The Use of Transdermal Buprenorphine to Relieve Radiotherapy-Related Pain in Head and Neck Cancer Patients

Cancer Investigation, 31:412 420, 2013 ISSN: 0735-7907 print / 1532-4192 online Copyright C 2013 Informa Healthcare USA, Inc. DOI: 10.3109/07357907.2013.800094 IMAGING, DIAGNOSIS, PROGNOSIS The Use of Transdermal Buprenorphine to Relieve Radiotherapy-Related Pain in Head and Neck Cancer Patients Johan Menten, Isabelle Carpentier, Harlinde Deschutter, Sandra Nuyts, and Karen Van Beek Radiation Oncology Department, University Hospital Leuven, Herestraat, Leuven, Belgium Many head and neck cancer (HNC) patients experience painful therapy-related mucositis and dermatitis. This prospective observational study evaluated transdermal buprenorphine use in HNC patients to relieve treatment-related pain. During treatment with paracetamol or tramadol, visual analogue scale (VAS)-pain scores>30/100 occurred in 26/45 patients 4 weeks after starting cancer therapy, persisting for 2 weeks after treatment. These patients subsequently received transdermal buprenorphine. Pain therapy should be more accurately up-titrated to the maximum recommended dose (140 μg/hr) where necessary to maintain pain scores 30/100 and, for some patients, should be continued for 6 weeks after the last cancer treatment day. Keywords: Clinical trials, Head and neck cancer, Radiation oncology INTRODUCTION Pain experienced by cancer patients can be nociceptive (inflammatory) or neuropathic in origin, and is frequently a combination of both types (1). An understanding of the different pain types can assist in determining its cause and nature, allowing the most appropriate analgesic therapy to be selected (1). Based on World Health Organization (WHO) practice guidelines, strong opioids play an important role in the effective management of moderate to severe pain associated with cancer and cancer therapy (2). Moreover, due to recent safety concerns (e.g., risk of increased cardiovascular events) regarding the use of nonsteroidal antiinflammatory drugs (NSAIDs) in chronic nociceptive pain, particularly in older adults, it is recommended that NSAIDs are used cautiously and with restriction (3). A substantial proportion of head and neck cancer (HNC) patients experiences pain due to radiation-induced mucositis and dermatitis (4 7). In this population, pain is frequently continuous and persistent during a 4 8 week period. Pain typically begins after receiving radiation doses 20 Gy in 10 fractions and the intensity of pain is typically proportional to the intensity of administered radio/chemotherapy (6, 7). The intake of oral analgesics can be difficult or even impossible due to radiomucositis-related dysphagia. Pain therapy is, therefore, often postponed by the patient or administered at subtherapeutic doses, leading to the under treatment of pain (8). Transdermal delivery systems (TDS) offer a noninvasive administration and dose rate-controlled release of analgesics, which ensures stable plasma concentrations (9). These qualities are particularly attractive in the management of radiotherapy-induced painful mucositis and consequent dysphagia. Currently available transdermal opioids for cancer pain management include fentanyl and buprenorphine (10). In comparison with other opioids, buprenorphine possesses several unique pharmacological characteristics (11). It is a μ-opioid receptor agonist, and k-opioid receptor antagonist, binding to both receptors with high affinity. Buprenorphine is an ideal candidate for transdermal delivery because it binds tightly to the receptor and dissociates slowly. It is also ideal for patients with renal impairment because no dose adjustment is necessary. In addition, buprenorphine displays a pronounced antihyperalgesic effect (11). Historically, there were concerns of a possible analgesic ceiling effect with buprenorphine but these have since been disproved; nevertheless, buprenorphine displays a ceiling effect for respiratory depression, which is a positive safety characteristic (11). Buprenorphine is available as a transdermal slow-release matrix patch (Transtec R ) for the treatment of moderate to severe pain not responding to nonopioid