- Email: [email protected]
Post procedural pain with photodynamic therapy is more severe than skin surgery
Journal of Plastic, Reconstructive & Aesthetic Surgery (2015) 68, e28ee32
Post procedural pain with photodynamic therapy is more severe than skin surgery Anthony J. Dixon a,*, Stuart J. Anderson b, Mary P. Dixon c, John B. Dixon d a Cutaneous Oncology, Australasian College of Cutaneous Oncology, 66 Roslyn Rd, Belmont, Victoria, 3216, Australia b Maffra Medical Group, 160 Johnson St, Maffra, Victoria, 3860, Australia c SkinCancerOnly, 66 Roslyn Rd, Belmont, Victoria, 3216, Australia d Baker IDI Heart & Diabetes Institute, 75 Commercial Road, Melbourne, Victoria, 3004, Australia
Received 24 October 2012; accepted 11 February 2013
KEYWORDS Actinic keratoses; Reconstruction; Pain; Photodynamic; Analgesia; Prospective
Summary Objective: To compare prospective data on pain experienced by patients undergoing large facial skin cancer surgery with pain experienced with novel face photodynamic therapy (PDT). Design: A comparison of pain data sets from two prospective trials in the same centre. Setting: Referral skin cancer centre in Australia. Protocol: 34 PDT patients had two aminolevulinate treatments to the face two weeks apart. 68 Surgery patients, matched 2:1 for gender and age, had large skin cancer excisional surgery to the face and closure with flap, graft or wedge reconstruction. Main outcome measure(s): Severity of pain during and following procedure. Results: The only patients describing their experience as the worst pain of their life were 4 PDT patients (12%). The median and mean pain scores for PDT patients were significantly higher than for extensive facial large face surgery, (p < 0.001). Further analyses comparing PDT to patients having all skin cancer surgery on the face (N Z 170) matched for gender and age demonstrated more pain experienced with PDT. PDT is significantly more likely to result in pain requiring strong analgesia or pain beyond strong analgesics than skin cancer surgery including large facial operations. Discussion and conclusions: Clinicians should consider explaining the relative likelihood of more severe pain whenever PDT is considered over surgery. The pain experienced with this PDT product may not reflect the pain experienced with other PDT products. ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. E-mail addresses: [email protected] (A.J. Dixon), [email protected] (S.J. Anderson), [email protected] (M.P. Dixon), [email protected] (J.B. Dixon). http://dx.doi.org/10.1016/j.bjps.2013.02.002 1748-6815/ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Post procedural pain with photodynamic therapy is more severe than skin surgery
Introduction Photodynamic therapy (PDT) has become an established option in the management of skin cancers1e3 and precancerous skin lesions.4e7 It has emerged as an option that can be offered as an alternative or adjunct to surgical excision.2,8 PDT active ingredients are applied to the affected skin and a light source is then applied to the skin for an illumination following an incubation period. The active ingredient is absorbed and intracellularly converted to protoporphyrin IX, a light-reactive intermediary protein. Activation of protoporphyrin IX by the PDT light source creates free radicals which are essential to the mechanism of action. Patients commonly perceive surgery, including skin surgery, as a painful experience.9e11 PDT has also been reported to frequently cause pain.12e15 When patients have two treatments of PDT pain is frequently severe with the second treatment.15 Pain can be more severe when a larger field is treated with PDT.12 Kasche16 demonstrated that pain during activation can be such that patients request discontinuation of treatment before reaching the required light dose has been reached. This was more likely if the patient was being treated with aminolevulonic acid (ALA) than if treated with methyl aminolevulinate (MAL). There is a report that pain experienced with PDT in Australia may be greater than elsewhere.17 Patient pain perceptions may lead them to seek a topical alternative to an invasive approach in the hope that their procedure and postprocedure pain experience will be reduced.18 In 200719 we published a prospective study of patients’ perceptions of their skin cancer surgery. Included in those perceptions we detailed the level of pain experienced by patients following such surgery. We have since completed another prospective study involving photodynamic therapy with a novel preparation of ALA (Novel ALA) being used as the active ingredient. As part of the protocol for this PDT trial we prospectively recorded the pain patients’ experienced during and following their PDT treatment. We now report on the post procedural pain experiences and compare them to the patients that underwent surgery. The novel ALA product used to treat the patients described herein was developed by Allmedic Pty Ltd as a simple, premixed preparation and was promoted as having a prolonged shelf life and requiring a low intensity of activating light. The aim of the study was to compare a prospective database of patients undergoing skin surgery with a prospective database of patient undergoing PDT. The post procedural pain levels experienced by patients having skin cancer surgery including major skin cancer surgery to the face is to be compared with PDT patients.
