Bone Marrow Transplantation (2004) 33, 1247–1251 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $30.00 www.nature.com/bmt Mucositis Transdermal fentanyl in HSCT patients: an open trial using transdermal fentanyl for the treatment of oral mucositis pain F Demarosi1, G Lodi1, D Soligo2, A Sardella1, A Della Volpe2, A Carrassi1 and G Lambertenghi Deliliers2 1Unit of Oral Pathology and Medicine, Department of Medicine, School of Dentistry, University of Milan, Milano, Italy; and 2Bone Marrow Transplant Center, IRCCS Ospedale Maggiore, University of Milan, Milano, Italy Summary: cular weight, high potency (fentanyl is 75–100 times more potent than morphine on a molar basis) and high lipid Fentanyl is a synthetic opioid that can be delivered solubility make it suitable for delivery by means of a through a transdermal therapeutic system (TTS). The aim transdermal therapeutic system (TTS), which is designed to of this study was to assess the efficacy of fentanyl TTS in release the drug into the skin at a constant rate between 25 treating oral mucositis pain in 75 adult hematopoietic and 100 mg/h, although multiple patches can be applied in stem cell transplant (HSCT) patients. The analysis was order to achieve higher delivery rates.3 Peak serum levels are based on 62 patients who developed mucositis. Pain reached within 8–12 h. The TTS delivers fentanyl continu- control was assessed by the patients using a visual ously for 72 h and constant serum levels can be maintained analogue scale (VAS) from day 0 to day þ 33 after by applying another patch.4 It has been claimed that HSCT. Fentanyl TTS was administered at the patient’s transcutaneous administration reduces opioid-induced side request. In all, 20 patients did not require fentanyl (group effects, such as constipation, nausea and vomiting, sedation, A). The first 22 patients asking for the patch received drowsiness and hypoventilation rates.3,5 The most common fentanyl 25 lg/h (group B) and the subsequent 20 patients side effects are due to the adhesive used to attach the received 50 lg/h (group C). There were no significant systems to the skin, and include erythema, itching and differences in pain relief between groups B and C. The occasional pustule formation (o1%); their frequency is expected effect of a decrease in mean pain score (mean of about 10% and they are generally mild.5 the VAS scores of all of the patients in the same group Much of the early clinical experience with fentanyl TTS each day) following the application of fentanyl TTS was was obtained in patients with acute postoperative pain. not noted. We can conclude that fentanyl TTS at the doses However, because of the increased risk of respiratory used in this study may not adequately relieve oral complications, fentanyl TTS was contraindicated in this mucositis pain. setting and is now recommended in chronic cancer pain,6–8 Bone Marrow Transplantation (2004) 33, 1247–1251. and general pain including that of nonmalignant origin.3,9 doi:10.1038/sj.bmt.1704515 The aim of this study was to evaluate the efficacy of Published online 19 April 2004 fentanyl TTS in treating the pain related to oral mucositis Keywords: fentanyl; mucositis; pain; stem cell transplan- in HSCT patients. tation Patients and methods Oral mucositis is a major side effect of hematopoietic stem cell This prospective study consecutively enrolled adult patients transplant (HSCT) with the resultant pain being a major source with hematological malignancies undergoing HSCT at the of morbidity. It may be reduced by routine mouthwashes with Bone Marrow Transplant Center, Ospedale Maggiore, antiseptics, local steroids and local anesthetics, but most Milan (Italy). All of the patients gave their written informed patients require opiate analgesics to control it.1,2 consent before entering the study. We did not ask for Ethics Transdermal fentanyl is being increasingly used in the Committee approval because, like many other Cancer treatment of cancer pain. Fentanyl is a synthetic opioid with Centers, we already used fentanyl TTS for the treatment pure agonist activity and short-acting analgesic activity after of pain and the study did not include a placebo group. intravenous or subcutaneous administration. Its low mole- From the beginning of the conditioning therapy until hospital discharge, all of the patients received thrice-daily oral antimicrobial prophylaxis with nystatin oral suspen- sion 100 000 U and a 0.2% chlorhexidine mouthwash 10 ml, Correspondence: Dr F Demarosi, Unita` di Patologia e Medicina Orale, and oral hygiene was performed three times a day using Dipartimento di Medicina, Chirurgia e Odontoiatria, Via Beldiletto 1, Milano 20142, Italy; E-mail: [email protected] gauzes soaked in sodium bicarbonate solution under Received 21 August 2003; accepted 14 January 2004 supervision of a nurse. All of the patients underwent a Published online 19 April 2004 weekly oral examination by the same clinician who assessed Transdermal fentanyl for oral mucositis pain F Demarosi et al 1248 the degree of oral mucositis using the scoring system The demographic and transplantation details relating to proposed by the World Health Organization (WHO): the three groups are summarized in Tables 1 and 2. 