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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Disclosures: The authors disclosed receipt of the following financial support for the research, authorship, and publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the study and the manuscript, reviewed it, and agreed with its content. LG: AbbVie, Amgen, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, La Roche Posay, LEO Pharma, Merck Frosst, Novartis, Pfizer, Sun Pharmaceuticals, and UCB – consultant, investigator, and speaker; BMS Consultant and investigator.

Abstract

Introduction: Over the years, the number of surgical excisions, cryosurgery, electrodesiccation, curettage, and facial laser treatment has increased. Presently pre- and post-procedural care and minor wound management remain highly variable, and standards are lacking. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods: A panel of eight Canadian dermatologists (panel) who perform dermato-surgery convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment. The information from the literature searches, together with the panels’ expert opinions and experience, was applied in this review.

Results: Peri-procedural measures depend on individual patient factors and the type of treatment. Post-procedure moisturizer application may be beneficial for promoting wound healing. Studies have shown no differences in infection rates between post-procedural sites treated with topical antibiotics and petrolatum-based products. Moreover, topical antibiotics are among the top ten allergic contact dermatitis-causing agents.

Conclusions: Cutaneous healing should occur with minimal discomfort and an esthetic scar. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Standards for peri-procedural care and minor wound management may support healthcare providers in improving patient outcomes.

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Introduction

Over the years, the number of skin surgery procedures (surgical shave and elliptical excision, Mohs surgery, cryosurgery, electrodesiccation, curettage, electrodesiccation and curettage (ED&C), laser, and other facial rejuvenation treatments) has increased. The American Society for Dermatologic Surgery reported over 15.6 million cosmetic treatments performed in 2020 in the United States (U.S.) alone.¹ About 13.3 million of these were minimally invasive cosmetic procedures, including neuromodulator injections, soft tissue filler injections, microdermabrasion and chemical peels).¹ The top minimally invasive cosmetic procedures comprised neurotoxins 3.65 million (33%), dermal fillers 1.85 million (32%), skin treatment (chemical peels, hydro-facials) 1.39 million (6%), hair removal 0.45 million (2%), skin treatment (combination Lasers) 0.43 million (4%) and skin tightening 0.39 million (7%).²

While many guidance and consensus documents exist that describe best practices for performing skin surgery procedures, few discuss specific pre- and post-procedure measures. Surveys of aesthetic medicine providers confirmed a lack of consistency in the types and duration of peri-procedural measures for dermatosurgery, laser, and minimally invasive cosmetic procedures.^3,4 Presently, skin surgery pre and post clinical care and minor wound management remain highly variable and there are no standards,^3,4 however, cutaneous healing should occur with minimal discomfort and an esthetic scar. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods

The project aims to provide insights into skin conditions and lesions created when performing dermatosurgery, minimally invasive cosmetic procedures, and facial laser treatment, followed by developing standards for these measures.

A panel of eight Canadian dermatologists (panel) who perform skin surgery was convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment.

We searched PubMed and Google Scholar (secondary source) databases for studies published from 2010 until September 2022. We divided the search terms into four groups to allow optimal results and avoid duplications.

Group 1: Pre-/post-procedure measures AND surgical excision OR curettage OR ED & C) OR cryotherapy OR facial laser treatment; AND Guidelines OR Algorithms OR consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure; AND antimicrobial stewardship OR topical antimicrobials OR systemic antimicrobials

Group 2: Surgical excision, curettage, ED & C, cryotherapy AND healing by primary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 3: Surgical excision healing by secondary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 4: Peri-procedure measures for laser treatment; AND Guidelines OR Algorithms OR Consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure OR Skincare OR wound healing regimen

Exclusion criteria were no original data, information not specific to peri-procedure measures for skin surgery, minimally invasive procedures, and facial laser treatment, and publication in a language other than English. The results of the searches were evaluated independently by two reviewers (AA, TE) and yielded 98 papers. After reviewing abstracts and removing duplicates and papers that did not contribute to this review (n = 43), fifty-five remained. Guidance and consensus documents are available on dermatosurgery, minimally invasive procedures, and facial laser treatment; however, few discussed peri-procedural measures and wound treatment which did not allow for grading.

Results

Procedures Included in the Review

The review addresses the following procedures: surgical excision, cryotherapy, electrodesiccation, curettage, ED&C, and facial laser treatment.

Surgical Excision

A Canadian national survey amongst dermatologists showed that epileptiform excisions, shave excisions, punch biopsies, curettage, and ED&C was most frequently performed, whereas Mohs micrographic surgery (MMS) was the least frequent procedure.⁵ These procedures are used to remove benign and malignant lesions.⁵

Adverse events are usually minor and include bleeding, hematoma, wound dehiscence, infection, discoloration (post-inflammatory hyper (PIH) or hypopigmentation), and atrophic, hypertrophic, or keloid scar formation.⁵

Curettage and Electrodesiccation

Curettage or electrodesiccation can be used to remove benign (e.g. condyloma acuminatum, seborrheic keratosis, pyogenic granuloma, excess granulation tissue) and malignant lesions. With malignant lesions, curettage is often combined with electrodesiccation (ED&C) or cryotherapy. For many indications, ED&C has been replaced by curettage alone, as it yields similar cure rates and a better cosmetic outcome.^12-16 Dermatologists routinely perform these procedures in their offices.

The disadvantage of curettage with or without electrodesiccation or cryotherapy is the absence of histopathologic margin evaluation.^13-15 Studies on low-risk non-melanoma skin cancers show 5-year ED&C cure rates from 91 to 97%.^15,16

Cryosurgery

Cryosurgery has several indications for both benign and malignant lesions. Benign lesions that can be treated with cryosurgery include seborrheic keratosis, verruca, skin tags, molluscum contagiosum, solar or senile lentigo, and actinic keratosis.^16-20 In the case of exophytic lesions, curettage should be considered prior to cryotherapy. This procedure can be delivered quickly and cost-effectively in an outpatient setting.^16-20

Recurrence rates of actinic keratoses treated with cryotherapy vary significantly (1–39%) in prospective studies likely due to a lack of homogeneity in patient and tumor selection, follow-up period, and inter-operator performance approach.^19,20 Malignant lesions can be treated with this modality, but the depth and extent of freezing may not be known without the use of a cryoprobe. Light cryotherapy often leaves no mark but may not remove the desired lesions. A deeper freeze may be associated with permanent white marks due to the destruction of melanocytes, postinflammatory hyperpigmentation, pseudoepitheliomatous hyperplasia, and depressed scars, which may resolve spontaneously, alopecia which may be permanent due to the destruction of hair bulge cells, and tissue distortion (e.g. nail dystrophy or notching of cartilage) due to damage to the nail matrix/cartilage.¹⁶ Cryosurgery should not be used for conditions that can be exacerbated by cold exposure (cryoglobulinemia, multiple myeloma, Raynaud disease, cold urticaria) and a previous history of cold-induced injury or poor circulation at the site or in that body part.¹⁷ Vasoconstriction induced by cryosurgery in poorly perfused areas may lead to tissue necrosis.¹⁷

Facial Laser treatment

Many different types of lasers are available, and laser treatment has many indications.³ Pulsed dye lasers (PDL) may be used for the treatment of port wine stains in adults and children. A further indication for PDL may be the treatment of telangiectatic rosacea.³ Other indications include radiodermatitis, ulcerated hemangioma, and erythrose of the neck.

For hair removal, various types of lasers, such as pulsed diode lasers, Nd: YAG lasers, or intense pulsed light (IPL) lasers, can be used.³ With the proper preparation and an experienced provider, patients with richly pigmented skin can also safely undergo laser and light-based treatments for hair removal, pigment abnormalities, skin resurfacing, and skin tightening.²¹ Facial rejuvenation aims to correct rhytides, telangiectasias, lentigines, and skin texture.³ Laser and energy devices may be used for facial resurfacing, depending on clinical indication, individual subject characteristics, and the operator’s expertise.^3,4 Lasers, such as CO2 or erbium laser, can be used to remove tattoos, Ota’s nevus, and, to a lesser degree, liver spots and Becker’s nevus.^3,21-24 These lasers permit dermabrasion in treating verrucous hematoma, extensive benign superficial dermo-epidermal lesions, and the esthetic treatment of non-muscular wrinkles, i.e., excepting wrinkles of the forehead and nasal sulcus.^21-24 Laser-assisted administration of photodynamic therapy (PDT) photosensitizers has demonstrated efficacy for superficial BCC.^25-27 The recurrence rates of BCC were markedly reduced in two randomized controlled trials using aminolaevulinic acid PDT with erbium compared to PDT and erbium.^25-27

Cutaneous adverse events with all types of laser treatment, such as reactive hyperemia, edema, scarring, and discomfort, may occur.^3,21-24

Pre-procedural Measures

All Discussed Procedures

Skin conditions and infections can exacerbate and cause complications following skin surgery.^3,4,28,29 For all patients considering having a procedure done, medical history including current and previous treatments, including procedures for the lesion under question, what the patient and treating physician hope to accomplish with the proposed procedure, current medications, and allergies, history of systemic disease, history of abnormal wound healing such as post-inflammatory dyspigmentations, abnormal scarring.^3,4,28,29 In patients that have had previous surgical treatments anywhere on their body, it is often good to assess the resultant scars prior to agreeing to perform a procedure on the individual.

Before the procedure, patients should attend the clinic with clean skin without makeup or cosmetics in the area to be treated.^30-34 Hair should be secured away from the treatment area. Patients should not shave since shaving can cause micro-wounds and increase the risk of infection.

Curettage, Electrodesiccation, ED&C, and Cryotherapy

Typically, additional pre-procedural measures are not required.