Methods The PDT protocol was approved by Bond University Human Research Ethics Committee. The post procedural pain data following skin cancer surgery was acquired as part of completion of a randomized controlled trial approved by the Barwon Health Research and Ethics Committee.
e29
The primary PDT trial sponsor was Allmedic Pty Ltd (Taren Point, NSW, Australia). There was no sponsor for the surgery protocol. All patients were managed in a single skin cancer referral centre in southern Australia. Prospective data on the pain expectations of skin cancer surgery in this centre have been previously reported.19 From this data set of 576 patients, we age and gender matched patients that had more substantial skin cancer surgery to the face 2:1 for each PDT patient. The extensive facial skin cancer surgery group was defined by resections requiring closure by large full thickness wedge repair, full thickness skin grafting or larger random pattern or interpolation skin flap reconstructions or axial flap repairs. This extensive facial surgery group was the key control group of 68 patients. We also compared 170 patients (all facial surgery group) that had undergone all types of skin cancer surgery to the face (age and gender matched 5:1) to PDT patients. We further compared the whole surgery data set of 576 patients (all skin surgery group) to PDT patients. Patients treated with novel ALA for actinic damage had previously experienced one or more histologically proven and surgically cleared facial skin cancers. The protocol involved two PDT treatments 14 days apart. The patient was provided with a 10% alpha hydroxy acid solution to reduce thickened hyperkeratoses to be used twice daily for two weeks prior to PDT. Following a test dose, novel ALA (20% 5aminolevulinate solution) was applied to the whole face [except for eyelids and near mucosal surfaces] followed by a five hour incubation period during which exposure of light face to the face light was avoided. The border of the face was defined as the hairline superiorly, anterior to the tragus laterally and the lower margin of the mandible inferiorly. A 30 min illumination was then undertaken with the PDT light source provided by the sponsor (465 nm blue LED light at 48 J/cm2 for 20 min and then 625 nm red LED light at 64 J/cm2 for 10 min). The sponsor advised that efficacy and safety of their trial ALA had been optimized with this light source. They advised that a combination of blue and red lights was designed to allow for two levels of penetration within the skin. Incubation involved the liquid being massaged into each side of face to provide a thin and uniform cover. Prior to illumination, the face was washed with warm water and dried. During illumination, the eyes and eyelids of the patient were shielded from the light source. Each patient had an attendant(s) present at all times during illumination. A fan to reduce burning sensations was provided as required. The treatment was paused if requested by the patient and discontinued if unable to be tolerated. Following treatment, the patient was given extensive advice regarding minimizing sun exposure, analgesia etc. They were encouraged to remain indoors in a darkened room for at least 48 h and were provided with a sunscreen to apply when outside both before and after treatment. At follow up, patients in both studies were asked by the nursing staff to rate their level of pain experienced post procedure. The level of pain was classified as follows; 1) no pain experienced, 2) mild pain that did not require analgesia, 3) pain that was relieved with paracetamol (Panadol, Herron Paracetamol or Panamax), 4) pain that required stronger oral analgesics to obtain relief such as
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A.J. Dixon et al.
Table 1
Post procedure pain experiences of patients treated with PDT versus skin lesion excisions.
Pain experience
PDT
PDT %
All skin surgerya
All skin surgery %
Face surgeryb
Face surgery %
Large face surgeryc
Large face surgery %
No pain experienced Mild pain not requiring analgesia Pain relieved simply with paracetamol Relieved with stronger agents like codeine Pain not relieved with oral analgesics Worst pain ever experienced
2 11
6% 32%
187 221
33% 39%
53 69
31% 34%
19 29
28% 43%
9
26%
135
24%
39
23%
18
26%
5
15%
16
3%
8
5%
2
3%
3
9%
4
1%
1
1%
0
0%
4
12%
0%
0 p < 0.001 54% 67 40e91 68
0%
56% 70 40e91 34
0 p < 0.001 56% 70 30e98 170
0%
Percentage of patients male Average age of patients Range of ages of patients Total patient numbers
0 p < 0.001 56% 47 28e98 563
a b c
Surgery on all patients at all sites as per JAAD 2007.19 Face surgery of all types with five patients matched for age and gender for each PDT patient. Major face surgery with two patients matched as closely as possible for age and gender to each PDT patient.
codeine, 5) pain unrelieved with oral analgesics and 6) the worst pain experienced in their life thus far. Patient specific comments regarding their pain were noted.
