In-office Painless Aminolevulinic Acid Photodynamic Therapy: A Proof of Concept Study and Clinical Experience in More Than 100 Patients

Objective: To evaluate the efficacy, safety, and pain of in-office “painless” aminolevulinic acid photodynamic therapy aimed at decreasing treatment-associated pain in patients undergoing removal of actinic keratoses. Design: Prospective split-face study comparing short aminolevulinic acid incubation times of 15 minutes followed by extended exposure (60 minutes) of continuous blue light versus conventional aminolevulinic acid photodynamic therapy. Prospective assessment of pain in patients undergoing in-office “painless” aminolevulinic acid photodynamic therapy. Setting: Clinical practice office. Participants: Three patients with actinic keratoses participated in the split-face study and 101 in the pain assessment study. Measurements: Evaluations in the split-face study included removal of actinic keratoses, skin temperature, and pain measured on a 10-point visual analog scale. Pain was assessed using the visual analog scale in the pain assessment study. Results: In the split-face study, in-office “painless” aminolevulinic acid photodynamic therapy resulted in a 52-percent reduction in lesions versus 44 percent for conventional aminolevulinic acid photodynamic therapy. Maximum pain scores of in-office “painless” aminolevulinic acid photodynamic therapy were all 0 at each time point, and the average score for conventional aminolevulinic acid photodynamic therapy was 7. Baseline skin temperatures increased from a baseline of 29 to 32°C to 34 to 35°C by minute 10 of blue light activation on both sides of the face. Results from the pain assessment study indicated no or minimal (scores 0-2) pain in nearly all patients who received in-office “painless” aminolevulinic acid photodynamic therapy as monotherapy or in combination with 5-fluoruacil or imiquimod used as pretreatments. Conclusions: In-office “painless” aminolevulinic acid photodynamic therapy appears to be effective for removing actinic keratoses and is associated with little or no pain in nearly all patients. This procedure should be evaluated in large-scale controlled trials.Actinic keratoses (AKs) are part of the spectrum between photodamaged skin and invasive squamous cell carcinoma (SCC).1-5 They are a major health care concern because of their increasing prevalence worldwide,6-10 economic impact,9-11 and decreased quality of life of affected individuals.10,12 Results from observational studies have indicated that AKs evolve into primary invasive SCC or in situ SCC at a rate ranging between 1/1,000 lesions per year13 to 0.60 percent at one year and 2.57 percent at four years.14 It is recommended that all AKs be treated because it is not currently possible to predict which will evolve into invasive SCC.15-17A variety of therapeutic modalities are used to treat AKs.1,18-20 Focally destructive therapies, such as cryotherapy,21 electrodessication and curettage,22 and shave excision23 are most often used to treat individual AKs. Large areas of actinically damaged skin require “field therapies” such as 5-fluoruacil (5-FU),24-26 imiquimod,26-30 diclofenac gel,31-33 ingenol mebutate,34,36 aminolevulinic acid photodynamic therapy (ALA PDT)35,37 and methyl-aminolevulinic acid PDT (MAL PDT),38,39 chemical peels,40 dermabrasion,41-43 and laser resurfacing.44,45PDT produces reactive oxygen species that result in tissue destruction46 and it destroys AKs because of the preferential accumulation of the photosensitizing molecule, protoporphyrin IX (PpIX) within AKs following topical application of pro-drugs ALA47 and MAL.48 PDT is safe and effective for treatment of large surface skin areas, provides good adherence because it is performed under supervision in a clinic setting, has minimal post-treatment downtime versus other AK field therapies, and produces good-to-excellent cosmetic outcomes with minimal potential for scarring.49,50 PDT also has several drawbacks, most notably pain during the first few minutes of light activation phase.51-53 Nearly two-thirds of patients undergoing ALA PDT report this pain as “moderate-severe” following 1, 2, or 3-hour ALA incubations.54 Pain with PDT has been related to cellular destruction and inflammation and possibly a direct effect of PDT on nerve fibers55-57; it has now become clear that PDT-related pain is associated with PpIX tissue accumulation based on fluorescence and the fluence rate of the activating light source.58 Topical anesthetics,55 cooling devices,59-61 nerve blockade,61,62 and treatment interruption63 have limited efficacy in managing PDT-related pain, which can lead to reluctance of patients to undergo future PDT treatments.A novel approach to minimizing discomfort during PDT, daylight-mediated PDT, uses a brief (30-minute) incubation period followed by 1.5 to 2.5 hours of daylight exposure.64-66 The shortened incubation period is designed to minimize PpIX build-up in the targeted tissue prior to daylight PpIX activation, and photobleaching prevents further buildup of PpIX and minimizes patient discomfort.67,68 Limitations to daylight-mediated PDT include dependence on favorable weather conditions and patient adherence to the treatment protocol outside the clinic.65Based on the efficacy and improved tolerability of daylight-mediated PDT, an in-office painless (IOP) ALA PDT protocol was developed. It involves applying ALA topically to actinically damaged skin, incubating without occlusion for 15 minutes, and then 60 minutes of continuous blue light activation. This report summarizes results from a split-face comparison of IOP ALA PDT and a standard short (75 minute) ALA incubation protocol followed by the standard 1,000 seconds of blue light activation carried out in three patients, and assessment of pain associated with this treatment in 101 patients undergoing 121 treatments over a two-year time period. In the latter study, IOP ALA PDT was employed as either a full-face monotherapy or in combination with one week of prior treatment with 5% and 0.5% 5-FU and 3.75% and 5% imiquimod.