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A review of pain experienced during topical photodynamic therapy—Our experience in Dundee
Photodiagnosis and Photodynamic Therapy (2011) 8, 53—57
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/pdpdt
A review of pain experienced during topical photodynamic therapy—–Our experience in Dundee Sasi Kiran Attili ∗, Robert Dawe, Sally Ibbotson Department of Dermatology & Photobiology, Ninewells University Hospital, Dundee DD1 9SY, UK
KEYWORDS Photodynamic therapy; Pain; Phototosensitiser; 5-Aminolaevulinic acid; Methyl aminolevulinate
Summary Background: Topical photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) and its methylated ester, methyl aminolevulinate (MAL) is widely used to treat superficial nonmelanoma skin cancer (NMSC). It has been proposed that ALA PDT is more painful than MAL PDT. The aim of this paper was to compare pain scores of MAL PDT with ALA PDT in our patients and to analyse the relationship between various parameters and pain during PDT. Methods: We retrospectively reviewed case notes and electronic records for all patients with superficial NMSC treated with PDT from June 2007 to March 2009. Results: On univariate analysis of patients with single lesions only, we observed no association between pain and lesion diameter or pro-drug or dose or diagnosis. Pre-treatment PpIX fluorescence was significantly associated with pain. However on univariate analysis of all patients (whether single or multiple lesions) treated with PDT, MAL was associated with significantly less pain than ALA. When all the recorded variables were taken into account (multivariate analysis), diagnosis, pre-treatment PpIX fluorescence and lesion diameter were associated with pain. Conclusions: Our data lends some support to previous published reports suggesting that the MAL PDT regime is less painful than that for ALA PDT. However, PDT pain is multifactorial and choice of photosensitiser is probably not a major pain determining factor. A prospective randomised study, with the same incubation periods for each pro-drug, is needed to definitively answer the question as to whether or not MAL PDT causes less pain than ALA PDT. © 2011 Elsevier B.V. All rights reserved.
Introduction Topical photodynamic therapy (PDT) is effective for superficial BCC (sBCC), Bowen’s disease (BD) and nonhypertrophic actinic keratosis (AK), with high response rates and excellent cosmetic outcomes [1]. Topical PDT
∗ Corresponding author. Tel.: +44 1382660111; fax: +44 1382633916. E-mail addresses: [email protected], [email protected] (S.K. Attili).
utilises the ability of pro-drugs: 5-aminolaevulinic acid (ALA) or methyl aminolevulinate (MAL), to stimulate the production of a photosensitiser, protoporphyrin IX (PpIX). This photosensitiser preferentially accumulates in cells with high turnover, which explains the relative tumour specificity of PDT. Subsequent illumination of PpIX-enriched tissue leads to the production of singlet oxygen and free radicals, which induce tumour necrosis. We have almost 15 years experience in the use of topical PDT for NMSC and other skin diseases. Over this period, we have undertaken over 5000 PDT treatments. We initially routinely used ALA for more than 10 years and introduced the use of MAL in June 2007.
1572-1000/$ — see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2010.12.008
54
S.K. Attili et al.
MAL is currently the only licensed photosensitiser prodrug for topical PDT in the UK and is the methyl ester of ALA. It has been proposed that because of the enhanced lipophilicity [2], MAL can penetrate more easily into cells than ALA and may lead to more effective PDT. Pain is currently the main limiting factor for cutaneous PDT. The number of patients reporting significant pain and having to stop treatment because of this, varies considerably [3—5]. It is of interest that Kasche et al. reported that 54% of patients undergoing ALA PDT for AKs located on the scalp, had to stop treatment because of pain [4]. However, the exact mechanism of PDT-induced pain is unclear. Maximal pain usually occurs in the early part of irradiation during PDT and then gradually reduces [6,7]. A number of reports suggest that MAL PDT is less painful than ALA PDT [4,8—10]. However, pain associated with PDT is often reported to be multifactorial and there are a number of other studies, which have not found a difference between pain induced by either ALA or MAL PDT [11—15]. We reviewed pain experienced by our patients during MAL PDT and compared this with similar data from a cohort of patients treated with ALA PDT over the same period.
Aim The primary aim of this paper was to compare pain scores of MAL PDT with ALA PDT. The secondary aim was to analyse the relationship between various parameters with pain during PDT.
Methods We retrospectively reviewed case notes and electronic records for all patients with superficial NMSC (AK, BD and sBCC) treated with MAL from June 2007 to March 2009. Patients treated for other diagnoses were excluded to avoid confounding of results. Patients were identified from the in-house PDT database. All patients treated with ALA PDT within the same time period were included in the ALA cohort. Data collected included diagnosis, lesion size, pre-treatment PpIX fluorescence intensity and pain scores. When patients had multiple lesions the mean scores for the different parameters, were used for analysis i.e. data was analysed per patient rather than per lesion as it was considered that pain scores were more likely to reflect patient characteristics than lesion characteristics.