Statistical analysis was performed on the datasets Patient characteristics and differences between groups were assessed with analysis of variance using Tukey posthoc analysis, KruskaleWallis H test and Mann Whitney U test as appropriate. All key outcome incidences were analysed using the chi square test and PDT intervention was compared with control using 2 2 tables.
Results 34 patients underwent PDT at this trial centre. All patients had previously suffered one or more skin cancers to the face treated by surgical clearance and closure. The levels of pain experienced by many were severe and for this and other reasons pertaining to trial governance no further patients were treated with this novel PDT. Further recruitment of PDT trial patients was suspended. 19 of the 34 patients were unable to tolerate the complete PDT illumination protocol. Of the 576 patients that underwent skin surgery 563 reported their level of post procedure pain experience. The average age of all 563 surgery patients was 59.3 (range 28e98) and the average age of PDT patients was 70 (range 40e91). PDT patients were significantly older than surgery patients. The gender of 563 surgery patients was 47% male whereas 56% of PDT patients were male. The patients’ experiences of each level of pain are compared in Table 1. From the all skin surgery group we identified 68 patients as our key control group, the extensive facial large face surgery group. These were skin cancer surgery patients who had undergone larger facial
procedures matched as closely as possible for age and gender 2:1 for each PDT patient. 2 of 34 PDT patients experienced no post procedure pain compared with 33% of all skin surgery group patients (p < 0.0001). The likelihood of experiencing mild pain requiring no analgesia or pain only requiring paracetamol was similar in both groups. PDT patients were more likely to require strong analgesics: (5 of 34) versus surgery 3% (p < 0.0001). The likelihood of experiencing pain not relieved with analgesics was more likely in PDT group (3 of 34) versus surgery (1%) (p < 0.0001). The only patients describing their experience as the worst pain of their life were 4 PDT patients. When patients were questioned regarding the duration of pain 5 PDT patients reported experiencing pain for over a month. The PDT patient group is an older group with a different gender ratio than the all skin surgery group. Also, pain experienced from face procedures may be greater than pain at other sites. With this in mind we compared the all facial surgery group to the PDT group. (Table 1) Nine of the 170 (5.3%) all face surgery patients suffered pain that went beyond oral paracetamol compared with twelve of the 34 PDT patients (p < 0.0001). Given some of these facial procedures were small it was possible that this contributed to the lack of pain experienced by face surgery patients. Hence the key control group was the extensive facial surgery group. For each PDT patient it was not possible to exactly match these larger surgical patients for age and gender so we found the nearest possible age and gender match (Table 1). Only 2 of these patients (3%) required analgesia beyond paracetamol (p < 0.0001). We further analysed for pain variation by identifying the average and median pain experienced by each group of patients. A score was attributed to each of the pain thresholds as follows: No pain Z 1, minimal pain Z 2, simple analgesia Z 3, Stronger analgesics Z 4, unrelieved pain Z 5, and worst pain ever Z 6.
Post procedural pain with photodynamic therapy is more severe than skin surgery The average pain score was 3.2 (range 1e6) for PDT patients and was 2.0 (range 1e5) for each of the three surgical groupings analysed. The median pain score was 3 for PDT patients and 2 for surgical patients in each group. Pain in all individual surgery groupings was less than pain reported in the PDT group, Mann Whitney U test p < 0.001 for all surgical groupings (Figure 1).
Discussion Patients often consider surgery is likely to be painful following the procedure and can seek alternative treatments that may result in less pain.11 Patients might associate topical treatments with discomfort rather than pain. However topical treatments used in the management of premalignant skin lesions have been demonstrated to produce pain at the site treated,20e22 including persistent pain.23 The unlikely infrequent experience of severe pain in surgery patients contrasts with the 21% of PDT patients that suffered uncontrolled pain or pain they described as their worst in life to date. Existing published reports of pain associated with PDT do not include descriptions of pain persisting more than a month or of pain described by the patients as the worst of their life.12,14e16 It has previously been reported that morphine gel13 and tetracaine gel24 can be inadequate analgesia for PDT patients. Pain associated with PDT is most noted during the illumination phase.12,15 Reports to date suggest pain does not persist,16,25 yet six of our intervention patients reported prolonged pain with durations over 4 weeks and up to two months.
