prospective, randomized comparisons evaluating modifications of conventional protocols and their impact on efficacy and pain of ALA-PDT in AK (Table 1), as well as providing the author's clinical recommendations.
Adjunctive Measures to Reduce Pain During Illumination
Efficacy of topical anesthetics for pain management during PDT appears limited. In patients undergoing PDT for AK or other skin conditions, no significant pain reductions were observed with the use of morphine gel9 or a lidocaine 2.5%-prilocaine 2.5% mixture10 vs placebo. Standard fans and misting with water may also be used to alleviate pain during PDT.4 Patients receiving ALA-PDT for AK on the face or scalp reported significant reductions in pain scores with cold air analgesia compared with a standard fan, with no effect on the rate of complete AK clearance (Table 1).11
Efficacy of topical anesthetics for pain management during PDT appears limited. In patients undergoing PDT for AK or other skin conditions, no significant pain reductions were observed with the use of morphine gel9 or a lidocaine 2.5%-prilocaine 2.5% mixture10 vs placebo. Standard fans and misting with water may also be used to alleviate pain during PDT.4 Patients receiving ALA-PDT for AK on the face or scalp reported significant reductions in pain scores with cold air analgesia compared with a standard fan, with no effect on the rate of complete AK clearance (Table 1).11
Factors Influencing Pain During ALA-PDT
Incubation Time
The FDA labeling for ALA 20% solution and ALA 10% gel recommends incubation periods of 14 to 18 hours and 3 hours, respectively, for PDT of AK on the scalp or face.2,3 However, PpIX accumulation becomes statistically higher vs baseline after 2 hours in almost all AK lesions.14 The AAD guidelines for treatment of AK conditionally recommend 1- to 4-hour incubation when using ALA with red light PDT but do not specify incubation time before blue light PDT.1 Reduction in ALA incubation time (with or without adjustment to illumination time) to attenuate PpIX accumulation in the skin has been investigated as a way to reduce pain during illumination. The irony in the use of PDT today is that 14- to 18-hour incubation is tantamount to a daylight PDT regimen, which is technically off-label.
In a randomized, vehicle-controlled study, AK clearance rates following 1-, 2-, and 3-hour ALA incubation were all comparable and significantly greater relative to vehicle-PDT. However, moderate-to-severe stinging/burning during PDT was substantially more common with 2- and 3-hour vs 1-hour incubation, as were edema and moderate-to-severe erythema post-PDT (Table 1).15 Simultaneous light activation of PpIX during ALA incubation (simultaneous protocol) resulted in reduced mean pain scores with nearly identical lesion clearance after 3 months compared with 1-hour ALA incubation (conventional protocol) in a bilaterally controlled study (Table 1).16 Similarly, 15-min incubation with 20% ALA was associated with little or no pain in patients undergoing blue light PDT for AKs in a single-arm study; in a split-face pilot study, pain was substantially reduced with no loss of efficacy compared with incubation for 75 minutes (Table 1).17 These results suggest that incubation time can be reduced relative to conventional protocols to improve the tolerability of ALA-PDT without decreasing efficacy.
ALA Formulation
In a randomized, double-blind study, 40 patients with AK on the face or scalp were randomized to treatment with 10% ALA gel or 20% ALA solution with blue light illumination, although 10% ALA gel is labeled for use with red light. Clearance rates were high (greater than or equal to 95%) and comparable; pain scores were lower in patients treated with 20% solution vs 10% gel but not significantly different between groups, although erythema and scaling/dryness were significantly more common following treatment with 20% ALA solution (Table 1).18
Light Source
Use of daylight illumination for PDT may be an effective method to minimize pain while maintaining clinical efficacy. The AAD guidelines for treatment of AK conditionally recommend ALA-daylight PDT as less painful but equally effective compared with ALA-red light PDT based on a moderate quality of evidence from a prospective, randomized study in patients with AK of the face or scalp1 in which pain was significantly greater in patients treated with 10% ALA-red light PDT vs 10% ALA-daylight PDT, with lesion clearance exceeding 95% in both arms (Table 1).19
Combined PDT protocols using both daylight and conventional PDT have also been evaluated. In a randomized study of combined PDT vs conventional PDT in patients with AK on the scalp or face, the overall AK clearance rate was slightly higher in the conventional PDT arm, but the clearance rate was not statistically significantly different when lesion clearance was analyzed by grade. Both PDT-associated pain and the severity of erythema and edema were significantly lower in patients who received combined vs conventional PDT (Table 1).20
The primary advantage of daylight PDT is the near painlessness of the procedure. Furthermore, use of the sun as a light source is free of cost and saves clinic space and time.21 Limitations of daylight PDT include dependence on favorable weather conditions and the need for sunscreen to reduce ultraviolet exposure. Potential nonadherence to daylight illumination instructions and patients' inability to manage unpredictable local skin reactions outside the clinic are further challenges. Finally, reimbursement is problematic because FDA labeling specifies the blue light and red light illumination devices to be used with approved ALA products.2,3
Recent studies, reviewed in detail elsewhere, have explored simulated daylight (SDL)-PDT using an artificial light source emitting white, blue, yellow, or red light.21 SDL-PDT is usually
