Patients
Eligible patients, of either sex, were suffering from chronic pain and had been treated for the previous three months with either transdermal buprenorphine or transdermal fentanyl. Inclusion criteria required inadequate analgesia (Visual Analogue Scale [VAS] > 50 mm, and the presence of adverse events correlating with opioid analgesic treatment (sedation, dysphoria, nausea/vomiting and constipation).
Exclusion criteria included renal insufficiency (serum creatinine clearance less than 60 ml/min), moderate or severe hepatic disease (Child-Pugh score between 7 and 10 or between 10 and 15, respectively), history of hepatitis B or C, or acute hepatitis A in the last three months, HIV, clinically significant cardiovascular and/or respiratory diseases, pregnancy, lactation, alcohol consumption, psychotropic drug consumption. Also excluded were patients expecting chemotherapy or radiotherapy cycles during the study, those with known allergy to the medicines or matrix patch components, those with extensive skin disease, and patients who were currently participating in, or had within the last 30 days participated in, other clinical trials. Patients with neurological and/or psychological conditions that might hinder completing daily diaries and pain scales were also excluded.
Study procedure
The study was carried out according to the ethical principles of the current amended version of Declaration of Helsinki, after ethics committee approval. All the patients gave their signed informed consent before participation in the study.
The four-week study was organized with a Screening visit (V0) followed by a Recruitment visit (V1) one week later, when treatment was initiated. Three control visits (V2, V3, and V4) at weekly intervals then followed.
During the screening visit (V0) the age, sex and race of each patient was noted and a detailed history of the cancer disease and of the concomitant pain was taken. Each patient underwent a thorough a physical examination including height, weight and vital signs (blood pressure, respiratory frequency and heart rate). The presence or absence of other concomitant disease and their treatment was registered. Haematochemical analyses were carried out to evaluate hepatic and renal function (Transaminase, Electrolytes, Urea, Creatinine, Cholinesterase, Prothrombin and Partial Thromboplastin time, International Normalised Ratio) (Cr, NA, K, BU, GPT, GOT, γGT, CHE, PT, aPTT, INR). An ECG was performed together with a neurological examination. During the visit the type of transdermal patch and the dose were noted.
At the end of the screening visit the patients were discharged and told to continue the previous therapy. They were asked to return to the department for the recruitment visit one week later. All the patients received a diary in which to rate their pain every morning on awakening on a VAS scale. Patients were permitted to continue with rescue medication (20 mg oral immediate release (IR) morphine) up to a maximum of three daily doses, which was recorded in the diary.
During the recruitment visit each patient underwent a thorough physical examination: general appearance, eyes, lungs, heart, abdomen, musculoskeletal and vital signs were evaluated. The results of haematochemical examinations for renal and hepatic function and the results of the neurological and cardiological examinations were recorded. Adverse Events (AEs) were evaluated. The consumption of rescue medication in mg/day was recorded.
Patients complying with the inclusion criteria were divided into two groups according to the administered therapy up to the recruitment visit. The method used for transdermal patch switching was to replace the first opioid patch with the alternative one, deducting 50% from the dose calculated according to equianalgesic tables.
The FTDS group were patients at the screening visit who had taken buprenorphine TDS 70 μg/h and suffered side-effects and refractory pain and had taken this dose continuously during the pre-recruitment week. At the recruitment visit, the transdermal buprenorphine patch in these patients was replaced by a 25 μg/h transdermal fentanyl patch, positioned at different skin site on the thorax, arm or back.
The BTDS group were patients at the screening visit who had taken fentanyl TTS 75 μg/h and suffered side-effects and refractory pain and had taken this dose continuously during the pre-recruitment week. The transdermal fentanyl patch in these patients was replaced by a 52.5 μg/h transdermal buprenorphine patch, positioned at different skin site on the thorax, arm or back.
Rescue medication with 20 mg of immediate-release oral morphine was prescribed to each patient up to three times a day. At the end of the recruitment visit (V1) all the patients were asked to return after one week for the first control visit (V2), and to continue keeping their daily diaries.
Assessment of analgesic efficacy
Mean weekly pain on the basis of the VAS scores in diaries (VAS 0 = no pain to VAS 100 = intolerable pain) was recorded throughout the 4 week period. The Present Pain Intensity (PPI, 0 = no pain, 1 = mild, 2 = discomforting, 3 = distressing, 4 = horrible, 5 = excruciating) and Pain Rating Index (PRI) were assessed during each visit from V1 to V4. The PRI was taken from the Short-Form Mc Gill Pain Questionnaire and comprised 15 items investigating both the sensorial (11 items) and the emotional sphere of pain (4 items) with a score from 0 to 3 for each item (0–45). In all cases the necessity of rescue medication was registered as milligrams of oral morphine per day. Another parameter taken into consideration was the patients' satisfaction with the new therapy. It was evaluated by means of the simple question: "Are you satisfied with your analgesic treatment?" The patients could answer only "Yes/No".
The primary efficacy measure was pain reduction as recorded by patients both in a daily dairy using VAS and during the visits by PPI and PRI. The secondary efficacy measure was the reduction of rescue mediation consumption as milligrams of IR oral morphine per day.