In-Office Painless PDT with ALA and Vitamin D: Optimizing Outcomes, Minimizing Pain

ALA, a prodrug, is taken up by cells and converted via the heme synthesis pathway into protoporphyrin IX (PpIX), a naturally occurring molecule that plays a critical role in the biosynthesis of heme, the iron-containing compound in hemoglobin. It is produced in the mitochondria of nearly all eukaryotic cells via the heme synthesis pathway. When iron is inserted into PpIX by the enzyme ferrochelatase, the molecule becomes heme.

The medical relevance of PpIX emerged in the early 20th century as researchers began exploring porphyrins — a class of compounds with characteristic light-absorbing properties. PpIX itself was identified in the 1920s, and its strong fluorescence and light-sensitizing abilities were soon recognized. Scientists discovered that, under certain conditions, porphyrins could accumulate in cancerous or precancerous cells and generate reactive oxygen species (ROS) when exposed to light — a foundational principle for photodynamic therapy (PDT).

In dermatology, interest in PpIX was revitalized with the development of 5-aminolevulinic acid (ALA), a prodrug that drives PpIX accumulation selectively in dysplastic keratinocytes. In the United States, two FDA-approved formulations are available: Levulan® Kerastick®, a 20% ALA solution applied via single-use applicator, and Ameluz®, a 10% ALA gel delivered in a resealable tube. This targeted buildup of PpIX allows clinicians to exploit its phototoxic properties for therapeutic purposes—destroying precancerous cells while largely sparing surrounding healthy tissue.

While peak accumulation of PpIX typically occurs around 6 to 12 hours after ALA application, studies have shown that dysplastic keratinocytes begin accumulating clinically meaningful levels of PpIX within minutes of exposure. This differential uptake allows immediate light activation—without incubation—to selectively target AKs while sparing surrounding normal skin.

PpIX absorbs light most strongly at two wavelength ranges:

• Soret band (~417 nm, blue light)
• Q-bands (~630–635 nm, red light)

Blue light is often used in standard US PDT protocols for treating superficial actinic keratoses, particularly on the face and scalp. Its strong absorption by PpIX ensures robust phototoxic activity—but only in the upper layers of the skin, due to limited penetration.

Red light, while less efficient at triggering PpIX due to lower absorption, penetrates much deeper into tissue, making it useful for thicker or more deeply located lesions, such as hypertrophic AKs or superficial basal cell carcinomas. Red light is also preferred in European and field-directed PDT protocols using Ameluz®, which benefits from its enhanced penetration profile.

Clinical Tip: When performing "painless PDT" with no incubation, blue light tends to activate PpIX rapidly and may be sufficient for field AKs. However, red light is generally favored for thicker lesions or in investigational protocols evaluating PDT for superficial NMSC (not FDA-approved in the US).

Two FDA-approved options:

Standard PDT protocols with 1–3 hour incubation periods followed by light exposure are associated with significant pain in many patients. Data from clinical studies report the following rates of severe pain:

¹ MAL refers to methyl aminolevulinate, a derivative of ALA used in Europe (e.g., Metvix®). It is not currently FDA-approved in the US, but is widely studied in European PDT protocols.

Inspired by European daylight PDT but adapted for US practices, this method uses simultaneous application and activation of ALA with light exposure — no incubation required.

Protocol:

1. Apply ALA (Ameluz or Levulan)
2. Immediately illuminate with red or blue light
3. Continue light exposure for 30 minutes

Results from Split-Face Trials:

• Efficacy equivalent to standard PDT
• Pain reduced dramatically: patients report almost no discomfort

Key Differences:

• Traditional PDT: ALA is applied and allowed to incubate (usually 1–3 hours) to allow PpIX to accumulate before light exposure. The illumination phase is then typically 16 minutes and 40 seconds for blue light (BLU-U®) or up to 30 minutes for red light (depending on device).
• Painless PDT: Skips the incubation entirely and starts the light exposure immediately. The exposure duration (30 minutes) is chosen to ensure sufficient PpIX activation even though less has accumulated upfront.