Table 1
Results A total of 54 patients (77 lesions) treated with MAL PDT were identified from the PDT database. Twelve of these patients received PDT to more than one lesion. Over the same period 52 patients (95 lesions) were treated with ALA PDT of whom 20 had more than one lesion treated. The majority (91%) of lesions treated with MAL PDT were sBCC and BD whilst the
Relationship between PDT induced pain and lesion/treatment parameters (single lesions only, n = 71a ).
Variable
Pro-drug (ALA vs. MAL) Fluorescence (graded as 0—3) Lesion diameter (cm) Diagnosis (BD, sBCC, AK) Dose (J/cm2 ) a
For lesions receiving multiple treatments, VAS scores for the first treatment only were analysed. Our departmental PDT treatment protocol involves application of pro-drug (Metvix creamTM , Galderma, UK or 5-aminolaevulinic acid, 20% (w/v) in oil in water base, Manmed Pharmaceuticals, UK), for either three (MAL), four (AK & BD) or six (sBCC) hours (ALA), to lesions prepared by gentle abrasion (with a spatula or curette) without local anaesthetic. Visual fluorescence of the lesion was assessed using a Wood’s lamp and graded on a four-point scale for intensity (none, mild, moderate, strong). All patients were routinely offered cooled air treatment (Cynosure® ) during irradiation. Irradiation was performed using one of several light sources available in the department [5]. The Aktilite® LED source was used for MAL PDT but we also used either the 630 nm diode laser (Diomed® ) or the PDT1200 for ALA PDT. Initially MAL PDT was used at an irradiation dose of 37 J/cm2 , as per manufacturer recommendations. However, our early impression was that response to a single treatment cycle with MAL PDT amongst our patients was lower than expected and we therefore increased the dose to 75 J/cm2 . ALA PDT treated lesions were irradiated with a standard dose of 125 J/cm2 for laser and non-LED sources or 75 J/cm2 if using LED sources. The treatment cycle as above was repeated at one week for BD and sBCC. All patients routinely scored pain on a visual analogue scale (VAS) immediately after treatment. Pain scores in the ALA and MAL groups followed an approximately normal distribution with similar variances. Pain in these pro-drug groups was compared by examination of graphs and use of the Student t test. Associated methods were used to construct confidence intervals (CIs). To explore factors that might influence pain, a least squares linear regression model was constructed. The association between pain and each recorded variable was explored by both univariate and multivariate analysis. However to avoid confounding results we excluded patients with multiple lesions from this analysis. A p-value of ≤0.05 was regarded as ‘significant’.
Multivariate analysis (corrected regression coefficient)
Univariate analysis (crude regression coefficient)
Coefficient (95% CI)
p value
Coefficient (95% CI)
p value
−1.204 .958 .218 −.977 −.012
0.089 0.002 0.016 0.011 0.264
.723 .706 .101 −.570 .006
0.135 0.022 0.226 0.104 0.415
(−2.598 to .189) (.377 to 1.539) (.041 to .394) (−1.724 to −.229) (−.034 to .009)
(−1.676 to .230) (.107 to 1.306) (−.064 to .266) (−1.260 to .119) (−.009 to .021)
Total patients with single lesions = 71. However one patient had to be excluded due to incomplete data in case-notes.
Parameters that might potentially predict PDT pain.
Non-modifiable factors
Modifiable factors
Patient characteristics Age: None of the studies published have found a significant relation between age and pain [3,10,13,14,17,18,21].
Treatment protocols Light source (i.e. influence of wavelength): Conflicting data have been published regarding the benefit of red vs. green light irradiation [24,25]. Two studies have reported no difference in pain scores between broadband and LED light sources [5,26]. Interestingly variable pulsed light delivery seems to be less painful than a continuous LED light source [30]. Fluence: Ericson et al. reported that low fluences are associated with lower pain scores [6] and suggested that there is no increase in photobleaching (and hence efficacy) beyond 40 J/cm2 . Two further studies do not support this association [3,7], which might certainly be a threshold effect as it is well known that the majority of PDT pain is experienced within the first few minutes of irradiation. Low fluence rate: A number of studies have suggested significant (clinically relevant) reduction in pain scores when employing low fluence rates [5,17,19,23,27—29]. However, Ericson et al. [6] did not observe this association when comparing 30 mW/cm2 vs. 75 mW/cm2 . Moreover as with fluence, there might be a threshold effect and one might not observe a significant association beyond a certain threshold fluence rate (possibly of the order of 10—15 mW/cm2 ). Photosensitiser (ALA/MAL): A few studies have suggested that MAL is less painful than ALA [4,8—10]. However, the association might not hold true when other confounding factors are taken into account and at least four other studies do not support this association [11—14]. Duration of application of photosensitiser: None of the studies so far have been designed to study the effect of this on pain. 1st vs. 2nd treatment (probably a non-modifiable factor): Virgili et al. found no difference in pain scores between 1st and 2nd treatments [21], whilst three further studies reported conflicting data [10,17,22].
