Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period.

OBJECTIVE: This trial investigated the efficacy and long-term tolerability of intranasal fentanyl spray (INFS) 50 to 200 microg in the treatment of breakthrough pain in opioid-tolerant patients with cancer. METHODS: This Phase III, double-blind, randomized, placebo-controlled, crossover trial was conducted at pain centers, anesthesiology departments, palliative care units, and oncology clinics in Austria, Denmark, France, Germany, and Poland. Eligible patients were adults with cancer receiving a stable dose of long-term opioid treatment for the control of background pain. Patients were treated at home with their effective dose of INFS (50, 100, or 200 microg) or inactive spray (placebo) in a randomized sequence for 3 weeks, followed by a 10-month, open-label tolerability phase during which they received their effective dose of INFS. Throughout the study, patients were allowed to use their usual rescue medication, which was recorded in patient diaries. The primary efficacy end point was the pain intensity difference at 10 minutes after study drug administration (PID(10)), as assessed using an 11-point numeric rating scale (0 = no pain to 10 = worst pain imaginable). An effect size of 0.5 for PID was considered clinically relevant. The rate of response, defined as PID(10) >2, was also assessed. Adverse events (AEs) were recorded in patient diaries during the efficacy period and reported in monthly clinic visits and follow-up weekly telephone contacts during the extension period. RESULTS: In all, 120 patients were enrolled and achieved an effective dose; 113 were randomized and 111 were included in the intent-to-treat analysis set (56 men, 55 women; mean [SD] age, 60.6 [9.45] years; mean weight, 70.3 kg [men] and 65.3 kg [women]; white race, 107 [96.4%]; INFS 50 microg, 18; INFS 100 microg, 48; INFS 200 microg, 45; placebo, 110). PID(10) with INFS was 2-fold that with placebo (adjusted means, 2.36 vs 1.10; adjusted difference, 1.26 [greater than the clinically relevant difference of 0.5]; P < 0.001). Additional analysis revealed that the mean response rate with all 3 doses of INFS was 51.1% versus 20.9% with placebo. The prevalence of AEs was 22/111 (19.8%) during the efficacy period, during which the most frequently reported AEs were nausea (5 [4.5%]) and vertigo (2 [1.8%]). No serious AEs were considered related to the study drugs. In all, 108 patients entered the extension period, with a mean duration of exposure to INFS of 134.9 days. Progression of underlying malignant disease was the most common AE reported during this period (55 [50.9%]); this event was not considered treatment related. CONCLUSIONS: In these opioid-tolerant patients with cancer, INFS at doses of 50, 100, and 200 microg was associated with an onset of activity at 10 minutes and effective treatment of breakthrough pain compared with placebo. All doses were generally well tolerated and clinically efficacious.

The role of transdermal buprenorphine in the treatment of cancer pain: an expert panel consensus.

BACKGROUND: The semi-synthetic opioid, buprenorphine, has the general structure of morphine but differs from it in significant ways, both pharmacologically and clinically. A number of long-term studies have shown effective, long-lasting analgesia in moderate to severe cancer and non-cancer pain, including neuropathic pain, with a low incidence of constipation, nausea, dizziness and tiredness. The treatment of moderate to severe chronic pain has improved as a result of the development of new methods of administration of this substance, particularly the introduction of the transdermal drug delivery system, which offers a number of advantages over the usual oral and parenteral routes. SCOPE: A panel of experts specialising in palliative care and pain treatment was convened in November 2007 to discuss their clinical experiences with transdermal buprenorphine and other analgesics. The aim was to provide practical guidance on the treatment of cancer pain with transdermal buprenorphine, particularly when there is a need for increasing pain relief leading to high and increasing doses. A literature search on the use of transdermal buprenorphine was carried out for the panel meeting (based on a search of PubMed to November 2007 - since updated by an additional search for the period to February 2009) and a number of case histories were presented and discussed. This commentary article presents this evidence and the consensus findings of the expert panel. FINDINGS: The Panel reached consensus that transdermal buprenorphine was a valuable treatment for chronic cancer pain, including its neuropathic components. A number of general recommendations were made. Large-scale, randomised clinical studies are needed to provide product comparisons on the use of analgesics in the treatment of neuropathic pain although it was recognised that such studies may not be practicable. Data on the treatment of acute and chronic pain should be kept separate in general. Physicians should be made more aware of the problem of hyperalgesic effects of some opioids in long term use. Buprenorphine in contrast has been described to exert an antihyperalgesic effect. The development of analgesic tolerance with some opioids in long term use and the lack of it with buprenorphine requires further studies. The registered dose range of 35-140 microg/h was considered adequate to achieve sufficient pain relief in most patients although some members of the panel presented data showing that increases beyond this dose range provided improved pain relief if slow titration is used. However, it was generally felt that more evidence was needed before this could become generally acceptable. CONCLUSION: The consensus was that transdermal buprenorphine has a valuable role to play in the treatment of chronic cancer pain because of its efficacy and good safety and tolerability profile, including a low risk of respiratory depression, a lack of immunosuppression and a lack of accumulation in patients with impaired renal function.