Should isotretinoin be stopped prior to surgery? A Critically Appraised Topic
Authors: C.I. Wootton, R.P.E. Cartwright, P. Manning, H.C. Williams
Journal: British Journal of Dermatology (2014)

In patients taking isotretinoin, is postoperative skin wound healing impaired in comparison with similar people not taking isotretinoin? A 17-year-old boy sustained a sports injury to his right shoulder, resulting in dislocation. He was also taking isotretinoin 20 mg daily, which had been commenced 6 months previously for moderately severe acne. The patient had chosen to keep the isotretinoin dose low as he was undergoing school examinations and did not want any potential side-effects to disrupt his performance. The patient's orthopaedic consultant suggested that arthroscopic stabilization and repair of the capsular labral structures was the best treatment option for the shoulder injury. The patient's father, a general practitioner (GP), asked the supervising dermatologist whether his son should continue isotretinoin in the pre- and postsurgical period. Atypical or keloidal scarring following skin procedures such as laser treatment and dermabrasion has been reported in patients taking isotretinoin.1, 2 Prior to isotretinoin initiation, patients are often warned of the possible risk of abnormal scarring following such procedures, and this risk is also mentioned in the patient information leaflet for isotretinoin supplied by the manufacturers.3 Whether the risk of abnormal scarring extends to other forms of elective or emergency surgery is less clear. People taking isotretinoin tend to be young, otherwise healthy individuals who rarely require surgical procedures apart from for sports or road accidents. However, spontaneous keloid formation following isotretinoin therapy has been described in several case reports.4, 5 The retinoids have been shown to have a modulatory effect on connective tissue metabolism, including the suppression of collagenase,6 which may lead to excessive accumulation of collagen and hence keloid formation. We contacted our hospital's medicines information officer and the medical information officer for Roche Products Ltd, who manufacture isotretinoin, for pharmacovigilance information regarding impaired wound healing with isotretinoin. We also searched PubMed using the terms ‘isotretinoin’ AND ‘surgery’ AND ‘wound healing’ from inception until 18 December 2012. Using the hierarchy of quality of evidence,7 we looked for meta-analyses of adverse effect data, followed by randomized controlled trials, cohort studies, case series, case reports, pharmacovigilance data and animal studies. In total 329 articles were found, 29 of which were considered relevant to the clinical question. Within the 29 articles highlighted, 19 referred specifically to dermabrasion or laser procedures. While these are not the type of surgical procedures involved in our clinical question, we thought it important to include these data to ensure a comprehensive review. No pharmacovigilance data were found. Only 18 papers of the 29 originally highlighted provided any clinical data. The retrieved studies included one randomized controlled trial, seven cohort studies, seven case series and four case reports (one study reported both a case report and a case series)1 (Table 1). In addition, four experimental studies were identified; these have not been considered in this article. Bruno et al.8 performed a randomized control trial using two different dosages of isotretinoin (low dose 0·10–0·22 mg kg−1; high dose 0·75–1·21 mg kg−1) for the treatment of moderate-to-severe cystic acne. Overall, 94 patients were randomly divided into the two dosage groups and then monitored regularly for adverse effects during their 16-week treatment course. Two patients in the trial undergoing otolaryngological surgery had their isotretinoin stopped 2 days prior to surgery and for 1 week postoperatively. Both patients recovered normally from the surgery. A separate patient reported slow wound healing while on isotretinoin, but no additional information is provided. Interpretation of the data reported in this study is difficult due to the very small numbers and lack of a suitable control group. Allen and Rhee9 report three patients in whom isotretinoin was prescribed for acne within 2 years following a rhinoplasty procedure. All three developed nasal tip deformities within 6 months of isotretinoin initiation, all of which required subsequent surgical correction. All three patients were identified from the same surgeon's logbook. No patients were reported who took isotretinoin prior to or during the procedure, and no controls were described. Griffiths10 report a single case of a patient who underwent pilonidal sinus excision during isotretinoin treatment for acne. No