analgesics. The transdermal patch releases buprenorphine, incorporated into the adhesive polymer matrix, at a controlled rate during 96 hr after application at dosages of 35, 52.5, and 70 μg/hr (11). A low-dose, 7-day buprenorphine transdermal patch formulation (5, 10, and 20 μg/hr; Norspan R,BuTrans R )isalsoavailable in some markets; however, this formulation is not registered for the treatment of cancer pain and is not the focus of the current study. The present study aimed to evaluate the use and efficacy of transdermal buprenorphine (Transtec R )forthetreatment of moderate and severe radiotherapy-induced painful mucositis and/or dermatitis in HNC patients treated to a total Correspondence to: Johan Menten, MD, PhD, Department of Radiotherapy, University Hospital Leuven, Herestraat 49, B3000 Leuven, Belgium, email: johan.menten@uzleuven.be Received 7 December 2012; revised 23 April 2013; accepted 24 April 2013. 412

Transdermal Buprenorphine for Radiotherapy Pain 413 radiation dose of 50 72 Gy, with/without chemotherapy and with/without targeted therapy. METHODS Study design This prospective, observational study was conducted at the Radiotherapy-Oncology Department of the University Hospital Leuven between August 1, 2009 and February 28, 2010. The ethics committee approved the study protocol and all patients provided written informed consent before enrollment. Patients aged 18 years, treated (with curative intent) with radiotherapy ( 50 72 Gy) ± simultaneous chemo- ± targeted therapy (cetuximab) for HNC, were eligible for the study. Three groups of patients were defined, according to treatment received: <70 Gy or 70 Gy irradiation and a combined radio/chemotherapy ± targeted therapy group (Table 1). After providing written informed consent (visit 1, in the first or second week of irradiation), the following demographic and treatment-related variables were recorded: age, gender, pre-study medication, tumor site and stage, and anticancer treatment. During follow-up, the presence of mucositis and dermatitis was scored according to the Common Toxicity Criteria (CTC; version 3.0) (12), and pain levels were self-assessed by the patient using a visual analogue scale (VAS) score: 0 = no pain, 100 = the worst possible pain. From the time of study inclusion, patients were asked to document their daily medication use in a diary and were assessed weekly for clinical examination, VAS-pain registration and scoring of adverse events. The written standard pain protocol of the Radiotherapy Department advises the use of paracetamol (maximum dose: 4,000 mg/day) or tramadol (maximum dose: 400 mg/day). In case of insufficient pain relief (VAS score >30/100), the ward protocol states that transdermal buprenorphine treatment has to be prescribed at a starting dose of 17.5 μg/hr; the dosage has to be increased by 17.5 μg/hr at every subsequent patch application by the patient/physician until the VAS-pain score decreases to 30/100. Tramadol or sublingual buprenorphine or morphine, according to patient s preference, needs to be available for breakthrough pain, at doses equivalent to 1/12 or 1/6 of the daily maintenance dose of buprenorphine for VASpain scores below or above 50/100, respectively. The standard pain protocol also advises that weekly visits with the treating physician need to be continued until the patient s VAS-pain score is 30/100. Statistical analysis Data management and statistical analysis were performed using Statistica-9 software. Categorical variables are presented as frequencies with percentages, whereas continuous variables are presented as means and standard deviations (SDs). Comparisons between two groups of continuous variables (i.e., age) were performed using the t-test. The Fisher Exact test was implemented to test for associations between categorical variables (i.e., type of therapy and prior medication). A p value <.05 was considered statistically significant. RESULTS The total duration of radiotherapy (5 8 weeks) differed in each of the 3 defined patient groups (Table 1). Data presented herein therefore reflect the weeks after the start or end of radio/chemotherapy treatment, regardless of the length of