Laser Treatment

Laser devices are frequently used for facial rejuvenation. Device and treatment choice depends on individual patient characteristics, expectations, and physician expertise.^22-24 For optimal treatment outcomes, patients should be appropriately selected and screened, followed by a physical exam before treatment, depending on the type of procedure.^23,24 Outcomes of previous skin or surgical treatments are obtained, especially dermabrasion (if previously performed) responses.^28,29 People with hypertrophic scars, keloids, or changes in pigmentation will need peri-procedural cosmetic practices to reduce the risk of these complications or should be advised against the procedure.^28,29 Previously published surveys and algorithms confirmed more than 90% of clinicians recommended sun avoidance before, during, and after facial cosmetic treatments.^3,28,29

Peri-procedural measures are based on individual patient factors and the type of laser procedure.^21-24 For patients receiving ablative laser therapy, pre-treatment of underlying conditions, such as rosacea, dermatitis, and prevention of recurrences in patients with recurrent Herpes simplex, may reduce complications and enable adequate healing time to restore the skin’s barrier function.^3,28 Check patients for remote infections. Caution should be applied when considering extensive laser procedures in patients with compromised immune systems, such as HIV, cancer treatment, immunotherapy, or poorly controlled diabetes.^3-28

Measures During the Procedure

Surgical Excision

Prior to the procedure, the surgical site may be prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Povidone iodine is less commonly used since it is messy and permanently stains clothing. Chlorhexidine is an effective cleanser but may induce allergic contact dermatitis and can be toxic to the eyes and ears, whereas isopropyl alcohol is flammable and can irritate the skin.^31,32 Stabilized HOCL is highly active against bacteria, viruses, and fungal organisms without chlorhexidine’s oto or ocular toxicity; it has been proposed as a future gold standard for wound care.³³ HOCL has been shown to have dose-dependent favorable effects on fibroblast and keratinocyte migration compared to povidone-iodine and media alone.^33,34 It also increases skin oxygenation at treatment sites which may aid healing. There is evidence that HOCL may reduce the risk of hypertrophic scars and keloids as it reduces inflammation and the risk of infection. ^33,34

Local anesthesia and pain management can be customized depending need based on the procedure and patient factors and added at the treating physician’s discretion.

Cryosurgery, Electrodesiccation, Curettage, ED&C

Minimal skin preparation is needed for cryosurgery, ED or curettage if the procedure does not result in bleeding. Therefore, antiseptics are not typically indicated in the majority of procedures.¹⁶ However, topical antiseptics should be applied to lesions that are to be curetted or treated with ED&C.¹⁶

Pain management can be customized depending on the procedure and added at the treating physician’s discretion. Pre-procedure anesthesia should be considered for lesions to be curetted or treated with ED&C and large or extensive lesions. Topical anesthetics applied several hours before the procedure or intralesional anesthesia can help reduce surgical pain. For small lesions, injection of local anesthetic may be more painful than the procedure itself and is therefore not indicated.

Laser Treatment

Before the procedure, makeup removal and skin cleansing using a gentle cleanser is required.^30-34 The treatment site is prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Local anesthesia and pain management can be customized depending on the procedure and added at the discretion of the treating physician.^28,29

Post-procedural and Wound Healing Measures

Surgical Excision Healing by Primary Intent

A local anesthetic given before the procedure takes about 1-2 hours to wear off. For further pain management post-surgery, oral acetaminophen is preferred over aspirin, naproxen, or ibuprofen, as the latter encourages bleeding.

Topical postoperative wound care involves maintaining a protected wound and a clean, moisturized surface.^35,36 Wound care includes cleansing with either a gentle cleanser or water, applying a topical, and covering the wound with a dressing.^35,36 While previous investigators have evaluated methods for reducing risks of adverse events due to the treatment procedure, robust studies on post-procedural wound management for primarily closed wounds are lacking.^35-38

Physicians typically cover sutured wounds using either a dressing, adhesive tape strips, or both.^35-38 Wound dressings can be classified according to their function, material, and physical form of the dressing (Table 1).³⁵ Wound dressings for sutured wounds are typically left in place for 24-48 hours after surgery.^35-37 If there is a lot of tension on the wound or bleeding during the procedure, the dressing is typically left on for 2 or more days. The dressing can act as a physical barrier to protect the wound until skin continuity is restored and to absorb exudate from the wound, and prevent bacterial contamination from the external environment.^35-37 Some studies have found that the moist environment created by some dressings accelerates wound healing, although excessive exudate can cause maceration of the suture line and peri-wound skin.^35-37 A dressing should absorb wound exudate, minimize maceration and prevent bacterial contamination.³⁶

Table 1: Types of wound dressings and moisturizers

The utility of dressing surgical wounds beyond 48 hours of surgery is controversial, although^35-37 in addition to the above, dressings can prevent irritation from rubbing from clothing.

A systematic review on early versus delayed dressing removal after primary closure of clean superficial wounds found no detrimental effect on the patient when removing the dressing after 24 hours.³⁵ However, the point estimate supporting the conclusion is based on very low-quality evidence.³⁵

Cleansing the suture line after dressing removal post-procedure using an antimicrobial solution or applying an antimicrobial ointment is equally controversial.^35,36

The incidence of surgical site infections (SSI) varies between 1% and 80% depending upon the types of surgery, the hospital setting (community hospital, tertiary‐care hospital, etc.), the classification of surgical wounds, and the method of skin closure.³⁵ In addition, many skin surgeries are performed in the community in physician offices where infection rates range from 0.2% to 2.5%.⁴¹ Antimicrobial resistance is a growing concern, especially when antimicrobial products are used routinely and inappropriately.^39-44 Moisturizers are frequently used to keep the wound moist; however, evidence for beneficial effects on sutured wounds is inconclusive and mainly from small studies.^45-50

After suture removal, the topical application of a moisturizer containing madecassoside, panthenol, and copper-zinc-manganese has been shown to be beneficial.^45-48 The product is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48 Petrolatum jelly and water-free petrolatum-containing ointments or products containing HOCL may also be used postoperatively to keep the wound moist, however, since they are occlusive, they may induce maceration.^49,50

In a study on postoperative wound care after MMS procedures (N = 76) patients were randomized to wound care with an ointment containing petrolatum, humectants, and natural barrier lipids (group 1: n = 27), white petrolatum (group 2: n = 32) or no ointment (group 3: n = 17).⁵⁰ Group 1 demonstrated an incidence of swelling and erythema of 52% (14/27); in group 2 erythema occurred in 12% (4/32) and swelling and erythema in 9% (3/27); and in group 3 erythema was noted in 12% (2/17) and swelling and erythema in 6% (1/17) patients.⁵⁰ The use of antibiotic-containing ointments is best avoided as they may cause allergic reactions and contribute to antimicrobial resistance.^39-44 Moreover, the rate of surgical site infections in minor surgical wounds is low and preventive use of topical antibiotics is not indicated.^35,44-52

If a hypertrophic scar develops, treatment with a silicone gel sheet or gel may improve the scar appearance and pain. Another option is self-adhesive propylene glycol and hydroxyethyl cellulose sheeting; however, evidence of the efficacy of these products in improving scar appearance and reduction of pain is inconclusive.⁵³

Surgical Excision, Curettage, ED&C, and Cryosurgery Healing by Secondary Intent

In a simplified model, wound healing processes occur in four phases 1) vascular response, 2) coagulation, 3) inflammation, and 4) new tissue formation.^54-57 During the initial inflammatory phase, the adaptive immune system is activated to prevent infection at the wound site.^54-57 Macrophages remove neutrophils, bacteria, and debris from the wound site. They then change phenotype to M2 macrophages, starting the proliferative and epithelialization phase, producing anti-inflammatory mediators and extracellular matrices.^54-57 If this phase is hindered, wound healing may be disturbed. The proliferative or epithelialization phase overlaps with the inflammatory phase and usually takes two to three weeks post-procedure.⁵⁴ During this phase, the dermal matrix matures, and inflammatory processes continue in the reticular dermis. The reticular dermis is sensitive to wound stress and infection and is affected by patient-related conditions such as age, sun exposure, or genetic profile.^54-57 Persistent inflammation plays a role in the development of hypertrophic or keloid scars, although it may not be the entire cause.^54-57 During the remodeling phase the wound contracts, and collagen remodeling occurs, which can last for up to a year post-procedure.

Pain management is similar to that previously discussed for primary healing wounds. Patients should be instructed to avoid sun exposure to the treated area, along with sun protection measures such as sunscreen with SPF 50 plus UVA block to prevent discoloration.^3,4,28,29

When a dressing is used post-procedure, the patient should be instructed to keep it dry and leave it in place for 24-48 hours. After dressing removal, a gentle, non-irritating cleanser can be used twice daily to cleanse the treated area.^3,4,28,29 The wound site must be handled with care, particularly during the initial healing phase of 7-10 days when newly formed epithelium can be early inadvertly removed.^3,4,28,29

Moisturizers or products containing HOCL may be applied to keep the wound moist and to promote wound healing (Table 2).^49,50 Similar to what was discussed for sutured wounds, moisturizers containing antibiotics should not be used on wounds not showing signs of infection to avoid allergic reactions and antimicrobial resistance.^39-44,49-52

Table 2: Complications from laser treatment

A moisturizer containing madecassoside, panthenol, and copper-zinc-manganese may be beneficial.^45-48 It is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48,59 In an unpublished international observation study, 11,464 adults, children, and infants with a mean age of 31 years (1 week to 97 years) with superficial wounds applied the ointment for 14 days. Clinical (desquamation, cracks, erosion, erythema) and subjective symptoms (tightness, pain, burning sensation, pruritus) showed a significant improvement at 14 days, while tolerance and esthetic aspects of the ointment were rated good.

Wound Healing After Laser Procedures

For patients undergoing ablative procedures, prophylactic oral antivirals such as acyclovir (400 mg orally three times daily) or valacyclovir (500 mg orally two times daily), starting typically one day before resurfacing and continuing for 6–10 days post-procedure may be indicated.^3,28 Patients undergoing ablative laser treatment with baseline melasma or post-inflammatory hyperpigmentation may require pre-procedure lightening agents such as hydroquinone 2-4% cream twice per day in the morning and evening.^3,28

Gold and colleagues developed an algorithm for pre-/post-procedure measures for facial laser and energy device treatment and listed complications from laser treatment and actions that can be taken (Table 2).²⁸

Post-laser management is similar to that discussed for secondary healing wounds.