complications occurred with wound healing in this case. Very little information is provided about this case and it is difficult to draw any conclusions from a single case report. Picosse et al.11 performed a prospective cohort study involving 10 patients (four women, six men), assessing outcomes after chemical peels and dermabrasion for acne scarring. All of the patients had completed treatment with isotretinoin for their acne 1–3 months previously, with a minimum accumulated dose of 122 mg kg−1 per patient. Four patients had a Fitzpatrick skin type of IV or V and these patients received hydroquinone 4% cream 15 days before dermabrasion. All of the patients received antibacterial and antiviral prophylaxis before treatment. Treatment consisted of a medium-depth chemical peel with Jessner solution and 35% trichloroacetic acid to the entire face followed by manual dermabrasion with sterile water sandpaper to the scarred areas. Clinical evaluation and photographs were conducted at 6 months postprocedure. As it is not stated, it is assumed that these assessments were unblinded and no validated assessment tool was used. Five patients received low-potency topical corticosteroids due to the presence of erythema on day 7; this was used three to five times per week for 3–6 weeks. No hypertrophic or keloid scarring was found in any of the treated patients and no differences were noted in re-epithelization compared with the authors’ current results in patients not treated with isotretinoin, or who had discontinued the drug 6 months prior to treatment. Bagatin et al.12 report a prospective cohort study of seven patients (six women and one man), two with Fitzpatrick skin type V. The patients were on isotretinoin treatment for their acne. All of the patients had been taking the drug for a minimum of 1 month, with a dose range of 10–40 mg per day. A 1-cm2 area of depressed scarring was selected on each patient and manual dermabrasion with a diamond fraise was performed. Clinical evaluation and photographs were taken regularly over a 180-day follow-up period, but no further details of how these assessments were performed are provided; it is therefore assumed that these assessments were unblinded and no validated assessment tool was used. Satisfactory results of acne scar revision were found, with no complications and no hypertrophic or keloid scarring. No differences were noted between the study patients currently receiving isotretinoin therapy and other patients previously treated by the authors who had never taken isotretinoin, or who had discontinued treatment with isotretinoin > 6 months prior to dermabrasion. Roenigk et al.13 present a case series of nine patients (seven men and two women) who had full-face dermabrasion for acne scarring. Five were either still taking isotretinoin at the time of undergoing dermabrasion or had just completed the treatment course, and four had discontinued isotretinoin 2–11 months previously. The isotretinoin dosage for all patients was 0·5–1 mg kg−1 per day. No information was provided regarding skin type. The method of dermabrasion varied between patients. Milia occurred in two patients, but otherwise normal wound healing was found in all patients. One patient had a recurrence of acne several weeks after dermabrasion; this was felt to be due to stopping isotretinoin too soon. There was no defined follow-up period in this study and no validated assessment tool described. An addendum to the article states that since completion of the study two additional patients developed unusual keloid scarring following dermabrasion to the face after recent isotretinoin treatment; no additional information is provided regarding these patients. Rubenstein et al.2 present a case series of six patients (three men and three women) undergoing dermabrasion for acne scarring, three while still taking isotretinoin and three who had stopped taking isotretinoin 2·5–6 months previously. Skin type is mentioned for only two of the six patients: one was white and the other was Pakistani. The dose of isotretinoin was either 0·5 or 1 mg kg−1 per day, and the duration of treatment varied from 4 to 14 months. All of these patients developed keloid scars 1–3 months after dermabrasion. Topical and intralesional corticosteroids resulted in some clinical improvement or resolution of the keloids in all of these patients. As no explanation is provided, it is assumed that these assessments were unblinded and no validated assessment tool was used. Zachariae1 describes two patients (one man and one woman) treated with dermabrasion while on isotretinoin. The female patient had previously received dermabrasion to a traumatic scar on her cheek, which healed within 2 weeks. Further dermabrasion was performed while she was taking isotretinoin 60 