Sex (male): Only two studies have suggested an association between male sex and pain [3,14]. However multivariate regression analysis correcting for all confounding factors was not performed. A number of other studies have not supported this association [10,13,18,21]. Genetic, ethnic & cultural factors: No studies have looked at these so far.
Skin phototype: Lower skin phototypes have been shown to be associated with more pain in two studies [13,21]. However, three other studies do not support this association [3,14,18]. Chronic use of oral analgesics: No association reported [13]. Lesion characteristics
Topical photodynamic therapy
Table 2
Diagnosis: Two studies suggested that AK was associated with more PDT-induced pain than other NMSC [3,21]. However multivariate analysis correcting for all other confounding factors was not performed. Our data suggest that PDT-induced pain with BD > sBCC > AK. Size: Two studies, apart from our present review, have suggested that larger lesions might be associated with more pain during PDT [3,18]. However confounding variables were not corrected for. Two further studies did not support this association [13,17]. Body site: Three studies have suggested that lesions on head and neck are more painful than lesions at non-head and neck sites [3,14,21]. However confounding variables were not accounted for. Two studies found no effect of lesion location when other factors were accounted for [13,17]. Erythema of lesions: Only two studies have looked at this so far with one finding no relation [22] and the other suggesting a relation between pre-treatment erythema and pain. However correction for PpIX flouorescence or body site was not performed [18]. Pre-treatment fluorescence: Only one study apart from our case series, observed a positive correlation relation between PpIX fluorescence and pain on multivariate analysis [17]. Three other studies did not support this observation [3,6,23].
55
56 majority (84%) of lesions treated with ALA PDT were BD and AK. This difference reflects our departmental use of MAL PDT for its licensed indication and ALA PDT for field change AK. The mean VAS score for patients treated with MAL PDT [5.07; standard deviation (SD) = 2.06, range = 0.5—9] was lower (p = 0.01; difference between means = 0.97 cm, 95% confidence interval = 0.24—1.72 cm) than that for patients treated with ALA PDT (6.04; SD = 1.74, range = 2—10). The median lesion diameter for lesions treated with MAL PDT (2 cm; range = 0.5—10; inter-quartile range = 1.5—3 cm) was lower (p = 0.037, 95% confidence interval for difference in medians = −1.8—0) than that of lesions treated with ALA PDT (3 cm; range = 1—16; inter-quartile range = 1.5—8.05). This could have accounted for difference in pain scores observed between the pro-drug groups. When we analysed pain scores from patients treated with single lesions only, the difference in pain scores between the MAL and ALA groups did not reach statistical significance on univariate analysis (Table 1). Taking other recorded variables (including lesion diameter) into account (multivariate analysis) there was a suggestion of more of an association between pro-drug group and pain, but this was not significant. Of the variables we could include on univariate analysis, only pre-treatment PpIX fluorescence was significantly associated with pain. We observed no association between pain and lesion diameter or pro-drug or dose or diagnosis. However, when all the recorded variables were taken into account (multivariate analysis), diagnosis (pain for BD greater than for sBCC greater than for AK), pre-treatment PpIX fluorescence and lesion diameter were associated with pain (Table 1).
Discussion In keeping with previous studies [4,8—10], our survey findings when analysing all patients’ data, whether they had one or more lesions treated, supported the suggestion that MAL PDT is associated with less (albeit a small difference of 0.97 cm on the VAS scale) pain than ALA PDT, with these conventionally used regimes. This suggestion observed in previous studies has been a factor in clinicans choosing MAL in preference to ALA for cutaneous PDT. However most of these studies, like our survey, used different treatment protocols for MAL and ALA, which might explain the differences in pain observed. Moreover, it is important to note that the median diameter of MAL PDT treated lesions in our series was significantly lower than that of lesions treated with ALA PDT, which might have influenced pain scores. The association did not reach significance when we excluded patients with multiple lesions, even when other factors were corrected for (Table 1). In virtually all published studies (including our cohort) reported differences in pain scores were of a magnitude often less than 10—15%, which might not be a difference clinically perceptible by patients. Most previous studies assessed MAL PDT with shorter MAL incubation periods than for ALA [4,8]. This would be appropriate if there was evidence that ALA needed to be applied longer to achieve the same efficacy. There is no such evidence. The three studies that employed identical incubation times for ALA and MAL for the treatment of NMSC did not
S.K. Attili et al. detect any differences in pain scores between the pro-drugs [11,12,14]. Various factors influence PDT-induced pain (Table 2). None of these factors has consistently been reported across all studies to be associated with PDT pain. So, although evaluation of patient and lesion characteristics (Table 2) is interesting, it is not yet clinically very helpful as these are non-modifiable factors and can only be used for predictive (pain) purposes to tailor analgesia to the patient. The mechanism of PDT pain has yet to be completely elucidated. However, a number of mechanisms for PDT pain have been proposed including stimulation of free nerve endings, by hypoxia or by singlet oxygen itself, produced during irradiation [16]. Consequently it is conceivable that any process that increases the rate of tissue hypoxia and or singlet oxygen generation would increase the amount of pain experienced during PDT. Mikolajewska et al. used the rate of PpIX photobleaching as a surrogate marker of these factors and showed that the time for pain induction was proportional to the rate of PpIX photobleaching (for either MAL or ALA) [16]. They also demonstrated in normal skin that ALA induced three times more PpIX than MAL (although they were not able to demonstrate a significant relation between PpIX fluorescence and pain), which might explain the apparent difference in pain scores. However, if the rate of photobleaching of ALA or MAL can be reduced, the influence of photosensitiser on pain should theoretically be minimised. PDT at low fluence rates (which should consequently reduce the rate of tissue hypoxia) has been shown to be consistently associated with low pain scores [19,20] and this approach is promising for the future of PDT. Low fluence PDT is probably the single most influential modifiable factor that can be used to reduce PDT pain. None of the studies to date have shown a clinically significant reduction in pain scores after adjustment of the other treatment parameters (Table 2). Evaluation of patient and lesion characteristics (Table 2) though interesting, is clinically not very helpful as these are non-modifiable factors and can only be used for predictive (pain) purposes to tailor analgesia to the patient. There is a need for more work to determine the most appropriate techniques to reduce PDT-induced pain when it occurs. If it is possible to prevent (or reduce the severity of) pain by choice of pro-drug that would be helpful. A prospective randomised study, with the same incubation periods for each pro-drug, is needed to definitively answer the question as to whether or not MAL PDT causes less pain than ALA PDT.