Limitation

Although few studies on peri-procedural measures for dermato-surgery care and minor wound management are available, the advisors recommend applying a moisturizer without antibiotics for antimicrobial stewardship and contact allergy avoidance.

Conclusion

Peri-procedural measures depend on individual patient factors and the type of dermato-surgery. Standards are required to support healthcare providers to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Studies are required to evaluate purpose-designed moisturizers for dermato-surgery post-procedural application improving patient outcomes.

Introduction

Acne is among the most common dermatological conditions seen in primary care. It is estimated to affect 2 million Canadians, and 85 to 90% of adolescents.¹ Individuals of all ages can have acne, but most cases develop in adolescence.² Acne is considered a chronic disease with up to 50% of cases persisting into adulthood.³ Its impact on psychological, social, and emotional wellbeing can be devastating, and can be worse than that reported by patients with chronic asthma, epilepsy, back pain, or arthritis.⁴ Early and aggressive treatment is important to prevent scarring and help improve quality of life. Maintenance therapy is recommended for optimal outcomes. In this article, we provide a guide to address a growing need by primary care physicians to have a logical and practical approach to treating various forms of acne.

Background

• Acne is a chronic inflammatory disorder of pilosebaceous units of the skin.
• Acne nearly always affects the face (99%), but can also affect the back (60%) and chest (15%).⁵
• The pathogenesis of acne is multifactorial. The most notable pathophysiologic factors that influence its development are: hyperkeratinization, increased sebum production, Propionibacterium acnes colonization of the follicle, and inflammation. Studies have also suggested that genetic, hormonal, and dietary factors may also have a role.
• Treatment should target as many factors as possible in order to prevent the formation of microcomedones and prevent scarring and post-inflammatory hyperpigmentation.^5,6

The Lesions of Acne

• Microcomedones are microscopic plugged follicular openings that are not visible to the naked eye. They are the precursors for all acne lesions.
• Noninflammatory lesions include:
  • Closed comedones (whiteheads) are small, skin-colored papules that lack an obvious follicular opening.
  • Open comedones (blackheads) have a dilated follicular opening filled with a keratin plug, which has a black color due to oxidized lipids and melanin.
• Inflammatory lesions include:
  • Erythematous papules and pustules.
  • Nodules and cysts, which may contain pus or serosanguinous fluid.
• Inflammation has been demonstrated to some degree, in all acne lesions.
  • Inflammation localized to the pilosebaceous unit can be considered the defining feature of acne and should be addressed via multiple therapeutic pathways.⁷

Clinical Severity

Acne is commonly described as mild, moderate or severe. A descriptive scale, known as the Physician’s Global Assessment (PGA), is also used to categorize acne.⁸ The determination depend on types, severity, and number of lesions.

Treatments

Topical Treatments

Topical treatments are widely considered to be a mainstay of care because they effectively target the pathogenic factors and address the other key considerations of acne. Generally, once daily is the suggested frequency of application for any topical agent, to increase compliance and reduce irritation side effects. Most experts advocate only a thin layer of topical agent be applied to the affected areas. Topical treatments for acne include:

• Topical Retinoids
  • These are both anti-inflammatory and comedolytic (i.e. inhibit formation of or treat comedones).
  • Tretinoin is the most cost effective but is slightly irritating and the most photosensitizing; also available in a controlled release microsphere formulation for better tolerability and photostability.^9,10
  • Adapalene is the least irritating.¹¹
  • Tazarotene is the most potent but also the most irritating.¹¹
• Benzoyl Peroxide (BPO)
  • This is a potent antimicrobial with no antibiotic resistance. It kills P. acnes via the release of free radicals.
  • BPO also has mild comedolytic effects.
• Topical Antibiotics
  • Topical antibiotics act directly on P. acnes and reduce inflammation.
  • Clindamycin and erythromycin are most commonly used.
  • Antibiotics tend to be very well tolerated compared with other topical agents.
  • Should not be used as monotherapy due to the potential for antibiotic resistance.
• Combination Therapy
  • BPO with an antibiotic
  • BPO with a topical retinoid
  • Topical retinoid with an antibiotic
  • BPO and retinoids have a synergistic effect with topical antibiotics, increasing efficacy, and possibly mitigating the risk of developing resistant bacterial strains.
• Topical Dapsone
  • Dapsone is a sulfone with anti-inflammatory and antibacterial properties.
  • It has been shown to be more effective in female patients than males.^{12, 13}

Over-the-counter lotions and cleansers, such as those containing BPO, salicylic acid or alpha hydroxy acids are also available, but can be less efficacious than prescribed products depending on acne severity.

Oral Treatments

• Oral Antibiotics
  • Like topical antibiotics, these have both antimicrobial and anti-inflammatory properties.
  • The most common include doxycycline, minocycline and tetracycline.
  • Antibiotic resistance is a concern. Most experts suggest using oral antibiotics for no more than 6 continuous months of duration.
• Oral Retinoid (Isotretinoin)
  • Oral isotretinoin is used for severe and treatment-resistant acne.
  • It is the only agent that targets all four of the pathogenic mechanisms of acne.
  • It is teratogenic.
• Combination Oral Contraceptives
  • The estrogen component of combined oral contraceptives suppresses ovarian androgen production and prevents androgen-mediated effects on the sebaceous follicle.

A Physician’s Guide for Treating Acne

There is an increasing need by primary care physicians to have a logical and practical approach to treating acne. The following recommendations will effectively assist physicians in diagnosing and treating acne.

Grade I (Comedonal) Acne:

• Grade I acne (Figure 1) consists of only comedones (blackheads and whiteheads). No inflammation (i.e. no pimples or pustules) is present.
• The best topical treatment options are retinoids or fixed-dose combination as per Canadian guidelines.
  • Retinoids:
    • Tretinoin – 0.025%, 0.05%, 0.1% cream or gel
    • Tretinoin gel microsphere – 0.04% gel or 0.1% gel
    • Adapalene – 0.1% or 0.3% gel, 0.1% cream
    • Tazarotene – 0.1% cream or gel
  • Fixed-dose combinations:
    • Clindamycin 1%/ BPO 5%
    • Clindamycin 1.2% / Tretinoin 0.025%
    • Adapalene 0.1% / BPO 2.5% gel pump
    • Adapalene 0.3% / BPO 2.5% gel pump
    • Erythromycin 3% / BPO 5%

Grade II (Inflammatory) Acne

• Grade II acne (Figure 2) presents with inflammatory papules (pimples) with or without comedones.
• The best topical treatment options include:
  • Clindamycin 1.2% / Tretinoin 0.025%
  • Clindamycin 1% / BPO 5% gel pump
  • Adapalene 0.1% / BPO 2.5% gel pump
  • Adapalene 0.3% / BPO 2.5% gel pump

Grade III (Inflammatory) Acne

• Grade III acne (Figure 3) presents with more intense or widespread inflammatory papules (pimples) as well as pustules. Comedones may or may not be involved.
• The best topical treatment options include the following:
  • Clindamycin 1.2% / Tretinoin 0.025%
  • Clindamycin 1% / BPO 5% gel pump
  • Adapalene 0.1% / BPO 2.5% gel pump
  • Adapalene 0.3% / BPO 2.5% gel pump
  • An oral antibiotic such as doxycyline, minocycline, tetracycline, trimethoprim-sulfamethoxazole, or erythromycin can be used in combination with BPO.

Grade IV (Nodulocystic) Acne

• Grade IV acne (Figure 4) presents with nodules and/or cysts; inflammatory papules (pimples), pustules. Comedones and textural scarring may or may not be involved.
• The best treatment options include the following:
  • Oral isotretinoin
  • Systemic antibiotics in combination with topical benzoyl peroxide, with or without a topical retinoid for patients unwilling or unable to use oral isotretinoin and those with intolerance.¹⁴

Hormonal Acne

• Hormonal acne (Figure 5) is typically seen in females on the lower face (cheeks, chin, jawline), submental region and presents with monomorphic inflammatory papules and cysts that are deep-seated and tender.
• The best topical treatment options include:
  • Dapsone 5% gel or Clindamycin 1%/BPO 5% gel pump
  • WITH an oral anti-hormonal medication such as an oral contraceptive or spironolactone.

Perioral Dermatitis

• Perioral dermatitis (Figure 6) is typically seen in females. It presents around the mouth, nose and/or eyes with acneiform or eczematous papules that are superficial and deep.
• The best topical treatment options include:
  • Pimecrolimus 1% cream
  • Tacrolimus 0.1% ointment
  • WITH oral antibiotic such as doxycyline, minocycline, tetracycline, trimethoprim-sulfamethoxazole, or erythromycin and or in combination with BPO.

Practical Tips

• It is very important to focus on individual patient considerations.
• Topical therapies should be applied to entire affected areas of the face.
• Combination treatment leads to better patient adherence. Simpler and combined regimens provide increased convenience and better outcomes.
• Manage patient expectations (i.e. efficacy, side effects, and treatment duration). Minimum follow up time should be eight weeks between appointments. This will give sufficient time to see the effects of interventions.
• Consider patient tolerability and skin type.
  • Opt for a more tolerable retinoid, causing less irritation and dryness.
• Counsel patient on proper application and moisturizing.
  • Less is more.
  • Use non-oily moisturizers and gentle cleansers.