mg, and healing took > 2 months, with keloid formation reported 6 months later. The male patient was treated with dermabrasion for rhinophyma and commenced isotretinoin (60 mg daily) for his rosacea immediately after treatment. Healing of the dermabraded site took 4 weeks, and keloid formation was reported on the right side of his nose by 8 weeks. Dermabrasion was used in both of these patients for reasons other than acne scarring, making it more difficult to compare these data with those of the previous studies. Again there is no mention of whether the assessments were unblinded or performed using a validated assessment tool. Katz and MacFarlane14 report the case of a white woman who had full-face dermabrasion for acne scarring without complications. Her acne flared 2 months after dermabrasion so she was commenced on isotretinoin. Six weeks after treatment initiation she developed hypertrophic scarring on her right cheek, which gradually resolved with topical and intralesional corticosteroids. Similarly no details are given regarding blinding or use of assessment tools. Moradi et al.15 present a cohort of 148 patients (121 women and 27 men) who had been taking isotretinoin (1 mg kg−1 daily) for ≥ 4 months to treat acne. No information is provided regarding skin type. All the patients received three treatments with an NLite laser, and five weekly sessions with an erbium-doped yttrium aluminium garnet (Er:YAG) laser for acne scarring. Clinical evaluations were performed for a minimum of 6 months postlaser treatment, but no further details are provided, so it must be assumed that these assessments were unblinded and no validated assessment tool was used. Age-matched controls received isotretinoin but no laser treatment. No significant complications were found in the laser-treated cohort. Postinflammatory hyperpigmentation was found in patients from both groups, and there was no statistically significant difference between these groups. Hann et al.16 report a cohort study of 35 patients with Fitzpatrick skin types II–V. All patients had been on isotretinoin 10 mg per day for > 1 month prior to treatment with an infrared fractional laser (1550 nm Fraxel, Solta Medical, Inc., Hayward, CA, U.S.A.; reduced Microscopic Treatment Zone (MTZ) density in 94% of patients), the number of treatments ranging from two to seven. The clinical results were assessed by the investigators and patients with photographs and a five-point rating scale (ranging from no response to excellent), but no time point for assessment is provided nor is there any mention of blinding. There was no control group in this study. No hypertrophic scarring or keloids were found in this cohort following treatment. Khatri17 presents a prospective cohort of seven female patients on isotretinoin therapy for a minimum of 1 month (dosage range 20–80 mg per day) who underwent laser hair removal. All of the patients were Fitzpatrick skin type II or III. An 810-nm diode laser was used to treat either the axillary or bikini area in two treatment episodes, and six patients also had additional treatment to the chin area. Clinical evaluation and photographs were taken 1 week and 1 month after each treatment. No validated assessment tool was described and it is presumed that there was no blinding as this information was not provided. No scarring was found in any of the patients. One patient developed a bulla at 1 week after the second treatment, but this had resolved without scarring by 1 month post-treatment. No control group was described in this study. Khatri and Garcia18 report a prospective cohort study of six female patients on isotretinoin therapy for acne for a minimum of 2 months (dosage range 40–80 mg per day) who underwent hair removal treatment with a Long Pulse Flash lamp system (wavelength 650–1200 nm). All patients were Fitzpatrick skin type II. Two treatments were performed on each patient to either the axillary, bikini, chin or cheek area. Clinical evaluation and photographs were performed at 1 week, 3 weeks and 6 months after each treatment; again there is no mention of blinding or validated assessment tools. No scarring was found at any of the follow-up visits for any of the patients. No control group was described for this study. Alissa19 presents a study of 100 patients, all of whom were on isotretinoin therapy for acne when they underwent laser treatment. No information regarding isotretinoin dose or skin type is provided. The type of laser treatment used in each case varied between erbium laser, vascular laser, laser hair removal, Q-switched alexandrite, Q-switched 532-nm double frequency, Q-switched 1064-nm Nd:YAG laser and nonablative fractional laser. No hypertrophic scars or keloid development was found in this cohort of patients. No control group was