The Interventions to Minimize Pain During Photodynamic Therapy With 5-Aminolevulinic Acid for the Treatment of Cutaneous Diseases

November 2023 | Volume 22 | Issue 11 | 1082 | Copyright © November 2023


Published online October 17, 2023

Neal Bhatia MD

Therapeutics Clinical Research, San Diego, CA

performed indoors with a short incubation time, allowing simultaneous light activation of PpIX during PpIX formation and rendering the treatment almost painless.21 SDL-PDT addresses the weather-, adherence-, and monitoring-related limitations of daylight PDT, but requires a lamp and more time spent in the clinic. Additional research is needed to standardize pretreatment, incubation time, light source, and irradiation time for SDL-PDT.21 Similar to daylight PDT, reimbursement of SDL-PDT in the US is problematic because light sources are specified in the product labeling.2,3

Fluence Rates and Stepped Irradiance
Lower fluence rates (25 and 50 mW/cm2) were associated with reduced pain compared with a fluence rate of 75 mW/cm2 in patients with AKs undergoing ALA-PDT, with comparable proportions of patients achieving complete clearance at 3 months (Table 1).22 Two-step irradiance protocols using low radiances early in the PDT session before progressing to higher radiances have been developed with the aim of minimizing pain,23,24 but randomized studies in patients with AK are needed.

Brief Pauses During Illumination
A clinical trial evaluated pain and efficacy of different PDT protocols using ALA 20% with red light and incubation for 3 hours (Group 1), 1.5 hours (Group 2), or 1.5 hours with 2-minute pauses every 10 minutes during illumination (Group 3). Proportions of patients reporting low levels of pain during illumination were highest in Group 3, whereas Group 2 had the highest rates of severe pain. Mean reductions in AK lesion count at 30 days were comparable across the 3 groups (Table 1).25 In the author's experience, pausing at 3-minute intervals may be a more realistic protocol in clinical practice.

DISCUSSION AND CONCLUSIONS

Published recommendations for the management of pain associated with ALA-PDT include the use of cold air analgesia or a fan to cool the skin, short breaks during illumination, intralesional lidocaine injection prior to treatment, or use of topical anesthetics prior to or following treatment.4 Continuous activation of low levels of PpIX using shorter incubation times, lower irradiance, and daylight or combined PDT may decrease pain without loss of efficacy in AK.15,16,19,20 However, few modifications to conventional ALA-PDT protocols have been rigorously evaluated in clinical trials, and even fewer are backed by FDA approval. Larger, randomized, controlled studies, particularly those evaluating daylight and combination PDT, are needed to standardize these protocols, strengthen the evidence base, and support reimbursement in AK and other indications.

Our current methods for controlling pain and discomfort during and after ALA-PDT have been informed by the literature reviewed here, as well as clinical experience. Optimization of tolerability begins with taking care to identify patients with contraindications to ALA-PDT. These include patients taking known photosensitizers and those who are unable to avoid light exposure to treated skin for 24 to 48 hours after treatment.4 For topical pain control, we recommend refrigerated hypochlorous acid spray as a suitable alternative to the adjuncts above, and we anticipate with interest the publication of a recently completed clinical trial evaluating 5% menthol cream for pain reduction during PDT for AK (www.clinicaltrials.gov; NCT02984072). Antihistamines are not approved for the indication, but our practice has found them useful in reducing the immediate edema and itching believed to be caused by the degranulation of mast cells and basophils in response to ALA-PDT.12 Although controlled clinical trials have not been conducted to evaluate their effectiveness in this setting, anxiolytic ("talk-esthesia") may be effective for reducing pain and discomfort associated with ALA-PDT. In addition, a new antipruritic topical formulation containing aluminum acetate (Dermeleve, Advanced Derm Solutions, LLC)26 is useful as an adjunct during pretreatment in the author's experience, although it has not been clinically evaluated in AK. After treatment, the use of a skin-soothing spray (not containing sensitizers like benzocaine) for several days generally helps to manage burning and irritation, and patients should be strongly advised to use sunscreen.4 

The number of procedural variables involved in ALA-PDT and the range of conditions for which this modality is used confounds the development of standardized protocols to minimize pain and maintain efficacy. However, investment of time and funds toward this effort, as well as a commitment to information sharing among PDT practitioners, has the potential to significantly improve the use and effectiveness of PDT for a range of cutaneous diseases. 

DISCLOSURES

Dr. Bhatia has affiliations with Almirall, Biofrontera, Galderma, Ortho, and SunPharma.

ACKNOWLEDGMENT

Medical writing and editorial support were provided by Dana Lengel PhD of AlphaBioCom, a Red Nucleus company, and funded by Sun Pharma.