References [1] Morton CA, McKenna KE, Rhodes LE, British Association of Dermatologists Therapy Guidelines, Audit Subcommittee and the British Photodermatology Group. Guidelines for topical photodynamic therapy: update. Br J Dermatol 2008;159(December (6)):1245—66. [2] Peng Q, Warloe T, Moan J, et al. Distribution of 5-aminolevulinic acid-induced porphyrins in noduloulcerative basal cell carcinoma. Photochem Photobiol 1995;62(November (5)):906—13. [3] Grapengiesser S, Ericson M, Gudmundsson F, Larko O, Rosen A, Wennberg AM. Pain caused by photodynamic therapy of skin cancer. Clin Exp Dermatol 2002;27(September (6)):493—7.
Topical photodynamic therapy [4] Kasche A, Luderschmidt S, Ring J, Hein R. Photodynamic therapy induces less pain in patients treated with methyl aminolevulinate compared to aminolevulinic acid. J Drugs Dermatol 2006;5(April (4)):353—6. [5] Clark C, Bryden A, Dawe R, Moseley H, Ferguson J, Ibbotson SH. Topical 5-aminolaevulinic acid photodynamic therapy for cutaneous lesions: outcome and comparison of light sources. Photodermatol Photoimmunol Photomed 2003;19(June (3)):134—41. [6] Ericson MB, Sandberg C, Stenquist B, et al. Photodynamic therapy of actinic keratosis at varying fluence rates: assessment of photobleaching, pain and primary clinical outcome. Br J Dermatol 2004;151(6):1204—12. [7] Radakovic-Fijan S, Blecha-Thalhammer U, Kittler H, Honigsmann H, Tanew A. Efficacy of 3 different light doses in the treatment of actinic keratosis with 5-aminolevulinic acid photodynamic therapy: a randomized, observer-blinded, intrapatient, comparison study. J Am Acad Dermatol 2005;53(November (5)):823—7. [8] Moloney FJ, Collins P. Randomized, double-blind, prospective study to compare topical 5-aminolaevulinic acid methylester with topical 5-aminolaevulinic acid photodynamic therapy for extensive scalp actinic keratosis. Br J Dermatol 2007;157(July (1)):87—91. [9] Wiegell SR, Stender IM, Na R, Wulf HC. Pain associated with photodynamic therapy using 5-aminolevulinic acid or 5aminolevulinic acid methylester on tape-stripped normal skin. Arch Dermatol 2003;139(September (9)):1173—7. [10] Steinbauer JM, Schreml S, Babilas P, et al. Topical photodynamic therapy with porphyrin precursors—–assessment of treatment-associated pain in a retrospective study. Photochem Photobiol Sci 2009;8(August (8)):1111—6. [11] Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using 5-aminolevulinic acid versus methyl aminolevulinate. J Am Acad Dermatol 2006;54(April (4)):647—51. [12] Kuijpers DI, Thissen MR, Thissen CA, Neumann MH. Similar effectiveness of methyl aminolevulinate and 5-aminolevulinate in topical photodynamic therapy for nodular basal cell carcinoma. J Drugs Dermatol 2006;5(July—August (7)): 642—5. [13] Arits AH, van de Weert MM, Nelemans PJ, Kelleners-Smeets NW. Pain during topical photodynamic therapy: uncomfortable and unpredictable. J Eur Acad Dermatol Venereol 2010;26(April). [14] Gholam P, Denk K, Sehr T, Enk A, Hartmann M. Factors influencing pain intensity during topical photodynamic therapy of complete cosmetic units for actinic keratoses. J Am Acad Dermatol 2010;63(August (2)):213—8. [15] Schleier P, Berndt A, Kolossa S, Zenk W, Hyckel P, SchultzeMosgau S. Comparison of aminolevulinic acid (ALA)-thermogelPDT with methyl-ALA-thermogel-PDT in basal cell carcinoma. Photodiagn Photodynam Ther 2007;4(3):197—201, 9. [16] Mikolajewska P, Iani V, Juzeniene A, Moan J. Topical aminolaevulinic acid- and aminolaevulinic acid methyl ester-based photodynamic therapy with red and violet light: influence of wavelength on pain and erythema. Br J Dermatol 2009;161(November (5)):1173—9.
