Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. The evaluation of analgesic effects in cancer patients as exemplified by a double-blind, crossover study of immediate-release versus controlled-release morphine. Comparison of oral controlled-release morphine with transdermal fentanyl in terminal cancer pain. Association of transdermal fentanyl and oral transmucosal fentanyl citrate in the treatment of opioid naive patients with severe chronic noncancer pain. Transdermal fentanyl versus sustained release oral morphine in strong-opioid naïve patients with chronic low back pain. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group.
Oral transmucosal fentanyl citrate (OTFC) is a novel opioid formulation in which the potent synthetic mu-agonist fentanyl is embedded in a sweetened matrix that is dissolved in the mouth. It is undergoing investigation as a treatment for cancer-related breakthrough pain, a prevalent phenomenon defined as a transitory flare of moderate to severe pain that interrupts otherwise controlled persistent pain. There have been no controlled trials of other treatments for this condition. To evaluate the safety and efficacy of ascending doses of OTFC, a novel controlled dose titration methodology was developed that applied blinding and randomization procedures to the evaluation of recurrent pains in the home environment. The study was a multicenter, randomized, double-blind dose titration study in ambulatory cancer patients. The sample comprised adult patients receiving a scheduled oral opioid regimen equivalent to 60-1000 mg oral morphine per day, who were experiencing at least one episode per day of breakthrough pain and had achieved at least partial relief of this pain by use of an oral opioid rescue dose. After collection of 2 days of baseline data concerning the efficacy of the usual rescue drug, patients were randomly treated with either 200 or 400 microg OTFC unit doses in double-blind fashion. Up to two breakthrough pains each day could be treated with up to four OTFC unit doses per pain. OTFC in unit doses containing 200, 400, 600, 800, 1200 or 1600 microg of fentanyl citrate were available for the study. The unit dose was titrated upward in steps until the patient had 2 consecutive days on which breakthrough pain could be treated with the single unit dose, titration was ineffective at a 1600 microg unit dose, or 20 days elapsed. To maintain the double-blind, orders to titrate up were ignored one-third of the time according to a pre-defined randomization schedule accessible only to an unblinded study pharmacist. Main outcome measures included, numeric or categorical measures of pain intensity, pain relief, and global assessment of drug performance. Dose response relationships were found suggesting that the methodology was sensitive to opioid effects. Seventy-four percent of patients were successfully titrated. There was no relationship between the total daily dose of the fixed schedule opioid regimen and the dose of OTFC required to manage the breakthrough pain. Although the study was not designed to provide a definitive comparison between OTFC and the usual rescue drug, exploratory analyses found that OTFC provided significantly greater analgesic effect at 15, 30 and 60 min, and a more rapid onset of effect, than the usual rescue drug. Adverse effects of the OTFC were typically opioid-related, specifically somnolence, nausea and dizziness. Very few adverse events were severe or serious. This study demonstrated the feasibility of controlled trial methodology in studies of breakthrough pain. OTFC appears to be a safe and effective therapy for breakthrough pain, and dose titration can usually identify a unit dose capable of providing adequate analgesia. If the lack of a relationship between the effective OTFC dose and fixed schedule opioid regimen is confirmed, dose titration may be needed in the clinical use of this formulation. Further investigation of OTFC as a specific treatment for breakthrough pain is warranted. Oral transmucosal fentanyl citrate (OTFC); Actiq) is a drug delivery formulation used for management of breakthrough cancer pain. Previous studies with open-label comparisons indicated OTFC was more effective than patients' usual opioid for breakthrough pain. The objective of this study was to compare OTFC and morphine sulfate immediate release (MSIR) for management of breakthrough pain in patients receiving a fixed scheduled opioid regimen. This double-blind, double-dummy, randomized, multiple crossover study was conducted at 19 US university- and community-based hospitals and clinics and comprised 134 adult ambulatory cancer patients. Patients were receiving a fixed scheduled opioid regimen equivalent