REFERENCES

  1. Eisen DB, Asgari MM, Bennett DD, et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 2021;85(4):e209-e233. 
  2. LEVULAN KERASTICK (aminolevulinic acid HCL) for topical solution, 20%. Prescribing information. Sun Pharmaceutical Industries, Inc. 2018.
  3. AMELUZ (aminolevulinic acid HCL) topical gel, 10% [package insert]. Biofrontera Inc. 2022.
  4. Zeitouni NC, Bhatia N, Ceilley RI, et al. Photodynamic therapy with 5-aminolevulinic acid 10% gel and red light for the treatment of actinic keratosis, nonmelanoma skin cancers, and acne: current evidence and best practices. J Clin Aesthet Dermatol. 2021;14(10):E53-E65.
  5. Kasche A, Luderschmidt S, Ring J, Hein R. Photodynamic therapy induces less pain in patients treated with methyl aminolevulinate compared with aminolevulinic acid. J Drugs Dermatol. 2006;5(4):353-356. 
  6. Fink C, Enk A, Gholam P. Photodynamic therapy -- aspects of pain management. J Dtsch Dermatol Ges (J Ger Soc Dermatol). 2015;13(1):15-22.
  7. Lev-Tov H, Larsen L, Zackria R, et al. Microneedle-assisted incubation during aminolaevulinic acid photodynamic therapy of actinic keratoses: a randomized controlled evaluator-blind trial. Br J Dermatol. 2017;176(2):543-545.
  8. Meierhofer C, Silic K, Urban MV, et al. The impact of occlusive vs non-occlusive application of 5-aminolevulinic acid (BF-200 ALA) on the efficacy and tolerability of photodynamic therapy for actinic keratosis on the scalp and face: a prospective within-patient comparison trial. Photodermatol Photoimmunol Photomed. 2021;37(1):56-62.
  9. Skiveren J, Haedersdal M, Philipsen PA, et al. Morphine gel 0.3% does not relieve pain during topical photodynamic therapy: a randomized, double-blind, placebo-controlled study. Acta Derm Venereol. 2006;86(5):409-411.
  10. Langan SM, Collins P. Randomized, double-blind, placebo-controlled prospective study of the efficacy of topical anaesthesia with a eutetic mixture of lignocaine 2.5% and prilocaine 2.5% for topical 5-aminolaevulinic acid-photodynamic therapy for extensive scalp actinic keratoses. Br J Dermatol. 2006;154(1):146-149.
  11. Silic K, Kammer M, Sator PG, et al. Efficacy of two different methods of cold air analgesia for pain relief in PDT of actinic keratoses of the head region -- a randomized controlled comparison study. Photodiagnosis Photodyn Ther. 2022:103190.
  12. Brooke RC, Sinha A, Sidhu MK, et al. Histamine is released following aminolevulinic acid-photodynamic therapy of human skin and mediates an aminolevulinic acid dose-related immediate inflammatory response. J Invest Dermatol. 2006;126(10):2296-2301.
  13. Vanaman Wilson MJ, Jones IT, Wu DC, Goldman MP. A randomized, double-blind, placebo-controlled clinical trial evaluating the role of systemic antihistamine therapy for the reduction of adverse effects associated with topical 5-aminolevulinic acid photodynamic therapy. Lasers Surg Med. 2017;49(8):738-742.
  14. Warren CB, Lohser S, Wene LC, et al. Noninvasive fluorescence monitoring of protoporphyrin IX production and clinical outcomes in actinic keratoses following short-contact application of 5-aminolevulinate. J Biomed Opt. 2010;15(5):051607.
  15. Pariser DM, Houlihan A, Ferdon MB, et al. Randomized vehicle-controlled study of short drug incubation aminolevulinic acid photodynamic therapy for actinic keratoses of the face or scalp. Dermatol Surg. 2016;42(3):296-304.
  16. Kaw U, Ilyas M, Bullock T, et al. A regimen to minimize pain during blue light photodynamic therapy of actinic keratoses: bilaterally controlled, randomized trial of simultaneous versus conventional illumination. J Am Acad Dermatol. 2020;82(4):862-868.
  17. Martin GM. In-office painless aminolevulinic acid photodynamic therapy: a proof of concept study and clinical experience in more than 100 patients. J Clin Aesthet Dermatol. 2016;9(2):19-26.
  18. Nestor MS, Berman B, Patel J, Lawson A. Safety and efficacy of aminolevulinic acid 10% topical gel versus aminolevulinic acid 20% topical solution followed by blue-light photodynamic therapy for the treatment of actinic keratosis on the face and scalp: a randomized, double-blind study. J Clin Aesthet Dermatol. 2019;12(3):32-38.
  19. Zhu L, Wang P, Zhang G, et al. Conventional versus daylight photodynamic therapy for actinic keratosis: a randomized and prospective study in China. Photodiagnosis Photodyn Ther. 2018;24:366-371.
  20. Saenz-Guirado S, Cuenca-Barrales C, Vega-Castillo J, et al. Combined versus conventional photodynamic therapy with 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) for actinic keratosis: a randomized, single-blind, prospective study. Photodermatol Photoimmunol Photomed. 2022;38(4):334-342.
  21. Heerfordt IM, Philipsen PA, Wulf HC. Bringing the gentle properties of daylight photodynamic therapy indoors: a systematic review of efficacy and safety. Photodiagnosis Photodyn Ther. 2022;39:102858.
  22. Apalla Z, Sotiriou E, Panagiotidou D, et al. The impact of different fluence rates on pain and clinical outcome in patients with actinic keratoses treated with photodynamic therapy. Photodermatol Photoimmunol Photomed. 2011;27(4):181-185.
  23. Cottrell WJ, Paquette AD, Keymel KR, et al. Irradiance-dependent photobleaching and pain in delta-aminolevulinic acid-photodynamic therapy of superficial basal cell carcinomas. Clin Cancer Res. 2008;14(14):4475-4483.
  24. Zeitouni NC, Paquette AD, Housel JP, et al. A retrospective review of pain control by a two-step irradiance schedule during topical ALA-photodynamic therapy of non-melanoma skin cancer. Lasers Surg Med. 2013;45(2):89-94.
  25. Salvio AG, Stringasci MD, Requena MB, et al. Field cancerization treatment: adjustments to an ALA red light photodynamic therapy protocol to improve pain tolerance. Photodiagnosis Photodyn Ther. 2021;35:102415.
  26. Dermeleve (aluminum acetate cream). Prescribing information. Advanced Derm Solutions, LLC. 2022.

AUTHOR CORRESPONDENCE

Neal Bhatia MD nbhatia@therapeuticsresearch.com
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