57 [17] Wiegell SR, Skiveren J, Philipsen PA, Wulf HC. Pain during photodynamic therapy is associated with protoporphyrin IX fluorescence and fluence rate. Br J Dermatol 2008;158(April (4)):727—33. [18] Sandberg C, Stenquist B, Rosdahl I, et al. Important factors for pain during photodynamic therapy for actinic keratosis. Acta Derm Venereol 2006;86(5):404—8. [19] Attili SK, Lesar A, McNeill A, et al. An open pilot study of ambulatory photodynamic therapy using a wearable low-irradiance organic light-emitting diode light source in the treatment of nonmelanoma skin cancer. Br J Dermatol 2009;161(July (1)):170—3. [20] Wiegell SR, Haedersdal M, Philipsen PA, Eriksen P, Enk CD, Wulf HC. Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study. Br J Dermatol 2008;158(April (4)):740—6. [21] Virgili A, Osti F, Maranini C, Corazza M. Photodynamic therapy: parameters predictive of pain. Br J Dermatol 2010;162(February (2)):460—1. [22] Lindeburg KE, Brogaard HM, Jemec GB. Pain and photodynamic therapy. Dermatology 2007;215(3):206—8. [23] Cottrell WJ, Paquette AD, Keymel KR, Foster TH, Oseroff AR. Irradiance-dependent photobleaching and pain in deltaaminolevulinic acid-photodynamic therapy of superficial basal cell carcinomas. Clin Cancer Res 2008;14(July (14)): 4475—83. [24] Fritsch C, Stege H, Saalmann G, Goerz G, Ruzicka T, Krutmann J. Green light is effective and less painful than red light in photodynamic therapy of facial solar keratoses. Photodermatol Photoimmunol Photomed 1997;13(October— December (5—6)):181—5. [25] Morton CA, Whitehurst C, Moore JV, MacKie RM. Comparison of red and green light in the treatment of bowen’s disease by photodynamic therapy. Br J Dermatol 2000;143(4): 767—72. [26] Babilas P, Travnik R, Werner A, Landthaler M, Szeimies RM. Split-face-study using two different light sources for topical PDT of actinic keratoses: non-inferiority of the LED system. J Dtsch Dermatol Ges 2008;6(January (1)):25—32. [27] Wiegell SR, Haedersdal M, Eriksen P, Wulf HC. Photodynamic therapy of actinic keratoses with 8% and 16% methyl aminolaevulinate and home-based daylight exposure: a double-blinded randomized clinical trial. Br J Dermatol 2009;160(June (6)): 1308—14. [28] Langmack K, Mehta R, Twyman P, Norris P. Topical photodynamic therapy at low fluence rates—–theory and practice. J Photochem Photobiol B 2001;60(April (1)):37—43. [29] Moseley H, Allen JW, Ibbotson S, et al. Ambulatory photodynamic therapy: a new concept in delivering photodynamic therapy. Br J Dermatol 2006;154(April (4)):747—50. [30] Babilas P, Knobler R, Hummel S, et al. Variable pulsed light is less painful than light-emitting diodes for topical photodynamic therapy of actinic keratosis: a prospective randomized controlled trial. Br J Dermatol 2007;157(July (1)):111—7.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/pdpdt
A review of pain experienced during topical photodynamic therapy—–Our experience in Dundee Sasi Kiran Attili ∗, Robert Dawe, Sally Ibbotson Department of Dermatology & Photobiology, Ninewells University Hospital, Dundee DD1 9SY, UK
KEYWORDS Photodynamic therapy; Pain; Phototosensitiser; 5-Aminolaevulinic acid; Methyl aminolevulinate
Summary Background: Topical photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) and its methylated ester, methyl aminolevulinate (MAL) is widely used to treat superficial nonmelanoma skin cancer (NMSC). It has been proposed that ALA PDT is more painful than MAL PDT. The aim of this paper was to compare pain scores of MAL PDT with ALA PDT in our patients and to analyse the relationship between various parameters and pain during PDT. Methods: We retrospectively reviewed case notes and electronic records for all patients with superficial NMSC treated with PDT from June 2007 to March 2009. Results: On univariate analysis of patients with single lesions only, we observed no association between pain and lesion diameter or pro-drug or dose or diagnosis. Pre-treatment PpIX fluorescence was significantly associated with pain. However on univariate analysis of all patients (whether single or multiple lesions) treated with PDT, MAL was associated with significantly less pain than ALA. When all the recorded variables were taken into account (multivariate analysis), diagnosis, pre-treatment PpIX fluorescence and lesion diameter were associated with pain. Conclusions: Our data lends some support to previous published reports suggesting that the MAL PDT regime is less painful than that for ALA PDT. However, PDT pain is multifactorial and choice of photosensitiser is probably not a major pain determining factor. A prospective randomised study, with the same incubation periods for each pro-drug, is needed to definitively answer the question as to whether or not MAL PDT causes less pain than ALA PDT. © 2011 Elsevier B.V. All rights reserved.
