title: Fentanyl buccal tablet for the relief of breakthrough pain in opioid-tolerant adult patients with chronic neuropathic pain: a multicenter, randomized, double-blind, placebo-controlled study.
abstract: BACKGROUND
  Patients with chronic noncancer pain, including neuropathic pain, may have transitory exacerbations of pain (median duration, 60 minutes), termed breakthrough pain (BTP), that may reach peak intensity within minutes. Typical short-acting oral opioids may not provide sufficiently rapid relief (30- to 60-minute onset of analgesia). The fentanyl buccal tablet (FBT) provides a rapid onset of analgesia (10-15 minutes) by enhancing fentanyl absorption across the buccal mucosa.
  
  
  OBJECTIVE
  This study evaluated the efficacy and tolerability of FBT in opioid-tolerant patients with BTP associated with chronic noncancer neuropathic pain.
  
  
  METHODS
  This was a multicenter, randomized, double-blind, placebo-controlled study in men and women aged 18 to 80 years who were opioid tolerant; had a >/= 3-month history of chronic persistent neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, traumatic injury, or complex regional pain syndrome; and reported having episodes of BTP. After an open-label titration period to identify an effective FBT dose (the dose at which the patient reported receiving adequate pain relief within 30 minutes after administration of a single tablet of that dose during at least 2 of 3 BTP episodes), patients were randomly assigned to treat 9 consecutive episodes of BTP over the next 21 days with 1 of 3 double-blind dose sequences of FBT and placebo tablets. Pain intensity (PI) (rated on an 11-point pain scale, from 0 = no pain to 10 = worst pain) and other outcomes were assessed before dosing and for 2 hours after dosing. The primary efficacy measure was the sum of PI differences (PIDs) for the first 60 minutes (SPID(60)). Secondary efficacy measures included the proportion of BTP episodes with >/= 33% and >/= 50% improvement in PI from baseline; PID at other time points (5, 10, 15, 30, 45, 60, 90, and 120 minutes after dosing); pain relief (PR) at the same time points (rated on a 5-point Likert scale from 0 = none to 4 = complete); proportion of BTP episodes with meaningful PR; time to meaningful PR; and proportion of BTP episodes in which supplemental medication was required after administration of study drug. Adverse events (AEs) spontaneously reported by the patient or elicited by the investigator were recorded throughout the study.
  
  
  RESULTS
  Of 102 patients in the open-label titration period, 80 identified an effective dose of FBT and 79 entered the double-blind phase. Of these 79 patients, 77 (97%) completed the study and 75 (95%) were evaluable for efficacy. Of the 79 patients who entered the double-blind phase, 63% were women and 92% were white; their mean (SD) age was 48.3 (10.42) years, and their mean weight was 96.8 (33.42) kg. Baseline demographic and pain characteristics were similar between the overall population and the double-blind population. SPID(60) was significantly greater for BTP episodes treated with FBT compared with those in which placebo was administered (mean [SE], 9.63 [0.75] vs 5.73 [0.72], respectively; P < 0.001). Significant differences between FBT and placebo were seen beginning at 10 minutes for PID (mean, 0.740 [0.149] vs 0.427 [0.081]; P < 0.047) and PR (mean, 0.561 [0.087] vs 0.324 [0.056]; P < 0.001). A >/= 33% improvement in PI from baseline was seen in a greater proportion of BTP episodes treated with FBT compared with placebo from 10 minutes (9% vs 3%; P = 0.008) through 2 hours (66% vs 37%; P < 0.001). Patients were almost 4 times less likely to require supplemental opioids when BTP episodes were treated with FBT compared with placebo (odds ratio = 0.28; 95% Cl, 0.18-0.42). AEs were reported by 64 (63%) of 102 patients. The most commonly reported AEs were those typical of opioids (nausea [13%], dizziness [13%], somnolence [10%], and vomiting [5%]) and occurred more often during the dose-titration phase (55/102 [54%]) than during the double-blind phase (22/79 [28%]).
  
  
  CONCLUSIONS
  In these opioid-tolerant patients with chronic neuropathic pain who identified an effective FBT dose, FBT had a rapid onset of action and was effective and well tolerated in the treatment of BTP.
authors.affiliation: Mount Sinai School of Medicine, New York, New York 10029, USA. david.simpson@mssm.edu
authors.forename: David M
authors.initials: DM
authors.lastname: Simpson
authors.forename: John
authors.initials: J
authors.lastname: Messina
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Martin
authors.initials: M
authors.lastname: Hale
mesh_terms: D000278:Administration, Buccal; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000503:physiopathology; D013607:Tablets
chemical_list: D000701:Analgesics, Opioid; D013607:Tablets; D005283:Fentanyl