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The severe and prolonged pain adverse events noted in this study have been reported to the Therapeutic Goods Administration (TGA) in Australia. The prolonged and severe pain of PDT reported in this study may be due to a preparation variation between this novel agent and existing ALA products. A limitation of the study may be that the numbers of patients managed with PDT was small compared with the surgical treatment group. Nevertheless difference in pain scoring between procedures clearly demonstrates the power was sufficient. PDT patients were having their whole face treated rather than a part of the face. The larger area of treatment may account for part of the explanation of the pain variation experienced. Surgery patients were given local anaesthetic prior to their procedure whereas the PDT patients were not given local anaesthetic. Therefore the circumstances are not completely similar. However the pain measurements in these data sets were post procedural pain reports in the days and weeks following the procedure, not over the minutes or hours post procedure.
Conclusion This novel PDT is more likely to result in pain requiring strong analgesia or pain beyond strong analgesics than major facial skin cancer excisions and reconstruction. Clinicians should consider explaining the relative likelihood of greater pain whenever surgery versus PDT is considered. The pain experienced with this PDT product may not reflect the pain experienced with other PDT products.
Disclosure Family interests of author AD have shares in the sponsoring company. This holding has and is being managed independently with all profits (if any) directed to independent medical research.
References
Figure 1 Median and interquartile range of pain scores for study groups examined. All individual groups report less pain than the PDT group (p < 0.001 for all), (ManneWhitney U test) and when all groups are compared using Kruskal Wallace test the PDT group is significantly different to all others (p < 0.001). There was no difference in pain scores between the 3 surgical comparator groups.
1. Christensen E, Mork C, Skogvoll E. High and sustained efficacy after two sessions of topical 5- aminolaevulinic acid photodynamic therapy for basal cell carcinoma: a prospective, clinical and histological 10-year follow-up study. Br J Dermatol 2012; 166:1342e8. 2. Rhodes LE, de Rie M, Enstrom Y, et al. Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Arch Dermatol 2004;140:17e23. 3. Mosterd K, Thissen MR, Nelemans P, et al. Fractionated 5aminolaevulinic acid-photodynamic therapy vs. surgical excision in the treatment of nodular basal cell carcinoma: results of a randomized controlled trial. Br J Dermatol 2008;159: 864e70. 4. Lehmann P. Methyl aminolaevulinate-photodynamic therapy: a review of clinical trials in the treatment of actinic keratoses and nonmelanoma skin cancer. Br J Dermatol 2007;156: 793e801. 5. Wiegell SR, Fabricius S, Gniadecka M, et al. Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses
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A.J. Dixon et al. of the face and scalp: a randomized multicentre study. Br J Dermatol 2012;166:1327e32. Sotiriou E, Apalla Z, Chovarda E, Goussi C, Trigoni A, Ioannides D. Single vs. fractionated photodynamic therapy for face and scalp actinic keratoses: a randomized, intraindividual comparison trial with 12-month follow-up. J Eur Acad Dermatol Venereol JEADV 2012;26:36e40. Kaufmann R, Spelman L, Weightman W, et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol 2008;158:994e9. Kuijpers DI, Smeets NW, Krekels GA, Thissen MR. Photodynamic therapy as adjuvant treatment of extensive basal cell carcinoma treated with Mohs micrographic surgery. Dermatol Surg 2004;30:794e8. Hoimyr H, von Sperling ML, Rokkones KA, et al. Persistent pain after surgery for cutaneous melanoma. Clin J Pain 2012;28: 149e56. Sniezek PJ, Brodland DG, Zitelli JA. A randomized controlled trial comparing acetaminophen, acetaminophen and ibuprofen, and acetaminophen and codeine for postoperative pain relief after Mohs surgery and cutaneous reconstruction. Dermatol Surg 2011;37:1007e13. Official publication for American Society for Dermatologic Surgery [et al.]. Kuhn S, Cooke K, Collins M, Jones JM, Mucklow JC. Perceptions of pain relief after surgery. BMJ 1990;300:1687e90. Sandberg C, Stenquist B, Rosdahl I, et al. Important factors for pain during photodynamic therapy for actinic keratosis. Acta Derm Venereol 2006;86:404e8. Skiveren J, Haedersdal M, Philipsen PA, Wiegell SR, Wulf HC. Morphine gel 0.3% does not relieve pain during topical photodynamic therapy: a randomized, double-blind, placebo controlled study. Acta Derm Venereol 2006;86: 409e11. 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;157:111e7.
