Usually PDT shows excellent cosmetic results;
nevertheless, there are some reports of complica- tions during and after treatment. The most com- mon side effects of photodynamic therapy are pain, edema, and erythema, followed by less fre- quently observed pruritus, vesiculation, crusting, exfoliation, and hypo- or hyperpigmentation [ 1, 6, 7 ] . These side effects are needed to get good results; however, sometimes, patients are uncom- fortable with them. It is important to instruct the patient to have strict avoidance of direct sunlight
Table 7.1 Protocol for 20% ALA solution in a patented device (Levulan® Kerastick®)
1. Discontinue topical retinoids 3 days before treatment 2. Prepare skin degreasing with acetone or isopropyl
alcohol, rubbing gentle with gauze. Some patients with oily and thick skin could bene fi t of micro- dermabrasion before applying the photosensitizer 3. Apply 20% ALA solution on the skin avoiding
dripping into the eyes
4. Let the product incubate for 30 min to 3 h, depend- ing on the indication. After incubation, wash treated area with water and soap
5. Activate drug with light
(a) 417-nm blue light: 16 min 40 s
(b) IPL:22–25 J/cm 2 , double pulse (30% less fl uence in skin type III to IV)
(c) PDL: 10-mm spot, 7.5 J/cm 2 , 10–20 ms., double pulse
6. Pain management during illumination
(a) Cooling treatment site: cool air fl ow, iced water, fan, etc.
(b) 2–5 min rest periods during treatment (c) Shorten incubation time
(d) Diazepam 5–10 mg PO if needed
7. Wash treated area thoroughly with soap and water immediately after the procedure. Apply broad spectrum sunscreen in of fi ce and wear sunglasses, wide brim hat, and protective clothing
8. Avoid sun exposure and direct light for the following 48 h after treatment, including computer light.
Continue using broad spectrum sunscreen and wear sun glasses and protective clothing during this period of time. Apply ice cold soaks if needed
and/or indoor bright light for the fi rst 48 h after the procedure [ 6, 7 ] .
Skin preparation can affect the results and complications of PDT. Degreasing the skin with alcohol or acetone can affect drug absorption leading to a more intense reaction with better results, but more chances of side effects. Topical retinoids or other exfoliants may induce a more intense treatment, so patients need to stop their use 3–4 days prior to procedure. Discontinuing the use of topical exfoliants prior to the proce- dure can lead to fewer side effects [ 1, 6, 7 ] .
7.2.1 Pain
The most common adverse event of PDT is pain.
The application of ALA and MAL has been reported to cause a transient mild stinging sensa- tion immediately after its application, especially when the skin is ulcerated or with abrasions. In most cases, illumination is the trigger for the induction of pain and it is believed that the PpIX is the main target responsible. Pain has been described by patients as a sensation of burning, stinging, tingling, and prickling which commonly occurs in ranges from mild to severe and varies from patient to patient. It is most frequent in scalp and upper face region and is largely unpredictable [ 7 ] . When present, it usually occurs after the fi rst minutes of light exposure, reaching a maximum within several minutes and then subsides as the porphyrin is photobleached. Cessation of light exposure relieves the pain within seconds, which is consistent with direct neural stimulation. This mechanism is not fully understood, but this nerve stimulation and/or tissue damage can be similar to sunburn sensation. Pain can be a cause for discon- tinuation of treatment in patients treated with MAL-PDT [ 1– 3, 6– 10 ] . The majority of cases that experienced pain with ALA where described with the use of a not trademark- compounded cream and with red light. With the use of the 20%
ALA solution contained in a patented device, the pain is almost absent in most cases with short incubation times (e.g., 30 min to 1 h), but can be severe with longer incubation times (14–18 h) [ 11 ] . It is said that gamma-aminobutyric acid
(GABA) receptors in peripheral nerve endings are postulated to transport ALA but not MAL, thereby resulting in more pain with ALA, but no one has yet tested whether blockers of GABA receptors might be bene fi cial in reducing pain associated with ALA-PDT [ 3 ] . As mentioned above, the experience of pain varies from patient to patient as does its tolerability; however, studies have sug- gested that important factors for the discomfort of the patients are the type and localization of lesions, size of treated area, intensity of light delivery, curettage, occlusion, and light source [ 2, 3, 8, 9,
12 ] . PDT is more painful when performed on well-innervated areas of the skin, such as face, hands, and the perineal regions [ 3 ] . Additionally, pain is especially more referred when multiple lesions in sun-damaged areas are simultaneously treated, for example, AKs in face and scalp [ 3 ] .