described for this study and it is assumed that clinical assessments were unblinded and no validated assessment tool was used. Khatri20 reports the data from a study originally presented as a poster at the 9th International Congress of the European Society for Laser Aesthetic Surgery, 2006. Eleven patients were retrospectively reviewed, having had laser hair removal with pulsed Nd:YAG laser (1064 nm) while on treatment for acne with isotretinoin (0·5 mg kg−1 per day, minimum 2 months of treatment). Three patients were Fitzpatrick skin type III, five were skin type IV and three were type V. All patients received treatment to their face, and three of the patients also had laser hair removal on their arms, legs, axillae and trunk. The patients were evaluated at intervals of 4–10 weeks and 12 weeks after treatment; no validated assessment tool is described and there is no mention of blinding. One patient (skin type V) developed crusting after the last treatment session on the abdomen; they had completed isotretinoin treatment 7 months prior to that laser treatment. This resolved with temporary hyperpigmentation, which in turn resolved spontaneously. No scarring occurred in these patients. No control group is described. Cassano et al.21 present a case series of six women who had 810-nm diode laser hair removal performed on their face (upper lip, chin, cheeks) while on isotretinoin therapy for acne (0·5–1 mg kg−1 per day). All patients were Fitzpatrick skin type II or III. The isotretinoin dose was reduced to 0·3–0·5 mg kg−1 per day prior to laser treatment for these patients, and the total number of laser treatments varied from four to nine. Two further patients who had diode laser removal of facial hair soon after completing isotretinoin therapy are also discussed. No cutaneous changes or scarring was found in these patients at follow-up. No information regarding the time period, method or blinding of follow-up assessments is provided in this article, and no control group is described. Zachariae1 reports a woman taking isotretinoin for rosacea (60 mg per day) who was treated with argon laser pulse therapy for telangiectasia on her cheeks. Some 3–4 months previously, laser treatment to the same area on her left cheek and to her right cheek had healed within 1 week. However, the lesions that developed following laser treatment while on isotretinoin took > 8 weeks to heal, and 4 weeks later she develop keloid scarring at these sites. No blinding or assessment tools are described. Bernestein and Geronemus22 describe the case of an Asian woman who was being treated for a capillary vascular malformation on her neck with pulsed dye laser (585 nm). She had received five laser treatments without adverse effects. A further laser treatment was performed after commencing isotretinoin treatment (no dose information provided), and keloid scarring developed in the treatment areas 2 weeks subsequently. No validated assessment tool or blinding is mentioned in the article. Sharma et al.23 describe a historical cohort study of 339 patients treated with isotretinoin (no dose information provided). Patients were sent questionnaires to determine how many had undergone wisdom tooth extraction while on the medication or within 3 months of its discontinuation. Twenty-five patients (7·4%) had wisdom tooth extraction during treatment (17 male, eight female), and one patient (male) within 1 month of stopping isotretinoin. No complications occurred during the surgery, but three patients had experienced a dry socket postoperatively. These complications were all self-reported. Sharma et al. state that while the rate of dry socket or alveolar osteitis in this cohort of patients (11·4%) was higher than the average cited rates (3–5%), no association between isotretinoin and this complication can be confirmed due to the small sample size and the lack of a suitable control group. No other problems with wound healing were reported. The observational studies identified in this report only include very small numbers of patients undergoing surgery while on isotretinoin, leading to a lack of power. Only four studies reported the effect, or lack of effect, of isotretinoin on surgical wound healing in humans, amounting to 32 patients in total. The types of surgery undertaken, with only one exception, were maxillofacial (wisdom tooth extraction), facial or otolaryngological. While these types of procedures may be the most common in the typical cohort of isotretinoin-treated patients, the effect of isotretinoin on simple skin surgery wounds at other anatomical sites such as limbs or abdominal skin may be different. Of the patients described in these four studies, only those undergoing rhinoplasty procedures developed complications. None of these patients had been taking