15. Lindeburg KE, Brogaard HM, Jemec GB. Pain and photodynamic therapy. Dermatology 2007;215:206e8. 16. 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;5:353e6. 17. Tran DT, Salmon R. Field treatment of facial and scalp actinic keratoses with photodynamic therapy: survey of patient perceptions of treatment satisfaction and outcomes. Australas J Dermatol 2011;52:195e201. 18. Katz J, Feldman MA, Bass EB, et al. Injectable versus topical anesthesia for cataract surgery: patient perceptions of pain and side effects. The Study of Medical Testing for Cataract Surgery study team. Ophthalmology 2000;107:2054e60. 19. Dixon AJ, Dixon MP, Dixon JB. Prospective study of long-term patient perceptions of their skin cancer surgery. J Am Acad Dermatol 2007;57:445e53. 20. Cantisani C, Lazic T, Richetta AG, Clerico R, Mattozzi C, Calvieri S. Imiquimod 5% cream use in dermatology, side effects and recent patents. Recent Pat Inflamm Allergy Drug Discov 2012;6:65e9. 21. Marks R, Owens M, Walters SA. Efficacy and safety of 5% imiquimod cream in treating patients with multiple superficial basal cell carcinomas. Arch Dermatol 2004;140:1284e5. 22. Schmid-Wendtner MH, Wendtner CM. Intensified inflammatory reaction of actinic keratosis after single application of topical 5-fluorouracil in a patient treated with nilotinib for chronic myeloid leukemia. Dermatology 2009;219:341e3. 23. Yi BA, Nirenberg MJ, Goldstein SM, Berger TG. Chronic neuropathic pain associated with imiquimod: report of 2 cases. J Am Acad Dermatol 2005;52:57e8. 24. Holmes MV, Dawe RS, Ferguson J, Ibbotson SH. A randomized, double-blind, placebocontrolled study of the efficacy of tetracaine gel (Ametop) for pain relief during topical photodynamic therapy. Br J Dermatol 2004;150:337e40. 25. 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;151:1204e12.
Post procedural pain with photodynamic therapy is more severe than skin surgery Anthony J. Dixon a,*, Stuart J. Anderson b, Mary P. Dixon c, John B. Dixon d a Cutaneous Oncology, Australasian College of Cutaneous Oncology, 66 Roslyn Rd, Belmont, Victoria, 3216, Australia b Maffra Medical Group, 160 Johnson St, Maffra, Victoria, 3860, Australia c SkinCancerOnly, 66 Roslyn Rd, Belmont, Victoria, 3216, Australia d Baker IDI Heart & Diabetes Institute, 75 Commercial Road, Melbourne, Victoria, 3004, Australia
Received 24 October 2012; accepted 11 February 2013
KEYWORDS Actinic keratoses; Reconstruction; Pain; Photodynamic; Analgesia; Prospective
Summary Objective: To compare prospective data on pain experienced by patients undergoing large facial skin cancer surgery with pain experienced with novel face photodynamic therapy (PDT). Design: A comparison of pain data sets from two prospective trials in the same centre. Setting: Referral skin cancer centre in Australia. Protocol: 34 PDT patients had two aminolevulinate treatments to the face two weeks apart. 68 Surgery patients, matched 2:1 for gender and age, had large skin cancer excisional surgery to the face and closure with flap, graft or wedge reconstruction. Main outcome measure(s): Severity of pain during and following procedure. Results: The only patients describing their experience as the worst pain of their life were 4 PDT patients (12%). The median and mean pain scores for PDT patients were significantly higher than for extensive facial large face surgery, (p < 0.001). Further analyses comparing PDT to patients having all skin cancer surgery on the face (N Z 170) matched for gender and age demonstrated more pain experienced with PDT. PDT is significantly more likely to result in pain requiring strong analgesia or pain beyond strong analgesics than skin cancer surgery including large facial operations. Discussion and conclusions: Clinicians should consider explaining the relative likelihood of more severe pain whenever PDT is considered over surgery. The pain experienced with this PDT product may not reflect the pain experienced with other PDT products. ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. E-mail addresses: [email protected] (A.J. Dixon), [email protected] (S.J. Anderson), [email protected] (M.P. Dixon), [email protected] (J.B. Dixon). http://dx.doi.org/10.1016/j.bjps.2013.02.002 1748-6815/ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Post procedural pain with photodynamic therapy is more severe than skin surgery