References

1. Lynde C et al. J Cutan Med Surg. 2014 Jul-Aug;18(4):243-55.
2. James WD. N Engl J Med. 2005 Apr 7;352(14):1463-72.
3. Thiboutot D et al. J Am Acad Dermatol. 2009 May;60(5 Suppl):S1-50.
4. Mallon E et al. Br J Dermatol. 1999 Apr;140(4):672-6.
5. Nast A et al. J Eur Acad Dermatol Venereol. 2016 Aug;30(8):1261-8.
6. Gollnick H et al. J Am Acad Dermatol. 2003 Jul;49(1 Suppl):S1-37.
7. Dreno B, et al. J Eur Acad Dermatol Venereol. 2015 Jun;29(4 Suppl):3-11.
8. Pascoe VL et al. JAMA Dermatol. 2015 Apr;151(4):375-81.
9. Berger R et al. Clin Ther. Jun;29(6):1086-97.
10. Nyirady J et al. Cutis. 2002 Nov;70(5):295-8.
11. Kalita L. J Am Acad Dermatol. 2000 Aug;43(2 Pt 3):S51-4.
12. Zaenglein AL et al. J Am Acad Dermatol. 2016 May;74(5):945-73.
13. Tanghetti E, et al. J Drugs Dermatol. 2012 Dec;11(12):1417-21.
14. Asai Y. CMAJ. 2016 Feb 2;188(2):118-26.

¹Resident, University of Saskatchewan
²Faculty Dermatologist, University of Alberta

Introduction

There is a growing demand for the removal of unwanted facial and body hair in both men and women. The desire for hair removal is primarily for cosmetic and personal preference but in some cases there may be excessive hair growth that is secondary to systemic disease, hormonal alterations, and certain medications.¹ There are numerous hair removal methods which can be grouped either as temporary or permanent. Chemical depilatories have existed since ancient times as a temporary hair removal method.² Currently, several types of depilatory agents are available. They are commonly used, simple to apply, inexpensive and readily available. This article reviews their method of action, characteristics, advantages and disadvantages.

Method of Action

• Depilatories work by breaking down the keratin structure of the hair by inducing chemical reactions.
• Keratin is a structural protein that gives the hair its strength and is stabilized by disulphide bonds.^3,4
• All depilatories function by disrupting the disulphide bonds which then destabilizes keratin.² This weakens the hair so it can then be easily wiped off the surface of the skin.
• The difficulty in producing good depilatory agents arises from the fact that keratin is also found in the skin.
• The active ingredients in depilatories must preferentially target the keratin in the hair in order to be effective and decrease the risk of side effects on the skin (Table 1).³
• Fortunately, the skin is generally less susceptible to depilatory agents as it contains less disulphide bonds.⁵
• The most commonly used depilatory agents are thioglycolates and to a lesser extent, sulphides.^5-7
• The efficacy is increased in products which combine a strongly alkaline (basic) effect with a strongly deoxidizing reaction, hence their being combined with metal hydroxides.³

Chemical Composition of Depilatories

Thioglycolate-based Depilatories

• The most common active ingredient in chemical depilatories is thioglycolate (2-10%) mixed with calcium, sodium or potassium hydroxide (2-6%).²
• Calcium thioglycolate is the least irritating salt form. Its efficacy does not increase at a concentration of more than 4% and may be more irritating.⁷
• These preparations have an elevated pH (pH12-13) as alkalinity improves the efficacy of thioglycolate in dissolving disulphide bonds.³
• The strongly alkaline solution has two further functions:
  • it opens up the structure of the hair to allow the aqueous solution to penetrate and reach disulphide bonds;
  • it affects other bonds within keratin, further breaking apart its structure.
• When enough chemical bonds are broken, the hair can be wiped or washed off where it emerges from its follicle.²
• Health Canada permits thioglycolic acid at concentrations ≤5% with a pH of 7-12.7 in depilatory products.⁸

Health Canada permits thioglycolic acid at concentrations ≤5% with a pH of 7-12.⁷ in depilatory products.⁸

• These depilatories have a similar mechanism of action as thioglycolate-based depilatories.
• Preparations include strontium, calcium and barium sulphide.⁷
• They are all powder-based depilatories, which are mixed in equal parts with water.
• Sulfide-based depilatories are stronger, faster-acting, and more effective hair removers but are more irritating to the skin and must be used with care.^5,9
• This class of depilatory is ideal for individuals with dark and coarse hair, such as those of African descent.⁹

Recommendations and Usage

• Any depilatory should be tested first on a small non-facial area of the skin 24-48 hours before general use. If an allergic reaction or significant irritation occurs, such as redness or itching, the product should not be used.^3,7
• Depilatories should be applied to the skin at room temperature.
• Longer hair that will be treated should be trimmed short.
• The depilatory must be left on the skin for about 3-15 minutes, depending on the depilatory agent and the coarseness of the hair.²
• The weakened hair becomes gelatinous and the hair and depilatory should then be wiped off and the skin washed off with soap and water.⁷
• Burns or skin irritation may occur if the depilatory is left on longer than the manufacturer’s recommended time.
• Applying a hydrocortisone cream (~1%) or an acidic emollient after hair removal may decrease potential skin irritation.⁷
• Emollients include: CeraVe® moisturizing cream, Vaseline® lotion, Aveeno® daily moisturizing lotion, Cetaphil® moisturizing cream, etc.
• Depilatory formulations are specifically designed for specific skin areas and should not be interchanged.⁵
• They should not be used on the face unless specifically indicated.
• The product should not be used in patients with dermatological problems, nor should they be applied to broken, irritated or sunburnt skin.^3,5
• If the skin begins to sting, burn or itch during use, the depilatory must be washed off immediately, as the skin is becoming irritated.³

Indications

• Although chemical depilatories are generally used for cosmetic reasons, they are also indicated for hair removal in individuals with pseudofolliculits barbae, hypertrichosis and hirsutism.^4,6,11 The latter two conditions usually require medical treatment and will not be discussed at this time.

Pseudofolliculitis Barbae

• Depilatories are used to treat pseudofolliculitis barbae, an inflammatory skin condition commonly found in men due to ingrown facial hairs which can result from shaving. This is particularly common in individuals with coarse or curly hair.
• Depilatory agents are effective because they leave the distal ends of the hairs with soft, brush-like tips rather than the sharp tips produced by shaving which tend to ingrow.^9,12
• Stronger depilatories, such as sodium hydroxide, potassium hydroxide, strontium sulphide and barium sulphide, are often needed due to the coarseness of the hair.⁹ These stronger agents are more irritating to the skin and must be used with care.⁹

Selecting a Depilatory

• Depilatory creams are available in a variety of vehicles including: cream, gel, lotion, aerosol, roll-on, and powder forms.
• Creams and lotions are widely available but care must be taken to spread them evenly.
• Gels are a good alternative for those who do not like creams.
• Roll-on creams are neater to apply but may not come out as thick as needed.
• Aerosols are quick and easy to apply but care must be taken not to miss an area.
• Powders are easy to apply on the face and are typically used by men for the beard region.
• Numerous depilatory creams have been developed for men as well as women.
• There are numerous formulations that target different body areas.
• The concentration, pH, salt composition, and vehicle of a formulation is designed for a specific skin area or hair type.^4,5

Skin Area

• Face
• Arms
• Axillae
• Legs
• Bikini area
• Back and chest

Hair Type

• Fine to medium hair
• Medium to coarse hair

When Recommending a Cream

• Consider if the patient has a history of skin sensitivity or allergies.
• Some creams are formulated specifically for sensitive skin and include agents such as moisturizers and aloe to soothe irritated skin.
• If the patient has a history of skin allergic reactions, they should consult their physician.

Commonly Available Depilatory Brands

• Veet®
• Nair®
• Magic® Shave
• Olay®
• Bikini Zone®
• Andrea

Advantages

• Inexpensive
• Readily available²
• Easy and quick to apply⁷
• Can be done at home
• Pain free method²
• Longer lasting and softer hair regrowth when compared to shaving as the depilatory can settle deeper in the follicles, dissolving the hair at a deeper level.⁶
• Mild exfoliating effect leading to brighter and smoother skin.
• Removal of ingrown hairs.⁹

Disadvantages

• A temporary method of hair removal–lasting up to 10 days.⁷
• Have an unpleasant odour due to sulphur containing
  compounds in depilatories.⁷
• Can be messy
• May cause skin irritation including redness, burning, and
  itching if they are left too long or used inappropriately.^4,6
• May cause irritant and allergic contact dermatitis.⁵

Side Effects

• Irritant contact dermatitis (1-5%)
  • Is the most common side effect due to the high alkalinity
    of depilatories.⁷
  • May be avoided with the use of a topical corticosteroid
    applied after hair removal.^5,7
• May be controlled by:
  • Decreasing the frequency of use.
  • Selecting a different vehicle (gel, lotion, cream).
  • Using products with a lower concentration of active
    ingredient or lower pH.
• Allergic contact dermatitis is rare and usually caused
  by fragrances, lanolin derivatives or the thioglycolate
  compound.^5,7
• In an effort to decrease the risk of skin irritation, some
  products include post-treatment moisturizing creams,
  moisturizers in the depilatory creams, or a barrier-type
  substance to be applied to the skin prior to depilatory use.

Future Developments

• Lowering the pH of depilatory creams without increasing depilation time would be ideal as it would decrease the negative effects of these agents on the skin.
• A recent study suggests that decreased depilatory effect due to reduced pH could be compensated for with the addition of novel penetration enhancers such as ethanol, dimethyl sulfoxide, and peppermint oil.¹³ These enhancers were found to decrease depilation time and could eventually be incorporated in new lower pH formulations without affecting depilatory time.

Conclusion

The use of depilatories is rapidly growing and becoming widely accepted as a temporary hair removal solution. Their ease of use, widespread availability and broad product range has increased their popularity with consumers. Improvements in their formulation is associated with good cosmetic results have positioned them to become one of the most used methods of hair removal in North America.