radiotherapy. Table 2 presents relevant patient demographic data, recorded at visit 1. Forty-five patients were included in the study (Table 1); 19 patients maintained a VAS score 30/100 with paracetamol or tramadol and had no need for stronger analgesics. Twenty-six patients were given transdermal buprenorphine due to insufficient pain relief with paracetamol or tramadol (VAS score >30/100). One patient started transdermal buprenorphine 17.5 μg/hr in the first week of anticancer treatment due to cancer-related pain and 2 patients used transdermal buprenorphine 35 μg/hr during the second week of radiotherapy; however, the majority of patients started transdermal buprenorphine at week 4 or later, in response to the development of cancer treatment-related grade 3 or 4 painful mucositis. Prior to treatment, patients with advanced cancer (stage IVa and IVb) frequently experienced cancer-related pain, which resulted in a VAS pain score >30/100 without analgesics. Therefore, some patients were receiving paracetamol or tramadol (but not buprenorphine or strong opioids) and antiemetics, at study inclusion. Indeed, patients who were already receiving analgesic medication (paracetamol or tramadol) at the first visit due to cancer-related pain had a statistically greater (p =.01) risk for moderate to severe treatment-related pain because these stage IV patients received more aggressive cancer treatment (radiation dose 70 Gy or radio/chemotherapy ± targeted therapy) and subsequently experienced more intensive therapy-induced pain, Table 1. Patient Groups According to Type of Treatment for Head and Neck Cancer Treatment Length of Treatment Chemotherapy ± Targeted Therapy No. of Patients Group <70 Gy 5 6 weeks radiotherapy 18 Group 70 Gy 7 8 weeks radiotherapy 9 Group RT + CT 6 8 weeks radiotherapy +Chemotherapy at weeks 1 and 4 ± targeted 18 therapy Total 45 CT, chemotherapy; RT, radiotherapy. Copyright C 2013 Informa Healthcare USA, Inc.

414 J. Menten et al. Table 2. Demographic Data at Inclusion in Patients With and Without Transdermal Buprenorphine (Pain Under Control With Tramadol/Paracetamol or Not) Transdermal Buprenorphine Needed (N = 26) No Transdermal Buprenorphine Needed (N = 19) p Value Gender, N (%) p =.58 Male 20 (76.9%) 15 (78.9%) Female 6 (23.1%) 4 (21.1%) Mean (±SD) age, years 59.1 (± 11.0) 61.2 (± 9.2) p =.44 Mean (±SD) height, cm 172.0 (± 6.9) 174.1 (± 6.1) p =.62 Mean (±SD) body weight, kg 71.4 (± 12.7) 76.6 (± 10.9) p =.50 Type of therapy, N (%) Radiotherapy <70 Gy 6 (33%) 12 (66%) p =.02 Radiotherapy 70 Gy 7 (78%) 2 (22%) Radio/chemotherapy ± 13 (72%) 5 (28%) targeted therapy Prior medication, N (%) Analgesics 15 (57.7%) 4 (21.1%) p =.01 Mucositis cocktail 3 (11.5%) 3 (15.8%) p =.50 Laxatives 2 (7.7%) 1 (5.3%) p =.61 Antiemetics 5 (19.2%) 1 (5.3%) p =.18 which required more frequent transdermal buprenorphine (Figure 1). Indeed, patients receiving radiotherapy 70 Gy (n = 7) or radio/chemotherapy ± targeted therapy (n = 13) required statistically more frequent (p =.02) stronger analgesic medication (transdermal buprenorphine) than patients receiving radiotherapy <70 Gy (n = 6) (Table 2). Sincethisstudyaimedtoanalyzetheuseoftransdermal buprenorphine, the data presented here focus mainly on the buprenorphine-treated patients (n = 26). Occurrence of mucositis and dermatitis All patients treated with buprenorphine showed some grade of mucositis and/or dermatitis at some time points during the study. Radio/chemotherapy-induced grade 2 mucositis, scored according to CTC (version 3.0) (12), was present from week 2 of cancer treatment until week 5 after completing the cancer treatment; grade 3 mucositis was present from weeks 4 to 7 of cancer treatment until 4 weeks after the end of cancer therapy (Figure 2). To relieve mucositis-induced pain, a mucositis cocktail (hydrocortisone 200 mg, lidocaine 400 mg, 100,000 E/mL nystatin 30 ml, propylene glycol 10 ml, sodiumcarboxymethyl-cellulose 2 g, distilled water 500 ml) was prescribed for all patients. Patients used the cocktail at the maximal allowed application (6 times daily) and continued this use for more than 1 month after the termination of radiotherapy. Radiotherapy-related