Introduction Photodynamic therapy (PDT) has become an established option in the management of skin cancers1e3 and precancerous skin lesions.4e7 It has emerged as an option that can be offered as an alternative or adjunct to surgical excision.2,8 PDT active ingredients are applied to the affected skin and a light source is then applied to the skin for an illumination following an incubation period. The active ingredient is absorbed and intracellularly converted to protoporphyrin IX, a light-reactive intermediary protein. Activation of protoporphyrin IX by the PDT light source creates free radicals which are essential to the mechanism of action. Patients commonly perceive surgery, including skin surgery, as a painful experience.9e11 PDT has also been reported to frequently cause pain.12e15 When patients have two treatments of PDT pain is frequently severe with the second treatment.15 Pain can be more severe when a larger field is treated with PDT.12 Kasche16 demonstrated that pain during activation can be such that patients request discontinuation of treatment before reaching the required light dose has been reached. This was more likely if the patient was being treated with aminolevulonic acid (ALA) than if treated with methyl aminolevulinate (MAL). There is a report that pain experienced with PDT in Australia may be greater than elsewhere.17 Patient pain perceptions may lead them to seek a topical alternative to an invasive approach in the hope that their procedure and postprocedure pain experience will be reduced.18 In 200719 we published a prospective study of patients’ perceptions of their skin cancer surgery. Included in those perceptions we detailed the level of pain experienced by patients following such surgery. We have since completed another prospective study involving photodynamic therapy with a novel preparation of ALA (Novel ALA) being used as the active ingredient. As part of the protocol for this PDT trial we prospectively recorded the pain patients’ experienced during and following their PDT treatment. We now report on the post procedural pain experiences and compare them to the patients that underwent surgery. The novel ALA product used to treat the patients described herein was developed by Allmedic Pty Ltd as a simple, premixed preparation and was promoted as having a prolonged shelf life and requiring a low intensity of activating light. The aim of the study was to compare a prospective database of patients undergoing skin surgery with a prospective database of patient undergoing PDT. The post procedural pain levels experienced by patients having skin cancer surgery including major skin cancer surgery to the face is to be compared with PDT patients.
Methods The PDT protocol was approved by Bond University Human Research Ethics Committee. The post procedural pain data following skin cancer surgery was acquired as part of completion of a randomized controlled trial approved by the Barwon Health Research and Ethics Committee.
e29
The primary PDT trial sponsor was Allmedic Pty Ltd (Taren Point, NSW, Australia). There was no sponsor for the surgery protocol. All patients were managed in a single skin cancer referral centre in southern Australia. Prospective data on the pain expectations of skin cancer surgery in this centre have been previously reported.19 From this data set of 576 patients, we age and gender matched patients that had more substantial skin cancer surgery to the face 2:1 for each PDT patient. The extensive facial skin cancer surgery group was defined by resections requiring closure by large full thickness wedge repair, full thickness skin grafting or larger random pattern or interpolation skin flap reconstructions or axial flap repairs. This extensive facial surgery group was the key control group of 68 patients. We also compared 170 patients (all facial surgery group) that had undergone all types of skin