References

1. Ramos-e-Silva M, et al. Clin Dermatol. 2001;19(4):437-444.
2. Fernandez AA, et al. Cosmet Dermatol. 2013;12(2):153-162.
3. Ejersted A, et al. Survey of Chemical Substances in Consumer Products: Analysis of chemical hair-removal products. Survey no.31. Danish Environmental Protection Agency. 2003.
4. Blume-Peytavi U. Br J Dermatol. 2011; 165 Suppl 3:19-23.
5. Draelos Z. Curr Probl Dermatol. 1995;7(2):45-64.
6. Fisher EJ, et al. J Am Acad Dermatol. 2006; 55(2):320-323.
7. Olsen EA. J Am Acad Dermatol. 1999; 40(2 Pt 1):143-155.
8. List of Prohibited and Restricted Cosmetic Ingredients (The Cosmetic Ingredient Hotlist). Health Canada. March 2011: p31
9. Cole PD, et al. Semin Plast Surg. 2009; 23(3):168-172.
10. Toedt J, et al. Chemical Composition of Everyday Products. Westport; London: Greenwood Press, 2005.
11. Lapidoth M, et al. Dermatology. 2010;221(1):34-42.
12. Kelly AP. Dermatol Clin. 2003; 21(4):645-653.
13. Moghimi HR, et al. J Cosmet Dermatol. 2013;12(1):41-48.

ABSTRACT

Acne scarring is often challenging to manage. Various laser treatments are helpful in addressing abnormal color and texture in order to improve the appearance of an acne scar. This paper will review the appropriate use and side-effects of these laser treatments.

Key Words:
acne vulgaris, laser therapy, scarring

Introduction

Scarring caused by inflammatory acne is extremely bothersome to the patient and often challenging to treat. The senior author uses a classification method for acne scarring based on both color and texture (Table 1).¹ Both features must be addressed independently in order to improve the visible quality of the scar. Topical, physical, surgical, and light modalities may be used alone or in combination to improve the appearance of acne scars. This paper specifically addresses laser modalities to treat abnormalities in color and texture in acne scarring.

Laser Options Targeting Skin Color

Red Scars

Erythema is the result of visible dilated capillaries beneath the skin surface. The intensity of the erythema is dependent on the concentration, lumen size, and depth of blood vessels. Lasers and light sources used to decrease erythema of acne scars include the pulsed dye laser (PDL), potassium-titanyl-phosphate (KTP) laser, intense pulsed light (IPL), and neodymium:yttrium-aluminumgarnet (Nd:YAG) laser. Suggested laser settings are shown in Table 2. The number of treatments will vary according to several factors including patient response after each laser session, laser technology used, and parameters of treatment.

PDL is the gold standard for treating erythema from acne scarring.² This laser has an output wavelength of 585 nm or 595 nm, targeting oxyhemoglobin within red blood cells by approximating a major hemoglobin absorption peak at 577 nm. Treatments may be safely performed on all skin types and over hair-bearing areas without fear of follicular destruction. Tolerability of laser treatments is improved with dynamic cooling in the form of cryogen spray. Purpura occurs with extravasated red blood cells, indicating immediate vascular photocoagulation. It is advocated as a clinical endpoint of treatment, lasting a maximum of 7-10 days and resolving without sequelae.

The KTP, or frequency-doubled Nd:YAG laser, has an output wavelength of 532 nm, targeting the first peak of the oxyhemoglobin absorption curve. The penetrative depth of the KTP laser is confined to the papillary dermis of the skin and unsuitable for deeper vessels. KTP lasers generally cause only mild purpura and minimal postinflammatory hyperpigmentation on all skin types.

IPL systems are comprised of noncoherent light (approximately 500-1200 nm) released by a flashlamp within the device, which is then filtered to narrower ranges of wavelengths that simulate the monochromatic nature of true laser light. IPL devices have the benefit of larger spot sizes and a wider range of pulse duration and fluences, thereby allowing for treatment at greater depth and faster speed, coverage of larger surface areas, and concurrent therapy of multiple conditions. However, specificity for treating a single condition may be poor due to absorption competition from multiple tissue targets. Postinflammatory hyperpigmentation in darker skin types may be seen with IPL therapy.³

Nd:YAG lasers may be useful for treating erythema in scars with dilated blood vessels in the deep dermis. New microsecondpulsed Nd:YAG lasers are of benefit for targeting superficial dermal vessels due to the short pulse duration, low fluence, and quick repeated laser bursts.

Brown Scars

Hyperpigmentation of acne scars is common, particularly with darker skin types. Lasers used to treat scar hyperpigmentation include IPL, quality-switched (Q-switched), microsecond-pulsed Nd:YAG, both confluent and fractionated ablative erbium:YAG (Er:YAG), and yttrium-scandium-gallium-garnet (YSGG). Suggested laser settings are presented in Table 3. Concomitant use of lightening creams and sunscreen, as well as sun avoidance, is advocated to further reduce scar contrast with surrounding skin.

IPL devices, with their ability to vary output wavelength, pulse duration, and fluence, can treat several skin conditions including superficial pigmentation.³ Care must be taken to protect the epidermis from overheating, which may cause pigment incontinence and further hyperpigmentation. Parallel cooling (extracting heat from the epidermis during the light pulse) is usually provided through the use of a sapphire window handpiece that generates surface cooling to approximately 5°C.

Q-switched lasers have the unique property of extremely short pulse durations, thereby allowing these devices to target very small pigment cells and particles, such as melanocytes, with minimal competition from the hemoglobin absorption curve. The Q-switched lasers, i.e., ruby (694 nm), alexandrite (755 nm), and Nd:YAG (1064 nm), are useful for treating skin pigmentation.⁴ The endpoint of treatment is mild superficial crusting. Care must be taken to use the lowest energy settings possible to achieve pigment reduction, as too much energy may result in punctate bleeding, cell rupture, scarring, and increased pigmentation.

Microsecond-pulsed Nd:YAG lasers (1064 nm) target both melanin pigment and small blood vessels to reduce erythema and stimulate collagen production without inducing injury to surrounding tissue. This laser may be used for any skin type.⁵

Confluent laser treatment involves laser light striking the entire surface of the skin in a given area, whereas fractionated laser therapy creates microscopic thermal wounds while sparing adjacent tissue over the targeted site.⁶ Confluent ablative Er:YAG (2940 nm) and YSGG (2790 nm) lasers have tremendous water absorption capacity, translating into vaporization of surface tissue with minimal collateral heating, limited damage to surrounding tissue, and reduced risk for further hyperpigmentation.⁷ These lasers ablate approximately 30 microns of the epidermis, inducing exfoliation and improving superficial hyperpigmentation. Test spots should be performed when using any ablative laser on darker skin.

Fractionated ablative Er:YAG and YSGG lasers release light energy at high peak power to create channels in skin tissue.⁶ These channels are physically ablated, leaving true air channels that allow removal of surrounding pigment via transepidermal elimination.

White Scars

Ultraviolet (UV) light stimulates melanogenesis in areas where melanocytes are intact. UV light can stimulate the migration of melanin-producing cells to melanocyte-deficient areas, increasing pigment in these regions.¹ Excimer (excited dimer) lasers have a wavelength in the UV range (308 nm), providing concentrated melanin stimulation to white scars.

Fractionated ablative lasers (Er:YAG, YSGG, and carbon dioxide) create air channels that ultimately contract to reduce the surface area of the white scars, making them appear smaller in diameter.⁷

Laser Options Targeting Skin Texture

Hypertrophic Scars

When evaluating a scar that exhibits both color and elevation defects, it is preferrable to treat the texture before addressing the color, because both vascular-targeting and pigment-targeting lasers provide optimal penetration through scars that are flat and soft.¹ Topical corticosteroids, alone or in combination with intralesional corticosteroids, used concomitantly with laser therapy are recommended to achieve softening and flattening of elevated scars.

Fractionated ablative lasers (Er:YAG, YSGG, and carbon dioxide) can help soften elevated scars by ablating channels of condensed collagen that contribute to the scar’s thickness and firmness.⁷ Fractionated ablative and nonablative lasers must be used with caution in softening elevated scars because their collateral thermal damage has the profibrotic potential to further thicken and harden scar tissue. As an aside, fractionated ablative laser treatment may also improve topical drug delivery by providing a theoretical route for transepidermal drug penetration via ablative channels created by the laser.⁸

Confluent ablative laser treatment (Er:YAG, YSGG, and carbon dioxide) has been shown to decrease the size and thickness of scar recurrence after surgical excision, provided laser therapy is performed at the base of the excised area immediately after surgical removal.⁹ Repeated pulses to the base of the excised tissue establish hemostasis and thin eschar formation. A viscous moisturizer (e.g., petrolatum) under occlusion should be applied for 3 days post-treatment, followed by a nonviscous moisturizer until the skin re-epithelializes. At the first sign of recurrent scar formation, topical corticosteroids or imiquimod are suggested to prevent progression of fibrosis.

Atrophic Scars

Depressed (Icepick and Boxcar) Scars

In treating icepick and boxcar scars, the goals are to soften the edges between the indentation and surrounding normal skin, and stimulate collagen production within the depressed area.

Resurfacing of depressed facial scars with confluent ablative Er:YAG, YSGG, and carbon dioxide lasers causes thermal injury to the epidermis and a portion of the dermis, resulting in vaporization, collagen injury, and re-epithelialization. In particular, Er:YAG lasers are highly selective for water, therefore leading to maximal tissue vaporization and reduced residual thermal damage. These devices decrease post-treatment erythema, are safe for use on darker skin types, and preferred for superficial atrophic scars due to shorter recovery times. The production of increased dermal fibrotic elements through greater collateral thermal heating capacity is enhanced with use of the YSGG and carbon dioxide lasers, making them more beneficial for deeper scars. Ablation typically requires 1 pass with the carbon dioxide laser at 300 mJ, 1-2 passes with the YSGG laser at 3.5 J/cm², and 2-3 passes with the Er:YAG laser at 5 J/cm². Deep treatment with the Er:YAG laser typically results in bleeding due to its limited effects on blood vessel photocoagulation.