1 ¼ soreness, erythema; 2 ¼ erythema, ulcers, can eat solids; The following statistical tests were employed: Fisher’s 3 ¼ confluent ulcers, requires liquid diet only; 4 ¼ oral exact test to compare binomial results of unpaired groups; alimentation not possible, hemorrhage.10 Student’s t-test to compare means of unpaired groups; w2 Pain was measured by the patients once a day 12 am test to compare three unpaired groups; Wilcoxon’s test and from the day of the transplant to day þ 33 using a visual Mann–Whitney’s test to compare scores of unpaired analogue scale (VAS)11 ranging from 0 (no pain) to 10 groups. (worst pain), provided by the company producing fentanyl (Figure 1). A mean pain score (MPS) was used to indicate the mean VAS scores of all of the patients each day. Fentanyl TTS was administered at the patients’ request and Results a new patch of the same dose was applied every 72 h if necessary. Patients were informed about the nature of the The male:female ratio was highest in group A (16:4), thus drug releasing by the patch, but not about its dosage. The reflecting the greater demand of females in comparison with application site (upper torso) had to be free of any skin males (24/28 vs 18/34; Fisher’s exact test, p ¼ 0.0071). The irritation. mean age of the patients in group A (52.3079.61 years) No other topical or systemic agents were employed to was higher than that of the patients requiring the patch reduce oral mucositis pain. Fentanyl side effects were (groups B þ C: 45.67712.74 years, with no difference recorded every day. between the two groups) (Student’s t-test: p ¼ 0.043). The aim of the study was to record systematically the In all, 15 (88.2%) of the 17 allograft recipients and 23 effect of fentanyl TTS on mucositis pain in HSCT patients. (63.8%) of the 36 autografted patients required fentanyl, Owing to the lack of published studies of oral mucositis but only four (44.4%) of the nine patients who underwent and therefore data concerning the minimum effective NHSCT (w2 test: p ¼ 0.056). dose, we initially used the patch with the lowest delivery Fentanyl was required by 38 (71.2%) of the 53 patients rate (25 mg/h). undergoing conventional myeloablative conditioning regi- The study involved 75 hospitalized adult patients under- mens, and four (44.4%) of the nine receiving reduced going HSCT between November 2000 and December 2002. intensity conditioning: this difference was not significant The 13 patients who did not experience oral mucositis were (Fisher’s exact test: p ¼ 0.13). Of the 17 patients receiving excluded from the analysis, which was therefore based on a TBI, 15 (88.21%) required fentanyl compared with 23 of 36 total of 62 patients (82.7%: 34 males and 28 females) aged patients undergoing a conventional regimen without TBI 19–67 years (average 47.9 years). Of the transplants, 17 (Fisher’s exact test: p ¼ 0.10). were allografts (six from unrelated donors), nine were The patients who did not ask for the patch (group A) had nonmyeloablative hematopoietic stem cell transplants lower mucositis scores and a shorter duration of mucositis (NHSCT) and 36 were peripheral blood stem cell (PBSC) than those who asked for it (groups B þ C). These autografts. differences were highly significant (Wilcoxon’s test: Of the 62 patients, 20 (32.2%) did not require fentanyl TTS (group A). The first 22 patients (35.6%) asking for the patch received fentanyl TTS 25 mg/h (group B). As our Table 1 Demographic characteristics of patients preliminary results12 indicate that this dose was not Group A Group B Group C Total sufficient to control mucositis-related pain in the majority (no patch) (25 mg/h) (50 mg/h) of HSCT patients, the subsequent 20 patients (32.2%) received fentanyl TTS 50 mg/h (group C). Male 16 10 8 34 Female 4 12 12 28 Age range 28–67 19–57 19–61 19–67 (mean) (52.30) (45.14) (46.25) (47.90) Allogenic 2 8 7 17 NHSCT5229 Autologous 13 12 11 36 AML 3 5 3 11 ALL 0 1 3 4 CML1405 CLL 1 0 1 2 MM 4 4 4 12 NHL 9 6 6 21 HL1102 Other 1 1 3 5 Total 20 22 20 62 AML=acute myeloid leukemia; ALL=acute lymphoblastic leukemia; CML=chronic myeloid leukemia; CLL=chronic lymphoblastic leukemia; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; HL=Hodgkin lymphoma.