dermatitis within the irradiation fields was moderate to severe (grade 2 3), appearing from weeks 4 to 5 after starting cancer treatment and persisting for up to 4 weeks after the end of cancer therapy (Figure 3). Pain scores Pain was scored (VAS) at the first visit and at subsequent weekly follow-up visits during and after radiotherapy. In the group of patients who were subsequently treated with transdermal buprenorphine, pain intensity was already moderate to severe between weeks 3 and 5 after the start of cancer treatment, decreasing only after week 2 postradiotherapy. Patients in the combined treatment group had thehighestpainscoresatweeks6and7ofcancertreatment, and weeks 2 and 3 after cancer treatment (Figure 4). This figure also shows that VAS scores in both radiotherapy treatmentgroupsdecreasedbyweek5,whereasscoresstillincreased in patients receiving radio/chemotherapy ± cetuximab. At week 2 after treatment, pain scores were decreased in all 3 groups and, from week 3 post-treatment to study end, VAS scores were <30 in all buprenorphine-treated patients regardless of cancer treatment (Figure 4). Transdermal buprenorphine treatment Transdermal buprenorphine was used in >70% of patients receiving radiotherapy 70 Gy or combined radio/chemotherapy ± cetuximab and only in 33% of patients receiving <70 Gy radiotherapy (Figure 5). Differences in the use of transdermal buprenorphine between low- and high-dose radiotherapy, and between low-dose radiotherapy and combined radio/chemotherapy, were statistically significant (p =.04 and p =.02, respectively). There was no statistically significant difference in the use of transdermal buprenorphine for both intensively treated groups (p =.57) (Figure 5). Figure 6 shows clearly the difference in mean buprenorphine doses as a function of treatment modality, ranging between 17.5 and 64 μg/hr. Four patients used a maximum dosage of 70 μg/hr, and 4 patients used a maximum dosage of 105 μg/hr, although individual VAS pain scores were frequently still above 30/100. Patients in the <70 Gy group received a mean transdermal buprenorphine dose of 20 30 μg/hr. Mean transdermal buprenorphine doses were higher in the radiotherapy >70 Gy (40 50 μg/hr) and radio/chemotherapy (50 60 μg/hr) groups (Figure 6). Transdermal buprenorphine treatment duration was longer in the radio/chemotherapy ± targeted treatment versus radiotherapy-only groups, during Cancer Investigation

Transdermal Buprenorphine for Radiotherapy Pain 415 Figure 1. Staging of tumors and their subsequent treatment (buprenorphine = pain not under control with paracetamol/tramadol; no buprenorphine = pain under control with paracetamol/tramadol). CT, chemotherapy ± cetuximab or targeted therapy; RT, radiotherapy. (13.05 days vs. 7.62 days) and after (20.47 days vs. 9.4 days) radiotherapy. Transdermal buprenorphine was administered to combined radio/chemotherapy ± targeted therapy patients for 33.5 days versus 17 days for radiotherapy-only patients. Use of rescue analgesic medication and nonanalgesic medication Rescue analgesic medication (paracetamol or tramadol or sublingual buprenorphine) was available in addition to transdermal buprenorphine. If patients required 3 boosts of analgesics/day, the transdermal buprenorphine maintenance dose was up-titrated from 1 to 1 patch (35 μg/hr dosage), or 2 to the next dosage of buprenorphine patch (52 or 70 μg/hr) and above 70 μg/hr, we used up-titrating steps of 35 μg/hr. Paracetamol consumption was relatively stable from week 3 until week +2 (range: 1,500 2,500 mg/day); tramadol use wasmostintensiveatweeks6and7andatweek+1 until week +4 (Figure 7). Nonanalgesic medication and adverse events Patient diaries recorded the daily use of nonanalgesic medication. In transdermal buprenorphine recipients, laxatives were taken for an average of 18 days (during and after Figure 2. Incidence of mucositis in patients receiving transdermal buprenorphine. Grading based on Common Toxicity Criteria (version 3.0: 0 = none; 1 = erythema of the mucosa; 2 = patchy pseudomembranous reaction; 3 = confluent pseudomembranous reaction; 4 = necrosis or deep ulceration. W = week. Copyright C 2013 Informa Healthcare USA, Inc.