Confluent nonablative laser treatment such as PDL, IPL, microsecond-pulsed, and Q-switched Nd:YAG lasers, as well as a variety of lasers operating in the near infrared spectrum (e.g., 1320 nm, 1440 nm, 1450 nm, 1540 nm, and 1550 nm) target water within the deeper aspects of the dermis more efficiently, thereby creating bulk heating and more collagen stimulation, referred to as subsurfacing.¹⁰ Subsurfacing may be painful, often requiring systemic analgesia.

Fractionated ablative laser treatment creates microscopic channels of thermal injury on the skin, causing skin tightening and smoothening through ablation and re-epithelialization, as well as elevation of the floor of depressed scars through collagen remodelling.¹¹ Ablative fractional resurfacing is gentler on the skin compared with confluent resurfacing and can be safer for darker skin types; however, test spots should be performed before attempting laser resurfacing on this subset of patients. Er:YAG laser treatment is preferred for small diameter icepick and boxcar scars and for larger diameter defects in darker skin types; fractionated YSGG and fractionated carbon dioxide lasers are favored for icepick and boxcar scarring in white-skinned individuals.¹

Nonablative fractional resurfacing lasers produce wavelengths in the mid-infrared range and include fractionated 1440 nm, 1450 nm, 1540 nm, and 1550 nm lasers. Nonablative lasers create zones of microthermal skin injury, requiring minimal downtime. However, the treatment process may be painful to the point of requiring oral analgesia.

Depressed (Rolled) Scars
With rolled acne scarring, treatment success depends on the degree to which the skin is bound down at the base of the scar. If the skin contour is tightly tethered, it is advisable to perform surgical subcision before other treatments to loosen the surface adhesion and dampen the tethering effect.¹² Care should be taken to wait at least 2 weeks post-filler placement before attempting fractionated ablative or nonablative laser resurfacing to avoid disruption of filler placement.

Both confluent and fractionated nonablative laser treatments and fractionated ablative laser therapy may be used for rolled scars. In all cases, it is important for the laser energy to reach deeper components of the skin in order to stimulate collagen remodelling and weaken tethering adhesions.

Conclusion

Lasers are an important treatment option in the management of acne scarring as they can target both color and textural abnormalities. It is essential to understand both the pathophysiology of these skin defects as well as the distinct mechanisms and clinical effects of each laser. Such an appreciation enables selection of the most appropriate device and technique in order to optimize outcomes for a given patient.

References

1. Rao J. Treatment of acne scarring. Facial Plast Surg Clin North Am 2011 May; 19(2):275-91.
2. Alster TS, McMeekin TO. Improvement of facial acne scars by the 585 nm flashlamp-pumped pulsed dye laser. J Am Acad Dermatol 1996 Jul;35(1):79-81.
3. Ho SG, Chan HH. The Asian dermatologic patient: review of common pigmentary disorders and cutaneous diseases. Am J Clin Dermatol 2009; 10(3):153-68.
4. Kim S, Cho KH. Treatment of facial postinflammatory hyperpigmentation with facial acne in Asian patients using a Q-switched neodymium-doped yttrium aluminum garnet laser. Dermatol Surg 2010 Sep;36(9):1374-80.
5. Min SU, Choi YS, Lee DH, et al. Comparison of a long-pulse Nd:YAG laser and a combined 585/1,064-nm laser for the treatment of acne scars: a randomized split-face clinical study. Dermatol Surg 2009 Nov;35(11):1720-7.
6. Tierney EP, Hanke CW. Review of the literature: Treatment of dyspigmentation with fractionated resurfacing. Dermatol Surg 2010 Oct;36(10):1499-508.
7. Ross EV, Swann M, Soon S, et al. Full-face treatments with the 2790-nm erbium:YSGG laser system. J Drugs Dermatol 2009 Mar;8(3):248-52.
8. Haedersdal M, Sakamoto FH, Farinelli WA, et al. Fractional CO(2) laserassisted drug delivery. Lasers Surg Med 2010 Feb;42(2):113-22.
9. Morosolli AR, De Oliveira Moura Cardoso G, Murilo-Santos L, et al. Surgical treatment of earlobe keloid with CO2 laser radiation: case report and clinical standpoints. J Cosmet Laser Ther 2008 Dec;10(4):226-30.
10. Bhatia AC, Dover JS, Arndt KA, et al. Patient satisfaction and reported longterm therapeutic efficacy associated with 1,320 nm Nd:YAG laser treatment of acne scarring and photoaging. Dermatol Surg 2006 Mar;32(3):346-52.
11. Hedelund L, Moreau KE, Beyer DM, et al. Fractional nonablative 1,540-nm laser resurfacing of atrophic acne scars. A randomized controlled trial with blinded response evaluation. Lasers Med Sci 2010 Sep;25(5):749-54.
12. Alam M, Omura N, Kaminer MS. Subcision for acne scarring: technique and outcomes in 40 patients. Dermatol Surg 2005 Mar;31(3):310-7.

Division of Dermatology and Cutaneous Sciences, University of Alberta, Edmonton, AB

Introduction

Scarring, whether from planned surgical procedures or a sequela of inflammatory conditions such as acne, striae, burns or trauma, is often associated with considerable emotional impact. As a result, patients often seek the advice of physicians regarding scar revision. This paper focuses on a comprehensive and practical approach to classifying and managing scars in terms of colour and texture, and discusses topical treatments accessible to family physicians in more detail.

Scar Formation

• Scars are part of the normal healing process after cutaneous injury. The process is part of the remodeling phase of wound repair, following the phases of hemostasis and inflammation.
  • The wound repair phase involves re-epithelialization, neocollagenesis, neovascularization, and pigment deposition.
• Scar formation can take up to months to fully realize the severity and extent. Once the skin re-epithelializes (i.e., wound closure is established and intact), the structural integrity of the injured site should be amenable to most scar treatment protocols, which may then be initiated.
• Patients undergoing scar treatment should be cautioned to avoid direct sun exposure whenever possible to prevent excess vascular or pigment deposition in the repaired tissue.

Classification of Scars

• All scars can be categorized according to both colour and texture (Tables 1 and 2). Both of these components must be considered and addressed independently to attain improvement of the visible quality of the scar.¹
• Active inflammation must first be resolved before determining the correct classification of a scar. Inflammation is characterized by a purple discoloration, tenderness, and focal elevation of the skin.

Treatment Options

• Every scar can be broken down and categorized according to colour and texture, both of which must be addressed independently to improve the scar’s appearance.
• This paper will focus mainly on topical therapies used to improve the appearance of scars, although tables with comprehensive options for scar revision are presented.

Treatment Options Targeting Scar Colour

Table 3 lists comprehensive options targeting scars with abnormal colour. Topical therapies within each category will be discussed in more detail.

• Cosmetic camouflage using makeup creams and powders in a patient’s normal skin tone will help conceal the abnormal scar colour.
• Topical vasoconstrictors such as oxymetazoline, epinephrine or cocaine may be used to constrict blood vessels, decreasing a scar’s redness.
• Lightening creams containing hydroquinone, azelaic acid or kojic acid may be helpful to decrease brown hyperpigmentation.
• Hydroquinone 2%-5% alters conversion of dopa to melanin by inhibiting the activity of tyrosinase. Side-effects include allergic and irritant contact dermatitis, post-inflammatory hyperpigmentation, and cutaneous ochronosis. Animal studies have shown teratogenicity and induction of renal adenoma, but these findings have not been seen in humans.⁴
• Kojic acid 2% is a tyrosinase inhibitor produced by fungi such as Aspergillus oryzae. Side-effects may include irritation.
• Azelaic acid 15% (Finacea®) is a tyrosinase inhibitor and may be antiproliferative and cytotoxic towards melanocytes. Side-effects include erythema, scale, burning, and pruritus.
• Topical retinoids such as tretinoin 0.01%-0.1% (Retin-A Micro®, Stieva-A®), adapalene 0.1%-0.3% (Differin®, Differin® XP™), and tazarotene 0.1% (Tazorac®) may reduce brown pigmentation by inhibiting tyrosinase transcription, interrupting synthesis of melanin. Side-effects include xerosis, erythema, skin peeling, and sun sensitivity.
• Chemical peels involve the application of a chemical agent on the skin, causing controlled destruction of parts of the epidermis and dermis, potentially decreasing hyperpigmentation. This leads to exfoliation and later epidermal and dermal regeneration. Common chemical peel agents include alpha hydroxy acids (glycolic acid, lactic acid), beta hydroxy acids (salicylic acid) and trichloroacetic acid. Depth of the chemical peel varies depending on the chemical agent chosen. This should be done in consultation with a dermatologist. Side-effects may include pigmentary changes, infection, erythema, and scarring.⁵
• Topical calcineurin inhibitors such as tacrolimus 0.03%- 0.1% (Protopic™) and pimecrolimus 1% (Elidel®) have immunomodulatory effects that may help with repigmentation of white scars. Side-effects include burning and pruritus. Although the US FDA has a black box warning on these therapies regarding risk of lymphoma and skin cancer development, clinical evidence in humans has not suggested causality.⁶
• Silicone gels have been shown to reduce the redness of scars.⁷

Treatment Options Targeting Scar Texture

Table 4 lists comprehensive options targeting scars with abnormal texture. Topical therapies within each category will be discussed in more detail.