Introduction Topical photodynamic therapy (PDT) is effective for superficial BCC (sBCC), Bowen’s disease (BD) and nonhypertrophic actinic keratosis (AK), with high response rates and excellent cosmetic outcomes [1]. Topical PDT
∗ Corresponding author. Tel.: +44 1382660111; fax: +44 1382633916. E-mail addresses: [email protected], [email protected] (S.K. Attili).
utilises the ability of pro-drugs: 5-aminolaevulinic acid (ALA) or methyl aminolevulinate (MAL), to stimulate the production of a photosensitiser, protoporphyrin IX (PpIX). This photosensitiser preferentially accumulates in cells with high turnover, which explains the relative tumour specificity of PDT. Subsequent illumination of PpIX-enriched tissue leads to the production of singlet oxygen and free radicals, which induce tumour necrosis. We have almost 15 years experience in the use of topical PDT for NMSC and other skin diseases. Over this period, we have undertaken over 5000 PDT treatments. We initially routinely used ALA for more than 10 years and introduced the use of MAL in June 2007.
1572-1000/$ — see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2010.12.008
54
S.K. Attili et al.
MAL is currently the only licensed photosensitiser prodrug for topical PDT in the UK and is the methyl ester of ALA. It has been proposed that because of the enhanced lipophilicity [2], MAL can penetrate more easily into cells than ALA and may lead to more effective PDT. Pain is currently the main limiting factor for cutaneous PDT. The number of patients reporting significant pain and having to stop treatment because of this, varies considerably [3—5]. It is of interest that Kasche et al. reported that 54% of patients undergoing ALA PDT for AKs located on the scalp, had to stop treatment because of pain [4]. However, the exact mechanism of PDT-induced pain is unclear. Maximal pain usually occurs in the early part of irradiation during PDT and then gradually reduces [6,7]. A number of reports suggest that MAL PDT is less painful than ALA PDT [4,8—10]. However, pain associated with PDT is often reported to be multifactorial and there are a number of other studies, which have not found a difference between pain induced by either ALA or MAL PDT [11—15]. We reviewed pain experienced by our patients during MAL PDT and compared this with similar data from a cohort of patients treated with ALA PDT over the same period.
Aim The primary aim of this paper was to compare pain scores of MAL PDT with ALA PDT. The secondary aim was to analyse the relationship between various parameters with pain during PDT.
Methods We retrospectively reviewed case notes and electronic records for all patients with superficial NMSC (AK, BD and sBCC) treated with MAL from June 2007 to March 2009. Patients treated for other diagnoses were excluded to avoid confounding of results. Patients were identified from the in-house PDT database. All patients treated with ALA PDT within the same time period were included in the ALA cohort. Data collected included diagnosis, lesion size, pre-treatment PpIX fluorescence intensity and pain scores. When patients had multiple lesions the mean scores for the different parameters, were used for analysis i.e. data was analysed per patient rather than per lesion as it was considered that pain scores were more likely to reflect patient characteristics than lesion characteristics.
Table 1
Results A total of 54 patients (77 lesions) treated with MAL PDT were identified from the PDT database. Twelve of these patients received PDT to more than one lesion. Over the same period 52 patients (95 lesions) were treated with ALA PDT of whom 20 had more than one lesion treated. The majority (91%) of lesions treated with MAL PDT were sBCC and BD whilst the
Relationship between PDT induced pain and lesion/treatment parameters (single lesions only, n = 71a ).