to 60-1000 mg/day oral morphine or 50-300 microg/h transdermal fentanyl, were using a 'successful' MSIR dose (15-60 mg) as defined by entry criteria, and were experiencing 1-4 episodes of breakthrough pain per day. In open-label fashion, OTFC was titrated such that a single unit (200-1600 microg) provided adequate pain relief with acceptable side effects. Successfully titrated patients entered the double-blind phase of the study and received ten prenumbered sets of randomized capsules and oral transmucosal units. Five sets were the successful OTFC dose paired with placebo capsules, and five sets were placebo OTFC paired with capsules containing the successful MSIR dose. Patients took one set of study medication for each episode of target breakthrough pain. Pain intensity (PI), pain relief (PR) and global performance of medication (GP) scores were recorded. Pain intensity differences (PID) were calculated and 15-min PID was the primary efficacy variable. Adverse events were recorded. Sixty-nine percent of patients (93/134) found a successful dose of OTFC. OTFC yielded outcomes (PI, PID, and PR) at all time points that were significantly better than MSIR. GP also favored OTFC and more patients opted to continue with OTFC than MSIR following the study. Somnolence, nausea, constipation, and dizziness were the most common drug-associated side effects. In conclusion, OTFC was more effective than MSIR in treating breakthrough cancer pain. Supplemental, "as-needed," administration of an opioid is a common approach to the problem of breakthrough pain in cancer patients. Oral transmucosal fentanyl citrate (OTFC) is undergoing investigation as a new treatment for breakthrough pain. The primary purpose of the study was to demonstrate that a single-unit dose of OTFC can safely and effectively treat breakthrough pain. A secondary goal was to determine appropriate dosing guidelines.
                This was a multicenter, randomized, double-blind, dose-titration study in 62 adult cancer patients using transdermal fentanyl for persistent pain. Consenting patients provided 2 days of baseline data to evaluate the performance of their usual breakthrough pain medication. Patients then randomly received 200 microg or 400 microg OTFC in double-blind fashion. (Patients were always assigned, rather than randomized, to 200 microg if 400 microg represented > 20% of around-the-clock medication.) Pain intensity (PI), pain relief (PR), and global satisfaction scores were recorded. OTFC was then titrated until the patient received adequate PR for each episode using one OTFC unit. Orders to titrate up were ignored one third of the time to improve the blind. Two days of baseline data were compared with 2 days of OTFC data after titration identified an effective dose of OTFC.
                Most patients (76%) found a safe and effective dose of OTFC. There was no meaningful relationship between the around-the-clock opioid regimen and the effective dose of OTFC. In open-label comparisons, OTFC produced a faster onset of relief and a greater degree of PR than patients' usual breakthrough medication. Somnolence, nausea, and dizziness were the most common side effects associated with OTFC.
                Most patients find a single OTFC dosage that adequately treats breakthrough pain. The optimal dose is found by titration and is not predicted by around-the-clock dose of opioids. Patients with cancer frequently experience episodes of acute pain, i.e., breakthrough pain, superimposed on their chronic pain. Breakthrough pain is usually treated with short-acting oral opioids, most of which provide some relief after 15-20 minutes, with peak effects after 30-45 minutes. Oral transmucosal fentanyl citrate (OTFC), a unique formulation of the opioid fentanyl, has been shown to provide meaningful pain relief within 5 minutes in patients following surgery. We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of OTFC for cancer-related breakthrough pain.
                Patients who were 18 years of age or older, receiving the equivalent of at least 60 mg oral morphine or at least 50 microg transdermal fentanyl per day for chronic cancer-related pain, and experiencing at least one episode of breakthrough pain per day were studied. After titration to an effective OTFC dose, subjects were given 10 randomly ordered treatment units (seven OTFC units and three placebo units) in the form of identical lozenges. If acceptable pain relief was not achieved within 30 minutes, subjects were instructed to take their previous breakthrough pain medication (i.e., rescue medication). Pain intensity, pain relief, and use of rescue medication were evaluated at 15-minute intervals over a 60-minute period.