• Elevated scars
  • Strategies for prevention of hypertrophic and keloid scars during surgical procedures include minimizing tension and everting wound edges during closure, avoiding anatomic locations more prone to hypertrophic or keloid scars such as across joints, angle of the jaw, shoulders, mid-chest, and upper back, placing incisions in areas that follow skin creases, and achieving efficient hemostasis.²
  • Very high potency topical corticosteroids such as clobetasol propionate 0.05% (Dermovate®) or halobetasol propionate 0.05% (Ultravate®) ointments or creams may be used for minimally hypertrophic scars. They are usually ineffective with more hypertrophic or keloid scars.
  • Intralesional corticosteroids such as triamcinolone 10-40 mg/mL (Kenalog®) may help decrease the elevation seen in hypertrophic and keloid scars.
  • Corticosteroids act to suppress the immune responses as well as diminish collagen synthesis, inhibit fibroblast growth, and enhance collagen degeneration. Adverse effects of topical and intralesional corticosteroids include hypopigmentation around the injection site, dermal atrophy, telangiectasia, widening of the scar, and delayed wound healing.
  • Topical imiquimod (Aldara™) is an immunomodulator that stimulates interferon-α, inducing collagen breakdown. In off-label use, studies have shown that nightly application of imiquimod to keloidal scars improves cosmetic appearance over an 8-week period. Adverse effects of imiquimod include erythema and irritation.^8,9
  • Over-the-counter (OTC) topical silicone gel products (e.g., Kelo-cote® and Dermatix™ Ultra) applied twicedaily for 4 months have also shown beneficial effects on both treatment and prevention of hypertrophic and keloid scars.
    • The postulated mechanism of action involves reducing transepidermal water loss (TEWL), enhancing hydration, and decreasing activation of dermal fibroblasts through inhibition of cytokine production. These combined processes normalize collagen deposition and diminish scar hypertrophy.¹⁰
    • Silicone gel may be used for existing and new hypertrophic and keloid scars resulting from burns, surgical procedures, trauma, and wounds. Treatment has been shown to reduce redness, hardness, elevation, itching, and pain.^7,10
    • For post-surgical or -trauma treatment, it may be considered a first-line prophylactic strategy in the prevention and development of hypertrophic or keloidal scars.¹¹
    • Both gel and sheet products have comparable efficacy, but for greater practical contouring of flexural areas gels may be preferred, as optimal occlusion is achieved by close apposition of the product with the scar.¹⁰
    • The gel is well-tolerated with no common adverse effects.⁹
    • Spray formulations are especially useful on sensitive or larger skin areas.
    • Preparations containing silicon dioxide dry rapidly, allowing for cosmetics or sunscreen application over the silicone treatment.
  • Occlusive dressings such as pressure dressings and silicone gel sheeting (Cica-Care™) are commonly used to treat burn scars. The mechanism of action is through mechanical compression and reduction in oxygen tension, along with silicone’s effects discussed above. Pressure dressings must maintain a pressure of 25-40 mmHg, up to 24 hours a day, for 9-10 months for best results. Silicone gel sheets must be used 24 hours a day for 3-4 months.^8,9
  • Topical onion extract (Mederma®) and vitamin E are widely used OTC products for scar revision, but clinical effects were not found to be significant over placebo.⁹
• Depressed scars
  • Cosmetic camouflage using makeup creams and powders in a patient’s normal skin tone will help fill in and conceal dark shadows created by the scar’s depressions.
  • Chemical peels (see treatments for scar colour) serve to exfoliate and resurface the skin’s surface, decreasing the relative depth of depressed scars.

Conclusion

• All scars can be classified by their colour and texture. A multimodal approach targeting both aspects is essential to optimal scar management.
• Many topical therapies are available to family physicians to improve scar appearance. Failing this, referral to a dermatologist for further topical, physical, light, laser, or surgical interventions for scar revision should be considered.

References

1. Rao J. Facial Plast Surg Clin North Am 19(2):275-91 (2011 May).
2. Wolfram D, et al. Dermatol Surg 35(2):171-81 (2009 Feb).
3. Jacob CI, et al. J Am Acad Dermatol 45(1):109-17 (2001 Jul).
4. Nordlund JJ, et al. J Eur Acad Dermatol Venereol 20(7):781-7 (2006 Aug).
5. Khunger N. Indian J Dermatol Venereol Leprol 74 Suppl:S5-12 (2008 Jan).
6. Patel TS, et al. Am J Clin Dermatol 8(4):189-94 (2007).
7. Sepehrmanesh M. Komp Dermatologie 1:30-2 (2006).
8. Juckett G, et al. Am Fam Physician 80(3):253-60 (2009 Aug 1).
9. Reish RG, et al. J Am Coll Surg 206(4):719-30 (2008 Apr).
10. Mustoe TA. Aesthetic Plast Surg 32(1):82-92 (2008 Jan).
11. Mustoe TA, et al. Plast Reconstr Surg 110(2):560-71 (2002 Aug).

1. Forest Research Institute, Jersey City, NJ, USA
2. Queen’s University, Kingston, ON, Canada
3. Division of Dermatology, University of Alberta, Edmonton, AB, Canada

ABSTRACT
A vast spectrum of topical anti-acne agents has emerged in response to new insights that have been gained through the understanding of disease pathophysiology and the need for clinicians to adopt an individualized therapeutic approach. Because topical agents are most commonly used for acne management, this article reviews some novel vehicle delivery advances that are poised to further enhance the efficacy of topical acne formulations, and/or offer the possibility of simplified dosing regimens that may improve treatment outcomes.

Key Words:
acne vulgaris, drug administration, topical therapies

When it comes to the delivery of a drug to a specific site, topical formulations are probably among the most challenging products to develop. An effective topical formulation needs to provide a stable chemical environment in a suitable dispensing container in order to accommodate multiple compounds that may have different, if not incompatible, physicochemical characteristics. Once applied, a topical formulation must interact with the skin environment, which can influence the rate of the release of the compound(s) in order to achieve adequate skin absorption. The excipients themselves will exert additional physical effects on the skin, such as drying, occluding, or moisturizing. Research and technology have brought a better understanding of the physics, chemistry, pharmacodynamics, and pharmacokinetics for drugs used to treat acne. These insights have resulted in new delivery systems that are capable of enhancing the efficacy, tolerability, and cosmetic acceptability of topical formulations.^1-3

Formulary Considerations

The challenge of developing a successful topical product stems from the several requirements that a formulation must meet:

1. Container Selection and Product Stability

Depending on the properties of the combined ingredients, a dispensing container will be chosen (i.e., tube, jar, can, etc.) to provide a stable physicochemical environment that protects the active compound(s) from chemical degradation. The formulation can be a liquid or semi-solid, monophasic or multiphasic (e.g., oil-in-water or water-in-oil); it is largely dependent on the characteristics of the active compound(s) and on the condition of the skin to be treated.

2. Skin Penetration

Once the product is applied on the skin, a complex interaction occurs between the formulation, the active compounds, and the skin itself. The penetration of the active compound(s) into the skin follows Fick’s first law of diffusion, which describes the transfer rate of solutes as a function of the concentration of the various ingredients, the size of the treatment surface area, and the permeability of the skin. However, the skin’s permeability can be influenced by many factors, such as the drying, moisturizing, or occluding effects of the excipients in the formulation, which, in combination, can modulate the release of the product at the treatment site. In acne, the site of action is inside the pilosebaceous unit and, therefore, an efficacious anti-acne formulation should facilitate the penetration of the active compound(s) into this extremely lipophilic environment.

3. Cosmetic Acceptability

In today’s self-image conscious world, patients are looking for topical products that are not only safe and effective, but also cosmetically acceptable and easy to apply. This is especially true in acne, where the esthetic aspect is one of the primary reasons why patients seek dermatologic consultation. Moreover, acne patients are mainly comprised of teenagers or young adults, and therefore, products that offer convenience and are minimally disruptive to daily routines increase the level of compliance, and ultimately, the efficacy of the topical therapy. For example, vehicle considerations for prescribing should take into account the application of the drug on large, hairy surfaces like the chest and the back. This may require formulations that spread easily, or in the case of facial acne, the ideal formulation should leave minimal residue or oiliness.

Current Topical Therapy for Acne Vulgaris

Topical treatment is the most common and popular way to manage acne and there are a variety of therapies available (Table 1) that are frequently administered in combination in order to target concurrent multiple pathogenic factors. In general, topical monotherapy is indicated for mild-to-moderate acne, such as comedonal and/or papular variants; combination therapy is reserved for more severe or refractory disease.

Novel Topical Delivery Systems

Aerosol Foams

Aerosol foams have become an increasingly popular type of topical formulation for a variety of skin conditions including acne vulgaris. The vehicle base of the foam can have a liquid or semi-solid consistency that shares the same physicochemical characteristics of conventional vehicles like creams, lotions and gels, but it maintains desirable properties such as moisturizing/ fast-drying effects, or higher drug bioavailability. The aerosol base is dispensed through a gas-pressurized can that discharges the foam. The product characteristics (i.e., texture, bubble size and thickness, viscosity, density, persistence, stability, and spreadability) are determined by the type of formulation and the dispensing container that are selected to suit the specific treatment needs. In acne, foams may be preferred for application on large hairy surfaces (e.g., chest and back) or on the face as cleansers, because they are easier to apply.