Light-based treatments for acne extending back decades wherein ultraviolet light was used to combat this condition. Some other lights like blue and red light, broadband light, and pulsed dye laser, among other light sources, have been used in the treatment of acne [ 13 ] . The exact mechanism of action of PDT on acne is not clear. It is believed that acne vulgaris respond to light therapies alone (without ALA) because Propionibacterium acnes produces and accumu- lates porphyrins within the sebaceous glands and could be destroyed by the light, decreasing the count of the bacteria. Others have suggested that direct injury to sebaceous glands might underline the clinical bene fi ts of such treatment. The use of topical photosensitizers to potentially enhance the effects of light-based therapies has been reported in the scienti fi c literature [ 11 ] . However, if exog- enous ALA or MAL is used in the PDT regimen for acne, pain can be greater than light alone and can be quite severe in some cases [ 6, 11, 13 ] .
Pain induced in recalcitrant warts by 20%
ALA-compounded cream followed by illumina- tion with red light was of higher intensity and lasted longer in about one- fi fth of the treated warts (17%) when compared with placebo cream plus red light (2%). The relatively high incidence of severe pain reported from warts located on feet and hands in this study may be related to the rich enervation of these regions [ 14 ] .
7.2.2 Pain Management
Most of the treatments for pain induced by PDT reported in the medical literature are anecdotal.
The majority of open, randomized, and double- blind studies using topical anesthetics have been considered impractical due to the interactions with the photosensitizer agents and have failed to dem- onstrate any bene fi ts for its routine use to reduce pain during PDT. In one study comparing topical anesthetics versus cold water, patients experienced better results with the water [ 3 ] . Cooling the treat- ment site through cooling fans, cool air devices (e.g., Zimmer by Medizin Systems, Irvine, CA), cold water spritzing, and decreasing the room tem- perature to 20°C have been demonstrated by sev- eral studies to be the best way to manage pain during and after PDT [ 3, 7, 10 ] . There are several possible mechanism in pain reduction by skin cooling. Photochemistry of PDT is not inhibited by skin cooling, but porphyrin synthesis is potently inhibited at temperatures below 20°C [ 7 ] . Other possible mechanisms for pain reduction include a decrease of tissue metabolism (thus reducing the effects of injury) and vasoconstriction, which would reduce the in fl ow of in fl ammatory media- tors and thereby decrease edema. It has been shown also that cooling the skin stimulates myeli- nated A delta fi bers, thus activating inhibitory pain pathways and raising the pain threshold to noxious stimuli. Low temperatures may reduce the optimal activity of the capsaicin receptor also called TRPV1, thus decreasing its contribution to nocice- ption. Another candidate for involvement in pain amelioration by cooling is the cold and menthol receptor, also known as transient receptor potential cation channel subfamily M member 8 (TRPM8).
Several studies in 2007 identi fi ed TRPM8 as a key player in somatosensation and analgesia [ 3 ] .
Anecdotal evidence suggests that anesthetics injected locally can reduce the pain associated with PDT, including 0.5% lidocaine plus adrena- line (providing relief for 1.5 h), or a longer acting bupivacaine/adrenaline mixture (lasting 2–6 h) can be good options for localized treatment [ 3 ] . Tetracaine and prilocaine have been tested in ran- domized, clinical, placebo controlled studies, without any signi fi cant effect. Nevertheless, there
is no speci fi c pain relief protocol yet. Most of the anesthetic in fi ltration drugs reduce the blood circulation in the target area, especially when they are combined with epinephrine, resulting in a lower oxygen content, which in turn reduces the photodynamic ef fi ciency [ 8 ] . In conclusion, a suitable injected local anesthetic has been dif fi cult to fi nd and the ef fi cacy is generally low [ 3 ] .
Paoli et al. performed cranial nerve blocks on one side of the face in patients undergoing MAL- PDT for AK and demonstrated ef fi cient pain reduction on the anesthetized side [ 3 ] .