                Eighty-nine of 92 patients who received the randomized treatment were assessable (i.e., treated with at least one unit of OTFC and one unit of placebo). OTFC produced significantly larger changes in pain intensity and better pain relief than placebo at all time points (two-sided P<.0001). Episodes treated with placebo required the use of rescue medication more often than episodes treated with OTFC (34% versus 15%; relative risk = 2.27; 95% confidence interval = 1.51-3.26; two-sided P<.0001).
                OTFC appears effective in the treatment of cancer-related breakthrough pain. We compared the effects of controlled-release and immediate-release morphine preparations in adult patients with moderate-to-severe cancer pain and report methodologic approaches to pain evaluation. The study consisted of a two-phase randomized crossover trial preceded by a titration phase; all phases were conducted under double-blind conditions. To evaluate pain intensity, a visual analogue scale (VAS) and the Present Pain Intensity scale of the McGill Pain Questionnaire were used. Additional morphine solution for breakthrough pain was used as an outcome measure. Pain was evaluated nine times daily, which permitted correlation of pain scores with the pharmacokinetic patterns of the test drugs. Side effects were rated once daily, using a scale from 0 to 3. To assess the relative importance of side effects, a toxicity index was designed based on both the intensity and duration of each side effect. The overall VAS pain scores during treatment with controlled-release and immediate-release morphine were 1.3 (SD = 0.1) and 1.4 (SD = 0.2), respectively. Use of supplemental morphine solution for breakthrough pain expressed as the percentage of the daily dose of the test drug was 5.5% for the controlled-release drug and 10.9% for the immediate-release drug. Differences in pain scores, side effects, and supplemental morphine requirement between the two groups were not significant. We discuss methodologic issues in double-blind clinical trials of analgesics, in particular the validity of "Patient Preference" as an outcome measure and problems related to the titration phase. Controlled-release morphine (MST) given twice daily provides a simpler and more convenient treatment regimen than 4-hourly opioid administration for the control of cancer pain. Recently, a new formulation of transdermal fentanyl (TDF) has been developed which provides a new route for the treatment of cancer pain. The present study was designed to compare the analgesic efficacy, safety and adverse effects of MST and TDF in the management of chronic cancer pain.
                In this open, comparative and randomized study, patients were treated with oral morphine hydrochloride immediate-release (MHIR) in the stabilization phase and then the prescription was switched to MST or TDF for 14 days in the treatment phase. Oral MHIR was provided as rescue medication for breakthrough pain. Assessments of the pain intensity, pain frequency, degree of pain improvement, profile of mood states, quality of sleep, activity status and adverse effects were performed before and after the stabilization phase and before and after the treatment phase.
                Forty of 47 cancer patients completed the study with 20 patients in each group. There were significant (p < 0.05) improvements in pain intensity, pain frequency, mood states and quality of sleep in both groups before and after treatment, while improvement in the activity status was not significant. No specific adverse effects were encountered except for drowsiness which occurred in 6 patients treated with MST and 5 treated with TDF (p < 0.05). Insomnia was significantly improved (p < 0.05) with both regimens compared with that in the period before treatment. There were no significant differences between the two study groups in analgesic efficacy or adverse effects.
                These results suggest that TDF and MSt are safe and effective analgesics for the management of chronic cancer pain. However, TDF provides a simpler and more convenient treatment for those patients with severe nausea, vomiting or dysphagia. Chronic noncancer pain is often undertreated.
                To assess the efficacy of fentanyl transdermal therapeutic system (TTS) associated with oral transmucosal fentanyl citrate (OTFC) for breakthrough pain in patients with chronic noncancer pain.
                A total of 215 patients with chronic (> or =6 months), severe (VAS > or = 8) noncancer pain participated in a 6-month prospective study. The starting dose of 12 microg/h fentanyl TTS was titrated in 25 microg/h increments to a visual analog scale (VAS) score < or = 4. OTFC was administered as single-unit doses of 400 microg.