416 J. Menten et al. Figure 3. Incidence of dermatitis in patients receiving transdermal buprenorphine. Grading: 0 = none; 1 = faint erythema or dry desquamation; 2 = moderate to brisk erythema of a patchy moist desquamation, mostly confined to skin folds, moderate edema; 3 = confluent moist desquamation 1.5 cm diameter and not confined to skin folds, pitting edema; 4 = skin necrosis or ulceration of full thickness dermis. W = week. radiotherapy); patients not receiving transdermal buprenorphine took laxatives for a mean of 4 days. On average, antiemetics were taken for 22 days in combination with transdermal buprenorphine, and the frequency was higher during radiotherapy (17 days vs. 6 days). The addition of chemotherapy ± cetuximab to radiotherapy resulted in a clear increase in the requirement for antiemetic use. Table 3 gives an overview of the frequency of medication use to control pain, opioid-, and chemo-induced side effects in patients during and off treatment with transdermal buprenorphine. Transdermal buprenorphine was well tolerated. No cases of buprenorphine-related dermatitis, dry skin, or other skin problems were reported. No discontinuation of transdermal buprenorphine treatment resulted from skin reactions, or from any other adverse events related to buprenorphine. DISCUSSION Radiotherapy, with curative intent, causes some degree of mucositis or dermatitis with secondary pain, which Figure 4. VAS-pain scores (mean ± SD) in patients receiving transdermal buprenorphine, categorized by cancer treatment group. The majority of patients started to receive transdermal buprenorphine at week 4 (W4), at a starting dosage of 17.5 μg/hr. CT, chemotherapy ± targeted therapy; RT, radiotherapy. Cancer Investigation

Transdermal Buprenorphine for Radiotherapy Pain 417 Figure 5. Percentage of patients receiving transdermal buprenorphine, categorized by cancer treatment group. CT, chemotherapy ± targeted therapy; RT, radiotherapy. typically increases in intensity and duration with intensified radio/chemotherapy (4 7). Radiation-induced mucositis is a function of cumulative tissue irradiation dose and usually starts at doses of about 20 Gy in 10 fractions. Ulcerative mucositis is usually noted at doses of irradiation 30 Gy (6, 7). In this study, treatment-related pain intensity increased after the second week of radiotherapy and pain intensity was moderate to severe after week 4. Fifty-eight percent of patients in the current study were transferred to transdermal buprenorphine because paracetamol and/or tramadol did not provide sufficient pain relief. The majority of patients started transdermal buprenorphine at week 4 of cancer treatment. International and locally written guidelines advise tailoring pain treatment to the needs of the individual patient so that the VAS-pain score is 30/100. Basedonthisprospectiveobservationalstudy,onecan see how difficult it is for patients and caregivers to up-titrate analgesic doses in line with treatment protocols and international guidelines. Patients treated with radiotherapy >70 Gy or combined radio/chemotherapy ± cetuximab had, respectively,5and4weeksofmeanpainscores>30/100. In patients receiving transdermal buprenorphine, who were the focus of this study, VAS scores started to decrease after week 5 in only irradiated patients, but increased in chemo-radiotherapy patientsuntilweek 7. These painscores >30/100 may be partly explained by the fact that the starting dose of transdermal Figure 6. Buprenorphine dosages (mean ± SD) in the respective cancer treatment groups during (weeks 4 7 [W4 W7]), and up to 6 weeks after (W+1toW+6) radio (RT)/chemotherapy (CT) ± targeted therapy. Copyright C 2013 Informa Healthcare USA, Inc.

