led to iterative improvements in reducing bioavailability variation between fed and fasted conditions. Differences in bioavailability during fasting were 60% less for originator oral isotretinoin, 33% less for lidose-encapsulated form, and 20% less for micronized-isotretinoin formulation. The latter also demonstrated overall greater bioavailability such that a 20% dose reduction was required compared to the originator and lidose-encapsulated formulations. By reducing the effect of high-fat/high calorie food co-ingestion, this micronized formulation may facilitate clarity in determining appropriate oral isotretinoin dose requirements in achieving optimal patient outcomes.

Keywords: acne, isotretinoin, lidose, micronized, bioavailability

Oral isotretinoin was and continues to be the standard of treatment for severe or recalcitrant acne since regulatory approval was granted in the United States and Canada in 1982 and 1983, respectively ^1,2 While its efficacy remains unsurpassed, the past 4 decades have witnessed a barrage of reports regarding potential serious adverse events and attendant litigation. This began with the teratogenic potential of isotretinoin and consequential requirements for rigorous consenting and monitoring to mitigate pregnancy risks. Subsequent concerns including associations with depression, suicide, and inflammatory bowel disease led to studies to address these topics in a rigorous scientific manner and develop risk mitigation measures. It is thus a testament to the enduring value of this medication for people with acne and their caregivers that it remains an available therapy.

Mechanism of Action

Oral isotretinoin is a potent sebo-suppressive agent, likely due to its apoptotic effect on human sebocytes.³ Furthermore, it normalizes monocyte toll-like receptor 2 responses to Cutibacterium acnes (C. acnes).⁴ It has recently been found to induce expression of the transcription factor p53, which controls other pathways involved in the pathogenesis of acne vulgaris such as FoxO1, androgen receptor and genes involved in the induction of autophagy and apoptosis.⁵ These effects likely lead to downstream impacts including reduction in C. acnes proliferation, pro-inflammatory lipid mediators and direct and indirect anti-inflammatory effects in the pilosebaceous unit.⁵

Formulations (Table 1)

As isotretinoin is a lipophilic molecule, the originator product Accutane^® (Roche) was formulated with solubilization ingredients including hydrogenated vegetable oil and soybean oil.⁶ Nevertheless, it is only marginally soluble in the intestinal aqueous environment.⁶ Hence, co-administration with fatty meals was encouraged for greater absorption.⁶ Ingestion of a fatty meal can double drug bioavailability compared to the fasting state.⁶ Accordingly, important considerations include recognizing how varying dietary habits can influence drug absorption, which may in turn affect tolerability, safety, and efficacy.⁶

Subsequently, innovative formulations of isotretinoin have been developed to address the variability in absorption in fed and fasted states. The first iteration was lipid encapsulation, lidose-isotretinoin (Epuris^®, Cipher Pharma; Absorica^®, Sun Pharma), approved by the US FDA and Health Canada in 2012. Lipid encapsulation enhances bioavailability of isotretinoin with less dependency on high-fat, high-calorie meals. In this process, isotretinoin is presolubilized in a lipid matrix leading to greater and faster absorption with less food dependency.⁶ When compared with the conventional formulation of isotretinoin, lidose-isotretinoin was absorbed to a greater extent in the fasting state but equivalent in absorption when coadministered with a high-fat/calorie meal.⁷ It has been shown that lidose-isotretinoin delivered almost twice as much isotretinoin after an overnight fast.⁷ During fasting, isotretinoin bioavailability was 67% of that in the fed state with lidose-isotretinoin compared to 40% for conventional isotretinoin.^7,8 Moreover, lidose-isotretinoin was found to be noninferior to the conventional formulation in a blinded randomized controlled trial in efficacy and safety for severe recalcitrant nodular acne.⁹

A more recent development was a formulation combining isotretinoin micronization with a lidose vehicle carrier system (micronized-isotretinoin; Absorica LD^®, Sun Pharma) that was approved by the FDA in 2019 and Health Canada in 2023. This advancement was based on recognition that drug solubility is also dependent on particle size, with smaller sizes resulting in higher penetration and distribution across a larger total surface area. In micronization, isotretinoin particles are reduced to micrometer or nanometer size. The newest formulation of isotretinoin combines both micronization and lipid encapsulation to enhance solubility, absorption, and bioavailability.⁶ For comparison, conventional formulations of isotretinoin have a mean particle size of about 100 μm while micronized isotretinoin can reach a particle size of 10 μm and the median size (D50) is less than 15 μm.^6,10