Liposomes

Liposomes are frequently used as vehicles in pharmaceuticals and cosmetics for a controlled and optimized delivery to particular skin layers. Liposomes are spherical vesicles whose membrane consists of amphiphilic lipids (i.e., lipids that are hydrophilic on one side and lipophilic on the other side) that enclose an aqueous core, similar to the bilayer membranes of living cells. Because liposomes offer an amphiphilic environment, they may encapsulate hydrophilic substances in their aqueous core and lipophilic substances in their lipid bilayer. This unique dual release capability enables the delivery of 2 types of substances once they are applied on the skin; each differs in its effects on skin permeability, which may enhance the desired therapeutic benefit.^4,5

Nanoemulsions

Nanoemulsions are a class of emulsions (i.e., water-in-oil or oil-in-water formulations) that are characterized by the dispersion of very small-sized droplets when mixed. Nanoemulsions are not formed spontaneously, as they require unique thermodynamic conditions, specialized manufacturing processes, and specific surfactants that can stabilize the nano droplets. Nanoemulsions are suitable for the transport of lipophilic compounds into the skin and, therefore, they may be an ideal vehicle for use in acne to increase the penetration of the active compounds inside the lipophilic environment of the pilosebaceous unit. In addition, nanoemulsion particulates will not clog the pores and they can produce additional therapeutic effects, such as increased skin hydration and viscoelasticity.⁶

Polymers

Polymers are large molecules consisting of repeating structural units, or monomers that are connected by covalent chemical bonds. These compounds serve as the building blocks of natural (e.g., paper and amber), biological (e.g., proteins and nucleic acid), or synthetic (e.g., plastics and polyethylene) materials. Today, applications for synthetic polymers can be found in nearly every industry, and their versatility has given rise to technological advancements within the pharmaceutical sector that address a variety of medical needs. For example, in dermatology, there are new acrylic-acid polymers that turn into a gel in the presence of water by trapping water into microcells. Inside these aqueous microcells, hydrophilic compounds can remain in a solution, whereas non-hydrophilic compounds may be dispersed in suspension. The result is a stable gel-like formulation that is easy to use and releases the active compound(s) once they are applied on the skin. Moreover, these polymer-based gels can be mixed with other excipients, such as moisturizers and emollients, to provide additional clinical benefits. Recently introduced anti-acne formulations that combine clindamycin 1% with benzoyl peroxide 5% (Duac®, Stiefel Laboratories; BenzaClin®, Dermik) utilize this novel polymer-based gel technology that exhibits efficacy and excellent tolerability.⁷

Microsponges

Microsponges are biologically inert particles that are made of synthetic polymers with the capacity to store a volume of an active agent up to their own weight. Furthermore, the particles serve to protect the entrapped active compound from physical and environmental degradation. The microsponge technology can be utilized in a variety of formulations, but is more frequently manufactured as gels. Once applied on the skin, microsponges slowly release the active agent(s).

Emulsifier-free Formulations

Emulsifier-free formulations are also a growing area of development for dermatologic and cosmetic products. Most skin care products are emulsions, i.e., a mixture of 2 or more materials that are not miscible with each other; as such, according to the second law of thermodynamics, they are inherently unstable. As a result, they require the addition of surfactants (“emulsifiers”) that stabilize the formulation to guarantee an adequate shelf life. Furthermore, once these surfactant agents are applied on the skin, they tend to emulsify and remove the natural lipids of the epidermis. Consequently, the pharmaceutical industry has been developing surfactant-free emulsions as alternatives to conventional formulations by using stabilizers, such as polymeric emulsifiers or solid particles, in order to yield sufficiently stable products with a cosmetically pleasant appearance.

Fullerenes

Fullerenes are molecules composed entirely of carbon that resemble a hollow sphere. Rouse, et al., showed that once fullerenes come into contact with the skin, they migrate through the skin intercellularly, as opposed to moving through cells.8 Therefore, a fullerene could be used to “trap” active compounds and then release them into the epidermis once they are applied on the skin. Moreover, fullerenes, themselves, are thought to be potentially potent antioxidants. Data are reported in the literature showing that fullerenes are well tolerated and they hold substantial promise in dermatologic and cosmetic applications.^9,10

Conclusion

Much progress has been made to improve the performance of topical anti-acne care products in recent years. New excipients, refined processing techniques, and a better knowledge of the physicochemical properties of vehicles and drugs have led to the development of new delivery systems that may result in more advanced anti-acne therapies. Well controlled clinical trials will be required to confirm the clinical benefits of these new formulations in terms of efficacy, tolerability, compliance, and cosmetic acceptability.

References

1. Date AA, Naik B, Nagarsenker MS. Novel drug delivery systems: potential in improving topical delivery of antiacne agents. Skin Pharmacol Physiol 19(1):2-16 (2006).
2. Katz MA, Cheng CH, Nacht S. Methods and compositions for topical delivery of benzoyl peroxide. US Patent No 5,879,716 (1999 Mar 9).
3. Ting WW, Vest CD, Sontheimer RD. Review of traditional and novel modalities that enhance the permeability of local therapeutics across the stratum corneum. Int J Dermatol 43(7):538-47 (2004 Jul).
4. Schafer-Korting M, Korting HC, Ponce-Poschl E. Liposomal tretinoin for uncomplicated acne vulgaris. Clin Investig 72(12):1086-91 (1994 Dec).
5. Brisaert M, Grabriels M, Matthijs V, et al. Liposomes with tretinoin: a physical and chemical evaluation. J Pharm Biomed Anal 26(5-6):909-17 (2001 Dec).
6. Yilmaz E, Borchert HH. Effect of lipid-containing, positively charged nanoemulsions on skin hydration, elasticity and erythema–an in vivo study. Int J Pharm 307(2):232-8 (2006 Jan 13)
7. Zerweck C, Grove G, Fraser JM. Moisturization potential of two acne gels containing 5% benzoyl peroxide and 1% clindamycin. Presented at: AAD Summer Academy Meeting, July 26-30, 2006, San Diego, CA; P100.
8. Rouse JG, Yang J, Ryman-Rasmussen JP, et al. Effects of mechanical flexion on the penetration of fullerene amino acid-derivatized peptide nanoparticles through skin. Nano Lett 7(1):155-60 (2007 Jan).
9. Huczko A, Lange H. Fullerenes: experimental evidence for a null risk of skin irritation and allergy. Fullerene Sci Technol 7:935-9 (1999).
10. Fumelli C, Marconi A, Salvioli S, et al. Carboxyfullerenes protect human keratinocytes from ultraviolet-B-induced apoptosis. J Invest Dermatol 115(5):835-41 (2000 Nov).

Division of Dermatology and Cutaneous Sciences, University of Alberta, Edmonton, Canada

The Disease

• Acne vulgaris is a complex skin disorder of the pilosebaceous unit affecting almost all people at some point in their lifetime, especially among people aged 15–24 years.
• Acne can be physically and emotionally scarring, causing significant psychosocial morbidity and reducing self esteem.
• All forms of acne involve one or more of these pathophysiologic factors:
  • Hyperkeratinization of the follicular epithelium with comedone formation
  • Increased sebum production
  • Bacterial proliferation of Propionibacterium acnes (P. acnes)
  • Local immune hypersensitivity causing inflammation.
• Acne may be classified according to predominance of specific skin lesions:
  • Comedonal (non-inflammatory) – mild
  • Papular (inflammatory) – mild-to-moderate
  • Pustular (inflammatory) – moderate
  • Nodulocystic – severe
• This order also follows increasing severity, with cutaneous scarring as the ultimate result.

Make a Diagnosis

Existing therapies for acne can be divided into one of the following categories:

1. Physical or mechanical modalities
   • Includes comedone extraction and other forms of acne surgery, chemical peels, and microdermabrasion.
2. Light-based therapy
   • Includes laser treatment, the usage of noncoherent light sources and photodynamic therapy
3. Topical or systemic medications
   • Includes retinoids, antibiotics, benzoyl peroxide, and hormonal therapy.
   • Two major categories based on primary mechanism of action:
     • Antimicrobials: reduce P. acnes growth
     • Comedolytics: reduce and/or prevent comedone formation
4. Formulations (i.e., gel vs. cream) may decrease sebum production.

Combination Therapy

• It is necessary to address all pathophysiologic factors of acne for effective treatment.
• Most medications do not act against all four major pathophysiologic features of acne.
• Combination therapy with a few logically chosen agents has a greater chance of addressing more pathophysiologic factors in acne development.
• Other benefits of combination therapy:
  • Some combinations have demonstrated synergy (i.e., the combined effect is better than that seen by the individual agents).
  • Potential to decrease individual drug doses and exposure times
  • Potential to reduce and prevent antibiotic resistance
  • Potential cost-savings by reducing the use of expensive medications.

Recommendations for Treatment

• Topical and systemic agents are the mainstay of acne therapy and maintenance.
• Physical and light-based modalities should be used as second-line or adjunctive therapy.
• Hormonal therapies may be used as second choice or adjunctive therapy in women with contributing androgenic factors for acne.
• Choose agents with different, but complementary mechanisms of action (e.g., antimicrobial + comedolytic agent).
• Tolerability is related to compliance; choose agents with a good tolerability profile.
• Topical retinoids alone, or in combination with other medications, should be considered first-line therapy for both inflammatory and non-inflammatory acne.
  • Includes adapalene, tazarotene, tretinoin, and tretinoin gel microsphere.
  • Use early for best results.
  • Inhibits microcomedone formation, which is the precursor lesion in acne.
  • Clears mature comedones.
  • Improves inflammatory lesions.
  • Has synergistic effects with oral or topical antibiotics.
  • Induces remission of acne in maintenance therapy.
• Antibiotics are adjunctive therapy in inflammatory acne.
  • Oral antibiotics include minocycline, doxycycline, tetracycline, trimethoprim-sulfamethoxazole, and erythromycin.
  • Topical antibiotics include clindamycin and erythromycin.
  • Use only as long as necessary and combine with topical retinoids.
  • Antibiotics should not be used as monotherapy in order to prevent resistance and target more pathophysiologic factors.
  • Minimize duration of therapy to prevent resistance and side-effects.
  • If there is need to continue antimicrobials, use benzoyl peroxide or benzoyl peroxide/antibiotic combinations.

Recommendations for Maintenance

Acne Medications and Pregnancy

Some acne medications must not be used by women who
are pregnant or lactating, or who may become pregnant
because of the potential harm to a fetus or breastfed infant.
These medications include:

• Hormonal therapy
  • Estrogen and derivatives, flutamide, spironolactone

  Oral and topical isotretinoin

  • Established teratogenicity

  Oral tetracyclines

  • Tetracycline, doxycycline, minocycline
  • Dental discoloration noted

  Oral sulfonamides

  • Trimethoprim-sulfamethoxazole
  • Theoretical risk of teratogenicity, anemia, jaundice

  Topical retinoids

  • Adapalene, tazarotene, tretinoin
  • Theoretical risk of teratogenicity

Conclusion

Acne vulgaris remains a therapeutic challenge, in large part due to its multifactorial pathophysiology. Evidence for improved and quicker efficacy with safety and longer remission has been noted with combination therapies.