418 J. Menten et al. Table 3. Use of Additional Medication to Control Pain and Opioid-Induced Side Effects in Head and Neck Cancer Patients Receiving Transdermal Buprenorphine During or After Radiotherapy (RT). Data are Expressed as the Percentage of Days that Patients Received Additional Medication During and Off Buprenorphine Treatment Nonanalgesic Medication Percentage of Days Laxatives a Antiemetics b Mucositis Rescue Medication c Rescue Analgesics d Analgesic Medication Narcotic Analgesics e During RT Off buprenorphine 3.32 7.56 86.79 44.16 50.52 0.86 During 11.16 17.69 66.02 55.73 10.91 1.16 buprenorphine After RT Off buprenorphine 0.90 1.77 87.73 28.18 61.82 0.0 During 6.53 6.66 73.91 58.70 19.57 0.0 buprenorphine Total Off buprenorphine 3.82 8.55 86.62 37.75 55.84 0.65 During buprenorphine 16.25 22.65 67.39 57.80 12.26 0.76 NSAID Rescue a Osmotic laxative (macrogol or lactulose). b Alizapride 50 100 mg 3 times daily or metoclopramide 15 30 mg 3 times daily. c Mucositis cocktail (6 times daily): hydrocortisone 200 mg, lidocaïne 400 mg, 100,000 E/mL nystatin (30 ml), propylene glycol (10 ml), sodiumcarboxymethylcellulose (2 g), distilled water (500 ml). d Paracetamol or tramadol. e Buprenorphine sublingual or morphine. buprenorphine was low (17.5 μg/hr) but the subsequent dose titration was not sufficiently aggressive and not in line with the written ward protocol. Indeed, too few patients were sufficiently up-titrated with buprenorphine, while many mean VAS-pain scores were still >30/100 for several weeks. As this wasanoninterventionalstudy,thisreflectscurrentpracticein a Radiation-Oncology Department with written pain treatment protocols. The duration of transdermal buprenorphine use was longer in patients with the most intensive cancer therapy, since pain lasts longer with higher radiation doses and combined radio-chemotherapy. Several barriers limit the correct use of opioids for severe pain. In the current study, patients were informed to uptitrate but they and their caregivers were frequently reluctant to increase the dose due to a disproportionate fear of possible side effects. Even temporary use of step 3 opioids, especially in curative therapy, still remains a general taboo subject for both patients and caregivers. All too often, opioids for severe pain are still associated with palliative care and end-of-life settings rather than with appropriate pain management and good clinical practice. There is still the fear of opioid tolerance, addiction, respiratory depression, and life-shortening events (11). The need to develop scientific data concerning these opioid myths is paramount and the wider dissemination of appropriate evidence-based information is important (11). In this study, paracetamol or tramadol was used to control breakthrough pain although buprenorphine (sublingual) was Figure 7. Paracetamol (blue) and tramadol (red) consumption (mg; mean ± SD) in transdermal buprenorphine-treated patients during, and after, cancer treatment. Cancer Investigation

Transdermal Buprenorphine for Radiotherapy Pain 419 advisedandavailablebutonlyprescribedandusedexceptionally. Sublingual buprenorphine was not used in patients with full oral mucositis but was well tolerated in patients with pharyngeal or laryngeal mucositis. Morphine was prescribed by the treating physician for breakthrough pain in only 2 patients. One can speculate that this also reflects a degree of fear and prejudice. In transdermal buprenorphine recipients, paracetamol consumption was relatively stable from week 3 until week +2;tramadolusewasmostintensiveatweeks6 and 7 and at week +1 untilweek+4. Our analysis clearly shows the need for a more intensified treatment regimen using proportionated doses of opioids for severe treatmentrelated pain, when paracetamol or tramadol is insufficient, and that aggressive up-titration of opioid doses should not be feared, otherwise adequate pain relief (VAS scores 30/100) cannot be reached. This study shows that painful mucositis is present after the second week after the start of irradiation and continues 4 5 weeks after the termination of therapy. A mucositis cocktail, administered up to 6 times daily, only partially relieved symptoms. Additional analgesia is necessary in all patients and needs to be continued for 4 6 weeks after the end of radiotherapy, aslongaspatientsreportpain>30/100. Transdermal