Variable
Pro-drug (ALA vs. MAL) Fluorescence (graded as 0—3) Lesion diameter (cm) Diagnosis (BD, sBCC, AK) Dose (J/cm2 ) a
For lesions receiving multiple treatments, VAS scores for the first treatment only were analysed. Our departmental PDT treatment protocol involves application of pro-drug (Metvix creamTM , Galderma, UK or 5-aminolaevulinic acid, 20% (w/v) in oil in water base, Manmed Pharmaceuticals, UK), for either three (MAL), four (AK & BD) or six (sBCC) hours (ALA), to lesions prepared by gentle abrasion (with a spatula or curette) without local anaesthetic. Visual fluorescence of the lesion was assessed using a Wood’s lamp and graded on a four-point scale for intensity (none, mild, moderate, strong). All patients were routinely offered cooled air treatment (Cynosure® ) during irradiation. Irradiation was performed using one of several light sources available in the department [5]. The Aktilite® LED source was used for MAL PDT but we also used either the 630 nm diode laser (Diomed® ) or the PDT1200 for ALA PDT. Initially MAL PDT was used at an irradiation dose of 37 J/cm2 , as per manufacturer recommendations. However, our early impression was that response to a single treatment cycle with MAL PDT amongst our patients was lower than expected and we therefore increased the dose to 75 J/cm2 . ALA PDT treated lesions were irradiated with a standard dose of 125 J/cm2 for laser and non-LED sources or 75 J/cm2 if using LED sources. The treatment cycle as above was repeated at one week for BD and sBCC. All patients routinely scored pain on a visual analogue scale (VAS) immediately after treatment. Pain scores in the ALA and MAL groups followed an approximately normal distribution with similar variances. Pain in these pro-drug groups was compared by examination of graphs and use of the Student t test. Associated methods were used to construct confidence intervals (CIs). To explore factors that might influence pain, a least squares linear regression model was constructed. The association between pain and each recorded variable was explored by both univariate and multivariate analysis. However to avoid confounding results we excluded patients with multiple lesions from this analysis. A p-value of ≤0.05 was regarded as ‘significant’.
Multivariate analysis (corrected regression coefficient)
Univariate analysis (crude regression coefficient)
Coefficient (95% CI)
p value
Coefficient (95% CI)
p value
−1.204 .958 .218 −.977 −.012
0.089 0.002 0.016 0.011 0.264
.723 .706 .101 −.570 .006
0.135 0.022 0.226 0.104 0.415
(−2.598 to .189) (.377 to 1.539) (.041 to .394) (−1.724 to −.229) (−.034 to .009)
(−1.676 to .230) (.107 to 1.306) (−.064 to .266) (−1.260 to .119) (−.009 to .021)
Total patients with single lesions = 71. However one patient had to be excluded due to incomplete data in case-notes.
Parameters that might potentially predict PDT pain.
Non-modifiable factors
Modifiable factors
Patient characteristics Age: None of the studies published have found a significant relation between age and pain [3,10,13,14,17,18,21].
Treatment protocols Light source (i.e. influence of wavelength): Conflicting data have been published regarding the benefit of red vs. green light irradiation [24,25]. Two studies have reported no difference in pain scores between broadband and LED light sources [5,26]. Interestingly variable pulsed light delivery seems to be less painful than a continuous LED light source [30]. Fluence: Ericson et al. reported that low fluences are associated with lower pain scores [6] and suggested that there is no increase in photobleaching (and hence efficacy) beyond 40 J/cm2 . Two further studies do not support this association [3,7], which might certainly be a threshold effect as it is well known that the majority of PDT pain is experienced within the first few minutes of irradiation. Low fluence rate: A number of studies have suggested significant (clinically relevant) reduction in pain scores when employing low fluence rates [5,17,19,23,27—29]. However, Ericson et al. [6] did not observe this association when comparing 30 mW/cm2 vs. 75 mW/cm2 . Moreover as with fluence, there might be a threshold effect and one might not observe a significant association beyond a certain threshold fluence rate (possibly of the order of 10—15 mW/cm2 ). Photosensitiser (ALA/MAL): A few studies have suggested that MAL is less painful than ALA [4,8—10]. However, the association might not hold true when other confounding factors are taken into account and at least four other studies do not support this association [11—14]. Duration of application of photosensitiser: None of the studies so far have been designed to study the effect of this on pain. 1st vs. 2nd treatment (probably a non-modifiable factor): Virgili et al. found no difference in pain scores between 1st and 2nd treatments [21], whilst three further studies reported conflicting data [10,17,22].
Sex (male): Only two studies have suggested an association between male sex and pain [3,14]. However multivariate regression analysis correcting for all confounding factors was not performed. A number of other studies have not supported this association [10,13,18,21]. Genetic, ethnic & cultural factors: No studies have looked at these so far.
Skin phototype: Lower skin phototypes have been shown to be associated with more pain in two studies [13,21]. However, three other studies do not support this association [3,14,18]. Chronic use of oral analgesics: No association reported [13]. Lesion characteristics
Topical photodynamic therapy
Table 2
Diagnosis: Two studies suggested that AK was associated with more PDT-induced pain than other NMSC [3,21]. However multivariate analysis correcting for all other confounding factors was not performed. Our data suggest that PDT-induced pain with BD > sBCC > AK. Size: Two studies, apart from our present review, have suggested that larger lesions might be associated with more pain during PDT [3,18]. However confounding variables were not corrected for. Two further studies did not support this association [13,17]. Body site: Three studies have suggested that lesions on head and neck are more painful than lesions at non-head and neck sites [3,14,21]. However confounding variables were not accounted for. Two studies found no effect of lesion location when other factors were accounted for [13,17]. Erythema of lesions: Only two studies have looked at this so far with one finding no relation [22] and the other suggesting a relation between pre-treatment erythema and pain. However correction for PpIX flouorescence or body site was not performed [18]. Pre-treatment fluorescence: Only one study apart from our case series, observed a positive correlation relation between PpIX fluorescence and pain on multivariate analysis [17]. Three other studies did not support this observation [3,6,23].