                The mean (SD) VAS score decreased from 9.86 (0.35) at baseline to 2.05 (0.96) at 6 months. The percentage of patients with poor quality of sleep decreased from 99 percent at baseline to 2.8 percent at the end of the study. The percentage of patients with inadequate pain control decreased from 16.2 percent at month 1 to 2.3 percent at month 6. Pain control was achieved with the 50 microg/h dose in 48 percent of patients, the 75 microg/h dose in 18 percent, and the 100 microg/h dose in 5 percent (only two patients required >100 microg/h). The daily use of single-unit doses of OTFC decreased from 4.64 at month 1 to 2.62 at month 6. Headache, nausea/vomiting, constipation, and somnolence of mild or moderate intensity were the most common side effects. Treatment was discontinued because of nausea/vomiting in seven patients, somnolence in three, and dermatitis in two.
                Fentanyl TTS associated with OTFC for breakthrough pain is a feasible and effective strategy in opioid naïve patients with severe chronic nonmalignant pain. Open, randomized, parallel group multicenter study.
                To compare the efficacy and safety of transdermal fentanyl (TDF) and sustained release morphine (SRM) in strong-opioid naïve patients with chronic low back pain (CLBP).
                Most studies of TDF and SRM have involved patients already receiving strong opioids. This is the first large-scale study focusing on strong-opioid naïve patients with CLBP.
                Adults with CLBP requiring regular strong opioid therapy received either TDF or SRM for 13 months. Starting doses were 25 microg/hr fentanyl patches every 72 hours or 30 mg oral morphine every 12 hours. Doses were adjusted according to response. Participants assessed pain relief and bowel function using weekly diaries. Other assessments, including quality of life, disease progression, and side effects, were made by patients and investigators.
                Data from 680 patients showed that TDF and SRM provided similar levels of pain relief, but TDF was associated with significantly less constipation than SRM, indicating a greater likelihood of satisfactory pain relief without unmanageable constipation for patients receiving TDF. Other ratings were similar for TDF and SRM, but TDF provided greater relief of pain at rest and at night.
                TDF and SRM provided equivalent levels of pain relief, but TDF was associated with less constipation. This study indicates that sustained-release strong opioids can safely be used in strong-opioid naïve patients. Cancer patients requiring strong opioid analgesia (n = 202; mean age, 61.5 years; range, 18-89 years; 55% men) were recruited from 38 United Kingdom palliative care centers into a randomized, open, two-period, crossover study comparing transdermal fentanyl with sustained-release oral morphine. Patients received one treatment for 15 days followed immediately by the other for 15 days. Daily diaries were completed. Both treatments appeared equally effective in terms of pain control, as assessed by the Memorial Pain Assessment Card and European Organization for Research and Treatment of Cancer (EORTC) pain scores. Fentanyl was associated with significantly less constipation (p < 0.001) and less daytime drowsiness (p = 0.015) but greater sleep disturbance (p = 0.004) and shorter sleep duration (p = 0.008) than morphine. The World Health Organization (WHO) performance status and EORTC global quality of life scores showed no significant difference between treatment groups. Of those patients who were able to express a preference (n = 136), significantly more preferred the fentanyl patches (p = 0.037). We conclude that, in this study, transdermal fentanyl provided pain relief that was acceptable to cancer patients and was associated with less constipation and sedation than morphine. These reduced side effects may contribute to patients preference for the patches.
The randomised trial literature for morphine is small given the importance of this medicine. Most trials recruited fewer than 100 participants and did not provide appropriate data for meta-analysis. Trial design was frequently based on titration of morphine or comparator to achieve adequate analgesia, then crossing participants over in crossover design studies. It was not clear if these trials are sufficiently powered to detect any clinical differences between formulations or comparator drugs. Studies added to the review reinforce the view that it is possible to use modified release morphine to titrate to analgesic effect. There is qualitative evidence for effectiveness of oral morphine which compares well to other available opioids. There is limited evidence to suggest that transmucosal fentanyl provides more rapid pain relief for breakthrough pain compared to morphine.