cancer surgery to the face (age and gender matched 5:1) to PDT patients. We further compared the whole surgery data set of 576 patients (all skin surgery group) to PDT patients. Patients treated with novel ALA for actinic damage had previously experienced one or more histologically proven and surgically cleared facial skin cancers. The protocol involved two PDT treatments 14 days apart. The patient was provided with a 10% alpha hydroxy acid solution to reduce thickened hyperkeratoses to be used twice daily for two weeks prior to PDT. Following a test dose, novel ALA (20% 5aminolevulinate solution) was applied to the whole face [except for eyelids and near mucosal surfaces] followed by a five hour incubation period during which exposure of light face to the face light was avoided. The border of the face was defined as the hairline superiorly, anterior to the tragus laterally and the lower margin of the mandible inferiorly. A 30 min illumination was then undertaken with the PDT light source provided by the sponsor (465 nm blue LED light at 48 J/cm2 for 20 min and then 625 nm red LED light at 64 J/cm2 for 10 min). The sponsor advised that efficacy and safety of their trial ALA had been optimized with this light source. They advised that a combination of blue and red lights was designed to allow for two levels of penetration within the skin. Incubation involved the liquid being massaged into each side of face to provide a thin and uniform cover. Prior to illumination, the face was washed with warm water and dried. During illumination, the eyes and eyelids of the patient were shielded from the light source. Each patient had an attendant(s) present at all times during illumination. A fan to reduce burning sensations was provided as required. The treatment was paused if requested by the patient and discontinued if unable to be tolerated. Following treatment, the patient was given extensive advice regarding minimizing sun exposure, analgesia etc. They were encouraged to remain indoors in a darkened room for at least 48 h and were provided with a sunscreen to apply when outside both before and after treatment. At follow up, patients in both studies were asked by the nursing staff to rate their level of pain experienced post procedure. The level of pain was classified as follows; 1) no pain experienced, 2) mild pain that did not require analgesia, 3) pain that was relieved with paracetamol (Panadol, Herron Paracetamol or Panamax), 4) pain that required stronger oral analgesics to obtain relief such as
e30
A.J. Dixon et al.
Table 1
Post procedure pain experiences of patients treated with PDT versus skin lesion excisions.
Pain experience
PDT
PDT %
All skin surgerya
All skin surgery %
Face surgeryb
Face surgery %
Large face surgeryc
Large face surgery %
No pain experienced Mild pain not requiring analgesia Pain relieved simply with paracetamol Relieved with stronger agents like codeine Pain not relieved with oral analgesics Worst pain ever experienced
2 11
6% 32%
187 221
33% 39%
53 69
31% 34%
19 29
28% 43%
9
26%
135
24%
39
23%
18
26%
5
15%
16
3%
8
5%
2
3%
3
9%
4
1%
1
1%
0
0%
4
12%
0%
0 p < 0.001 54% 67 40e91 68
0%
56% 70 40e91 34
0 p < 0.001 56% 70 30e98 170
0%
Percentage of patients male Average age of patients Range of ages of patients Total patient numbers
0 p < 0.001 56% 47 28e98 563
a b c
Surgery on all patients at all sites as per JAAD 2007.19 Face surgery of all types with five patients matched for age and gender for each PDT patient. Major face surgery with two patients matched as closely as possible for age and gender to each PDT patient.
codeine, 5) pain unrelieved with oral analgesics and 6) the worst pain experienced in their life thus far. Patient specific comments regarding their pain were noted.
Statistical analysis was performed on the datasets Patient characteristics and differences between groups were assessed with analysis of variance using Tukey posthoc analysis, KruskaleWallis H test and Mann Whitney U test as appropriate. All key outcome incidences were analysed using the chi square test and PDT intervention was compared with control using 2 2 tables.