55
56 majority (84%) of lesions treated with ALA PDT were BD and AK. This difference reflects our departmental use of MAL PDT for its licensed indication and ALA PDT for field change AK. The mean VAS score for patients treated with MAL PDT [5.07; standard deviation (SD) = 2.06, range = 0.5—9] was lower (p = 0.01; difference between means = 0.97 cm, 95% confidence interval = 0.24—1.72 cm) than that for patients treated with ALA PDT (6.04; SD = 1.74, range = 2—10). The median lesion diameter for lesions treated with MAL PDT (2 cm; range = 0.5—10; inter-quartile range = 1.5—3 cm) was lower (p = 0.037, 95% confidence interval for difference in medians = −1.8—0) than that of lesions treated with ALA PDT (3 cm; range = 1—16; inter-quartile range = 1.5—8.05). This could have accounted for difference in pain scores observed between the pro-drug groups. When we analysed pain scores from patients treated with single lesions only, the difference in pain scores between the MAL and ALA groups did not reach statistical significance on univariate analysis (Table 1). Taking other recorded variables (including lesion diameter) into account (multivariate analysis) there was a suggestion of more of an association between pro-drug group and pain, but this was not significant. Of the variables we could include on univariate analysis, only pre-treatment PpIX fluorescence was significantly associated with pain. We observed no association between pain and lesion diameter or pro-drug or dose or diagnosis. However, when all the recorded variables were taken into account (multivariate analysis), diagnosis (pain for BD greater than for sBCC greater than for AK), pre-treatment PpIX fluorescence and lesion diameter were associated with pain (Table 1).
Discussion In keeping with previous studies [4,8—10], our survey findings when analysing all patients’ data, whether they had one or more lesions treated, supported the suggestion that MAL PDT is associated with less (albeit a small difference of 0.97 cm on the VAS scale) pain than ALA PDT, with these conventionally used regimes. This suggestion observed in previous studies has been a factor in clinicans choosing MAL in preference to ALA for cutaneous PDT. However most of these studies, like our survey, used different treatment protocols for MAL and ALA, which might explain the differences in pain observed. Moreover, it is important to note that the median diameter of MAL PDT treated lesions in our series was significantly lower than that of lesions treated with ALA PDT, which might have influenced pain scores. The association did not reach significance when we excluded patients with multiple lesions, even when other factors were corrected for (Table 1). In virtually all published studies (including our cohort) reported differences in pain scores were of a magnitude often less than 10—15%, which might not be a difference clinically perceptible by patients. Most previous studies assessed MAL PDT with shorter MAL incubation periods than for ALA [4,8]. This would be appropriate if there was evidence that ALA needed to be applied longer to achieve the same efficacy. There is no such evidence. The three studies that employed identical incubation times for ALA and MAL for the treatment of NMSC did not
S.K. Attili et al. detect any differences in pain scores between the pro-drugs [11,12,14]. Various factors influence PDT-induced pain (Table 2). None of these factors has consistently been reported across all studies to be associated with PDT pain. So, although evaluation of patient and lesion characteristics (Table 2) is interesting, it is not yet clinically very helpful as these are non-modifiable factors and can only be used for predictive (pain) purposes to tailor analgesia to the patient. The mechanism of PDT pain has yet to be completely elucidated. However, a number of mechanisms for PDT pain have been proposed including stimulation of free nerve endings, by hypoxia or by singlet oxygen itself, produced during irradiation [16]. Consequently it is conceivable that any process that increases the rate of tissue hypoxia and or singlet oxygen generation would increase the amount of pain experienced during PDT. Mikolajewska et al. used the rate of PpIX photobleaching as a surrogate marker of these factors and showed that the time for pain induction was proportional to the rate of PpIX photobleaching (for either MAL or ALA) [16]. They also demonstrated in normal skin that ALA induced three times more PpIX than MAL (although they were not able to demonstrate a significant relation between PpIX fluorescence and pain), which might explain the apparent difference in pain scores. However, if the rate of photobleaching of ALA or MAL can be reduced, the influence of photosensitiser on pain should theoretically be minimised. PDT at low fluence rates (which should consequently reduce the rate of tissue hypoxia) has been shown to be consistently associated with low pain scores [19,20] and this approach is promising for the future of PDT. Low fluence PDT is probably the single most influential modifiable factor that can be used to reduce PDT pain. None of the studies to date have shown a clinically significant reduction in pain scores after adjustment of the other treatment parameters (Table 2). Evaluation of patient and lesion characteristics (Table 2) though interesting, is clinically not very helpful as these are non-modifiable factors and can only be used for predictive (pain) purposes to tailor analgesia to the patient. There is a need for more work to determine the most appropriate techniques to reduce PDT-induced pain when it occurs. If it is possible to prevent (or reduce the severity of) pain by choice of pro-drug that would be helpful. A prospective randomised study, with the same incubation periods for each pro-drug, is needed to definitively answer the question as to whether or not MAL PDT causes less pain than ALA PDT.
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