isotretinoin at the time of their procedure, and there is concern regarding selection bias and lack of control cases. A slightly increased risk of dry socket postoperatively, reported following wisdom tooth extraction, and one postsurgical case reporting delayed healing (no further details provided) were the only other issues described following isotretinoin use. The 14 relevant studies looking at isotretinoin use and dermabrasion or laser treatment consisted of 350 patients in total; 213 of these patients were presented in six prospective cohort studies. In the absence of specific randomized controlled trials and pharmacovigilance data, cohort studies were the highest level of evidence found. None of these 213 patients, treated with either dermabrasion or laser, developed any atypical or keloid scarring despite isotretinoin use during treatment or within 3 months prior to treatment. Of the remaining 137 patients taken from case reports and case series, 13 were reported to have developed keloid scarring, two with laser treatment and 11 with dermabrasion. All of the studies described above are limited by information bias (lack of blinding and lack of validated assessments in particular) and a lack of control for confounding variables and selection and publication bias. Critical appraisal of this important topic is severely limited by the lack of relevant and high-quality clinical evidence from pharmacovigilance databases or randomized controlled trials. Given the widespread use of isotretinoin, it is perhaps surprising that so few data are available regarding the concern over wound healing with isotretinoin therapy. Within the existing studies the numbers are quite small, resulting in a lack of power to detect less common outcomes. Selection, information and publication bias, lack of control for confounding variables and lack of control patients are overriding concerns. The lack of evidence of direct relevance to our question makes it difficult to reach any clear recommendations. Our clinical question makes reference to comparison of wound healing in patients on isotretinoin with those not on the medication. Unfortunately, it is not possible for us to answer this question, not only because of the limited amount of evidence in the literature but also because of the lack of controls not on isotretinoin. It is reassuring that no significant issues regarding wound healing have been consistently demonstrated or reported with isotretinoin given its very widespread use, although absence of evidence of harm cannot be equated with evidence of no harm.24 On reviewing the limited available evidence, we conclude that there is some doubt that isotretinoin could interfere with wound healing, but overall the risk described in the larger and better reported studies8, 9, 12-15 was relatively small or absent. On the basis that isotretinoin was not essential for the patient at the time that a semiurgent procedure needed to be done, we decided that it was prudent to stop treatment prior to elective surgical procedures and restart after satisfactory wound healing had occurred. The patient's surgical wounds have healed well and without complication. He has also completed his course of isotretinoin without complications and with good results for his acne. I didn't particularly notice my worsening acne until New Year's Eve 2011; I had an excellent night, but after having seen my face in photos the next day, I realized it was time to do something. I managed to book an appointment with Professor Williams at The Queen's Medical Centre, Nottingham. After talking through all of the aspects and fulfilling various procedures, I was started on a dose (20 mg) equivalent to a quarter of my maximum. After weeks and months, and following consultation with the nurse, I slowly began to increase my dosage. At one point, I reached my maximum (80 mg) but, suffering from a noticeable muscle performance drop within a week, I decided to lower the dose. With exams looming and having seen the relatively severe side-effects of the drug, I (and also my worrying GP father) decided to restart the basic 20-mg dose. It was soon after my exams that I dislocated my right shoulder while diving for a ball in cricket. Four weeks later, I was having an operation to ‘fix’ my shoulder. It was decided, following consultation with my parents and Professor Williams, that I would cease my isotretinoin treatment until a suitable time during my healing process. I restarted on the drug to finish my recommended total dosage, and have not been taking it since January. My surgical scars have healed (seemingly) perfectly and my acne-affected skin is more or less sorted. We would like to thank Dr Jonathan Batchelor and Dr Sinead Langan for their assistance in advising and reviewing this article.