Transcutaneous nerve stimulation (TENS) is another technique used to relieve acute or chronic pain. The mechanism behind TENS is based on the gate control theory. A TENS unit consists of an external stimulator and electrodes applied directly to the skin. Hallidin et al. applied elec- trodes on shoulders during PDT of the face and scalp to deliver a pulsed current at a frequency of 80 Hz. They demonstrated that TENS reduces the VAS values during PDT when treating AK located on the face and scalp [ 3, 15 ] .
In conclusion, pain when present during PDT illumination is a dif fi cult problem. The consensus opinion is that cooling the skin with either iced water or with high-air fl ow cooling devices (e.g., Zimmer) represents the best topical intervention to control pain during PDT. Pain is a real problem during treatment with continuous sources of high irradiance, such as LEDs, lasers, and fl uorescent and fi ltered lamps. It is much less with pulsed sources and can be reduced during light exposure by lowering the source irradiance [ 7 ] .
The use of oral analgesics can be indicated to help the patient to minimize the pain sensation.
Improved strategies for relieving pain during PDT will require more controlled studies.
7.2.3 Erythema, Edema, and Exfoliation
After light exposure, erythema and edema fol- lowed by exfoliation are common and expected side effects. Redness and exfoliation can be observed as a normal PDT effect from 1 to 4 days posttreatment [ 1– 3, 6, 12 ] . Sometimes, edema
can last up to 1 week and erythema up to 2 weeks [ 1, 7 ] (Figs. 7.1 and 7.2 ). These reactions can be minimized with shorter drug incubation times. It is suggested to treat symptoms locally if they are problematic. Topical mild emollients, hyaluro nic acid creams, or topical mild steroids can be use- ful. If the edema is extreme, systemic steroids may be needed [ 1– 3, 6, 12 ] .
7.2.4 Vesiculation, Crusting, Ulceration, and Necrosis
Excessive light exposure after treatment can lead to phototoxic reactions. It is essential to educate patients about this potential side effect. Also, ther- apy for these events is indicated with topical and or systemic steroids. Very important recommenda- tion to patients after PDT therapy is to avoid sun- light, or powerful arti fi cial lights. The use of broad spectrum sunscreens and protective clothes is mandatory [ 6 ] . When patient has a history of her- pes simplex infection, antiviral prophylaxis must be prescribed before PDT to avoid the appearance of the infection and, rarely, eczema herpeticum.
7.2.5 Hyper- or Hypopigmentation
Post-in fl ammatory hyperpigmentation is sometimes seen after PDT in patients with skin type III and above. The use of intense pulse light (IPL) during PDT can lead to a linear hyperpigmentation in darker skin and with pulsed dye laser (PDL) to rounded hyperpigmented macules (attributed by shape of spot size) that tend to fade over a period of 4–8 weeks [ 7 ] . Hypopigmentation at treated sites is rare, but has also been reported. It is very important to begin the use of sunscreens and to wear protective clothing immediately after the procedure. Depigmenting therapy should begin after 2 weeks of fi nishing the session of photodynamic therapy [ 1, 6 ] .
7.2.6 Scarring
Is a very rare complication that has been reported only once. It could be a consequence of secondary
Fig. 7.1 Erythema 1 week after treatment with 20% ALA solution-PDT 14 h incubation + Blue light (BluU® – DUSA) for 1,000 s (Picture Courtesy, Dr. Martin N. Zaiac, Miami Beach, Florida, USA)
Fig. 7.2 Erythema 4 days after treatment with 20% ALA solution-PDT 3 h incubation+ Blue light (Clearlight® Lumenis®) for 15 min (Picture courtesy, Dr. Maria Emilia del Pino, Mexico City, Mexico)
infection or a result of curettage in patients treated with MAL-PDT [ 7 ] .
7.2.7 Residual Photosensitivity
As mentioned above, residual photosensitivity will be present for at least 48 h affecting not only the skin but the eyes. Therefore, intense visible light avoidance is recommended during this period. “Sunless tanning” creams or lotions con- taining dihydroxyacetone are mildly protective for porphyrin-mediated photosensitivity, have the advantage of lasting for about the same duration as ALA-induced skin photosensitivity, and help to camou fl age the acute skin reaction. Patients must wear sunglasses and protective clothing [ 7 ] .