Results 34 patients underwent PDT at this trial centre. All patients had previously suffered one or more skin cancers to the face treated by surgical clearance and closure. The levels of pain experienced by many were severe and for this and other reasons pertaining to trial governance no further patients were treated with this novel PDT. Further recruitment of PDT trial patients was suspended. 19 of the 34 patients were unable to tolerate the complete PDT illumination protocol. Of the 576 patients that underwent skin surgery 563 reported their level of post procedure pain experience. The average age of all 563 surgery patients was 59.3 (range 28e98) and the average age of PDT patients was 70 (range 40e91). PDT patients were significantly older than surgery patients. The gender of 563 surgery patients was 47% male whereas 56% of PDT patients were male. The patients’ experiences of each level of pain are compared in Table 1. From the all skin surgery group we identified 68 patients as our key control group, the extensive facial large face surgery group. These were skin cancer surgery patients who had undergone larger facial
procedures matched as closely as possible for age and gender 2:1 for each PDT patient. 2 of 34 PDT patients experienced no post procedure pain compared with 33% of all skin surgery group patients (p < 0.0001). The likelihood of experiencing mild pain requiring no analgesia or pain only requiring paracetamol was similar in both groups. PDT patients were more likely to require strong analgesics: (5 of 34) versus surgery 3% (p < 0.0001). The likelihood of experiencing pain not relieved with analgesics was more likely in PDT group (3 of 34) versus surgery (1%) (p < 0.0001). The only patients describing their experience as the worst pain of their life were 4 PDT patients. When patients were questioned regarding the duration of pain 5 PDT patients reported experiencing pain for over a month. The PDT patient group is an older group with a different gender ratio than the all skin surgery group. Also, pain experienced from face procedures may be greater than pain at other sites. With this in mind we compared the all facial surgery group to the PDT group. (Table 1) Nine of the 170 (5.3%) all face surgery patients suffered pain that went beyond oral paracetamol compared with twelve of the 34 PDT patients (p < 0.0001). Given some of these facial procedures were small it was possible that this contributed to the lack of pain experienced by face surgery patients. Hence the key control group was the extensive facial surgery group. For each PDT patient it was not possible to exactly match these larger surgical patients for age and gender so we found the nearest possible age and gender match (Table 1). Only 2 of these patients (3%) required analgesia beyond paracetamol (p < 0.0001). We further analysed for pain variation by identifying the average and median pain experienced by each group of patients. A score was attributed to each of the pain thresholds as follows: No pain Z 1, minimal pain Z 2, simple analgesia Z 3, Stronger analgesics Z 4, unrelieved pain Z 5, and worst pain ever Z 6.
Post procedural pain with photodynamic therapy is more severe than skin surgery The average pain score was 3.2 (range 1e6) for PDT patients and was 2.0 (range 1e5) for each of the three surgical groupings analysed. The median pain score was 3 for PDT patients and 2 for surgical patients in each group. Pain in all individual surgery groupings was less than pain reported in the PDT group, Mann Whitney U test p < 0.001 for all surgical groupings (Figure 1).
Discussion Patients often consider surgery is likely to be painful following the procedure and can seek alternative treatments that may result in less pain.11 Patients might associate topical treatments with discomfort rather than pain. However topical treatments used in the management of premalignant skin lesions have been demonstrated to produce pain at the site treated,20e22 including persistent pain.23 The unlikely infrequent experience of severe pain in surgery patients contrasts with the 21% of PDT patients that suffered uncontrolled pain or pain they described as their worst in life to date. Existing published reports of pain associated with PDT do not include descriptions of pain persisting more than a month or of pain described by the patients as the worst of their life.12,14e16 It has previously been reported that morphine gel13 and tetracaine gel24 can be inadequate analgesia for PDT patients. Pain associated with PDT is most noted during the illumination phase.12,15 Reports to date suggest pain does not persist,16,25 yet six of our intervention patients reported prolonged pain with durations over 4 weeks and up to two months.
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The severe and prolonged pain adverse events noted in this study have been reported to the Therapeutic Goods Administration (TGA) in Australia. The prolonged and severe pain of PDT reported in this study may be due to a preparation variation between this novel agent and existing ALA products. A limitation of the study may be that the numbers of patients managed with PDT was small compared with the surgical treatment group. Nevertheless difference in pain scoring between procedures clearly demonstrates the power was sufficient. PDT patients were having their whole face treated rather than a part of the face. The larger area of treatment may account for part of the explanation of the pain variation experienced. Surgery patients were given local anaesthetic prior to their procedure whereas the PDT patients were not given local anaesthetic. Therefore the circumstances are not completely similar. However the pain measurements in these data sets were post procedural pain reports in the days and weeks following the procedure, not over the minutes or hours post procedure.
Conclusion This novel PDT is more likely to result in pain requiring strong analgesia or pain beyond strong analgesics than major facial skin cancer excisions and reconstruction. Clinicians should consider explaining the relative likelihood of greater pain whenever surgery versus PDT is considered. The pain experienced with this PDT product may not reflect the pain experienced with other PDT products.
Disclosure Family interests of author AD have shares in the sponsoring company. This holding has and is being managed independently with all profits (if any) directed to independent medical research.
References
Figure 1 Median and interquartile range of pain scores for study groups examined. All individual groups report less pain than the PDT group (p < 0.001 for all), (ManneWhitney U test) and when all groups are compared using Kruskal Wallace test the PDT group is significantly different to all others (p < 0.001). There was no difference in pain scores between the 3 surgical comparator groups.
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