analgesic therapy is particularly appropriate for these patients with dysphagia caused by mucositis. Transdermal buprenorphine was well tolerated in our study. All side effects were consistent with those reported in the Summary of Product Characteristics (13). Constipation is a major problem in cancer patients and several factors contribute to this problem. Prophylactic use of laxatives was recommended in our study but this particular patient group had swallowing problems and was consuming less food, particularly less fibre-rich foods. As swallowing was painful, thesepatientswerealsolikelytodrinkfewerliquidsand, therefore, osmotic laxatives would be less effective. Although it is generally accepted that transdermal buprenorphine causes less constipation than other step 3 opioids (1), our resultsshowthattherewasaneedforlaxativesinabout50%of patients receiving transdermal opioid, compared with <10% of non-buprenorphine-treated patients. This can be caused by the combination of the opioid, changed food, and drink consumption, and less mobility and/or activity during treatment in patients experiencing pain. Nausea and vomiting, which has a negative impact on patient s quality of life, can be caused by curative radio/chemotherapy but can also be initiated by the use of opioids (14). Antiemetic use can relieve symptoms of nausea and vomiting. Our data show a more frequent use of antiemetics during cancer therapy in all patients. The overall use of antiemetics was more frequent in the group receiving opioid therapy. The current study is not without some limitations, mainly related to study design. We acknowledge that our study population is relatively small (26/45 patients treated with transdermal buprenorphine) and conducted in a single centre. Furthermore, the noninterventional nature of the study precludes some of the more robust features that are associated with a standard randomized, controlled, comparator study. However, the noninterventional design reflects daily clinical practice and, as such, provides valuable additional insight into the use of transdermal buprenorphine that cannot be gained within a strict clinical trial setting. Nevertheless, based on the available data, we can conclude that more than 50% of HNC patients undergoing radiotherapy (± chemotherapy ± cetuximab) experience moderate to severe pain caused by mucositis and/or dermatitis that can be treated with transdermal buprenorphine. Furthermore, we recommend that analgesics should be titrated as high and as aggressively as possible, within the limits of tolerability and product use recommendations, with the objective of relieving moderate to severe pain and, as pain is often still present after the end of treatment, pain therapy should be continued for several weeks after the termination of radiotherapy. Based on these results, we recommend better implementation of the ward treatment protocol by both patients and caregivers, and without fear of the recommended maximum doses of analgesics where appropriate to reach better pain control and, subsequently, an improved quality of life during such aggressive treatments. Future large, well-designed studies are warranted to evaluate effective pain control in cancer treatment if the written treatment protocol and existing guidelines are really implemented in clinical practice. ACKNOWLEDGMENTS Wewouldliketoacknowledgethepatientsfortheircollaboration in the study and Grünenthal for financing the statistical analysis. The authors also thank David P. Figgitt, PhD, Content Ed Net, for providing valuable editorial assistance in the preparation of the manuscript. DECLARATION OF INTEREST J. Menten has contributed to a medical advisory board for Grünenthal. Funding: This academic study was partially financed with a limited budget from Grünenthal for the statistical calculations. Editorial assistance was funded by Grünenthal GmbH. REFERENCES 1. Pergolizzi JV Jr, Mercadante S, Virizuela Echaburu A, Van den Eynden B, de Faría Fragoso RM, Mordarski S, Lybaert W, Beniak J, Orońska A, Slama O. The role of transdermal buprenorphine in the treatment of cancer pain: an expert panel consensus. Curr Med Res Opin 2009;25:1517 1528. 2. World Health Organization. Cancer Pain Relief With A Guide to Opioid Availability, 2nd edition. Geneva: World Health Organization. 1996. 3. 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