Bioequivalence

This micronized formulation was evaluated as an abbreviated new drug application as isotretinoin with lidose encapsulation had been previously approved by the FDA. The demonstration of bioequivalence required pharmacokinetic studies evaluating concentration maximum (Cmax; peak serum concentration after administration) and extent of absorption (AUC; area under the curve).¹¹

The pivotal trial for micronized-isotretinoin comprised 2 open-label, crossover pharmacokinetic studies comparing bioavailability of micronized-isotretinoin 32 mg against lidose-isotretinoin 40 mg in healthy adults. A prior internal study by the sponsor determined that micronized-isotretinoin 0.8 mg/kg would achieve similar plasma levels to lidose-isotretinoin 1 mg/kg, or a 20% dose reduction.¹² One study assessed bioequivalence in the fed state and assessed the effect of food (Figure 1A), and the second evaluated bioavailability in the fasted state (Figure 1B).¹² The fed state was based on administration of a standardized high-fat, high-calorie breakfast as defined by the FDA containing 150 protein calories, 250 carbohydrate calories, and 500 fat calories. In practice, this comprised 2 fried eggs, 2 bacon strips, 4 oz hash browns, 2 slices buttered toast, and 8 oz whole milk.¹²

In the first study, healthy adults of both genders aged 18 years or greater were enrolled in a 3 treatment, 3 period, crossover study. Subjects were sequentially exposed to a single dose of either micronized-isotretinoin 32 mg after an overnight fast (minimum 10 hours); micronized-isotretinoin 32 mg after a high-fat/caloric meal; or lidose-isotretinoin 40 mg after a high-fat/caloric meal. For each subject, crossover was undertaken with intervening durations of 21 days for exposure to each of the 3 treatments. Data were available for 65 subjects. In the fed state, Cmax and AUC parameters were similar for those receiving micronized-isotretinoin 32 mg and for lidose-isotretinoin 40 mg. The comparative results fell within the 80-125% range for bioequivalence, inferring that micronizedisotretinoin 32 mg was bioequivalent to lidose-isotretinoin 40 mg under fed conditions.¹²

The pharmacokinetic effect of food on micronized-isotretinoin 32 mg showed that the high-fat/calorie meal delayed maximum isotretinoin absorption (Tmax) by 1.5 hours. Furthermore, food increased AUC by just over 20%. By comparison, the food effect was 60% for originator isotretinoin and was 33% for lidoseisotretinoin.¹²

The second study evaluated relative bioavailability in the fasted state. Data from 18 subjects were available. Cmax and AUC results for micronized-isotretinoin 32 mg were almost double those for lidose-isotretinoin 40 mg. Under fasted conditions, micronizedisotretinoin 32 mg had almost 2 times greater bioavailability compared with lidose-isotretinoin 40 mg.¹²

Conclusion

Prior literature on oral isotretinoin regarding benefit/risk profiles of low versus conventional isotretinoin dosing and the utility of cumulative dosing in achieving remissions focused on originator and conventional formulations. The present micronized-isotretinoin formulation, due to greater bioavailability, requires transforming these metrics into doses 20% lower than those published for originator and conventional formulations. The pivotal trials for micronized-isotretinoin were comprised of fed bioequivalence, food effect and fasting studies compared to lidose-isotretinoin. As micronized-isotretinoin 32 mg was found to be bioequivalent to lidose-isotretinoin 40 mg under fed conditions, these formulations are not interchangeable. Furthermore, in fasted conditions, micronized-isotretinoin confers 2 times greater bioavailability compared with lidose-isotretinoin 40 mg. In comparing absorption during fed versus fasting conditions, a 20% increase was observed with micronized-isotretinoin compared to 33% with lidoseisotretinoin. Thus, micronized-isotretinoin bioavailability was less food dependent. Micronized-isotretinoin substantially reduced the food effect for oral isotretinoin bioavailability.

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