Hypothesis:
Oral vitamin D3 enhances the immune-mediated clearance of actinic keratoses (AKs), complementing the effects of photodynamic therapy (PDT). While PDT exerts its cytotoxic effects primarily through the generation of reactive oxygen species that destroy dysplastic cells, it also triggers a secondary inflammatory and immunologic response, which is important for long-term lesion clearance and field cancerization control.

Vitamin D is thought to prime the skin's immune microenvironment in several ways:

• It promotes the differentiation of keratinocytes and helps normalize epidermal growth patterns — potentially reducing the hyperproliferative tendencies of sun-damaged skin.
• It modulates the innate immune system, enhancing macrophage and dendritic cell function, which are involved in clearing damaged cells post-PDT.
• It upregulates cathelicidin (LL-37) and other antimicrobial peptides, which are also implicated in skin barrier repair and immune surveillance.
• It may increase expression of tumor suppressor pathways, making precancerous cells more susceptible to oxidative damage and immune clearance during PDT.

Together, these mechanisms may amplify the therapeutic window of PDT, particularly in vitamin D–deficient patients, by enhancing both the direct and indirect pathways of lesion destruction.

In a prospective study by Maytin et al., researchers investigated whether short-term oral supplementation with vitamin D3 could improve the efficacy of photodynamic therapy (PDT) for actinic keratoses (AKs). The study aimed to build on the hypothesis that vitamin D enhances immune-related clearance pathways, particularly in vitamin D–deficient individuals.

Study Design:

• Participants: Patients with multiple AKs on sun-damaged skin
• Groups:
  • Group 1 (Control): Received standard PDT alone
  • Group 2 (Intervention): Received 10,000 IU/day of oral vitamin D3 for 5 to 14 days prior to undergoing PDT
• All patients received ALA-based PDT with red light
• Vitamin D serum levels were measured before and after supplementation
• Lesion clearance was assessed several weeks after treatment

Key Variables:

• Patients were stratified by baseline vitamin D status (deficient vs. sufficient)
• Clearance rates were compared between groups to determine if vitamin D pre-treatment had a measurable impact

Findings:

The results showed a statistically significant improvement in lesion clearance in patients who received vitamin D3 prior to PDT — especially those who were initially vitamin D–deficient.

These findings suggest that even short-term correction of vitamin D deficiency may improve treatment response — likely by priming the local immune response and enhancing apoptosis of dysplastic keratinocytes during PDT.

Pre-treatment:

• 10,000 IU oral vitamin D3 daily × 2 weeks

Treatment Day:

1. Apply ALA
2. Immediately begin red or blue light exposure
3. Illuminate for 30 minutes
4. Treatment complete

While this article focuses on oral vitamin D3 as an adjunct to painless PDT, there is growing interest in the use of topical vitamin D analogs, such as calcipotriol, to enhance lesion clearance. These agents may help increase PpIX accumulation or augment immune-mediated destruction of dysplastic cells. However, clinical studies using topical calcipotriol have generally involved traditional or daylight PDT protocols, and patients often experienced more local irritation.

At present, topical vitamin D is not associated with "painless" PDT protocols, which rely on immediate light activation and are specifically designed to minimize discomfort. Further research is needed to determine whether topical formulations can be integrated into pain-minimized regimens without compromising tolerability.

References

1. Martin GM. In-office painless aminolevulinic acid photodynamic therapy: A proof of concept study. J Clin Aesthet Dermatol. 2016;9(2):19–26.
2. Kaw U, Ilyas M, et al. A regimen to minimize pain during blue light PDT of AKs. JAAD. 2020;82(4):862–868.
3. Bullock TA, Maytin EV. Oral vitamin D enhances PDT clearance of AKs. JAAD. 2022. https://doi.org/10.1016/j.jaad.2022.02.067