Search

Breakthrough cancer pain (BTcP) is a common condition in oncological patients. However, its management is still suboptimal. Improved knowledge of BTcP and its management in clinical practice may have immediate importance for all physicians involved in the supportive care of cancer patients. This review critically discusses the most important concepts for the correct diagnosis of BTcP and presents some intriguing cases of the management of this condition in clinical practice. Overall, the most appropriate therapeutic choice appears to be a rapid-onset opioid (ROO), and in particular, the nasal route of administration is the quickest and most convenient mode of administration for the management of BTcP, especially when the patient needs rapid resolution of pain. To this end, intranasal fentanyl spray may have a particular relevance in clinical practice. Future research should focus on accepted definitions of BTcP to investigate the optimal management of this highly heterogeneous pain condition. Therapeutic decision-making of patients, clinicians, and payers will likely be driven from results of well-designed clinical trials of ROOs., Video abstract

Background: Breakthrough cancer pain (BTCP) is complex and severe, affecting quality of life and increasing hospitalisation. BTCP has a rapid onset that requires fast acting medication with minimal side effects. Aim: This article compares the effectiveness of intranasal fentanyl spray (INFS) and oral transmucosal fentanyl citrate (OTFC) and their alleviation of BTCP within 10 minutes of administration. Method: The article considers pharmacokinetic and bioavailability studies demonstrating the efficacy of the route of administration, time-based effects of pain relief as well as patient preference. Conclusion: The data collected indicates that INFS is more effective than OTFC for BTCP.

The treatment of breakthrough pain (BTP) in cancer patients is often sub-optimal. Normal-release oral opioid formulations have a slow onset of action, such that the episode of pain has often spontaneously subsided by the time the opioid starts to work. Other oral formulations, such as oral transmucosal fentanyl citrate (OTFC), may be associated with administration problems in many cancer patients who have salivary gland dysfunction or mucositis. Thus, there is the need for a treatment that matches a typical BTP episode and that is easy to use. Intranasal fentanyl spray (INFS) has been developed as a new route of administration with a fast onset of action. INFS has been investigated in four key clinical studies involving cancer patients with BTP. Pharmacokinetic analysis has shown a dose response for maximal plasma concentrations ( C max ) of fentanyl and a short venous time to maximum plasma concentration ( T max ). A dose-ranging efficacy study demonstrated a significant improvement in pain intensity difference (PID) over placebo from as early as 10 min post-administration. A later titrated-dose efficacy study supported these findings. In a head-to-head comparative trial between INFS and OTFC, significantly more patients achieved a faster onset of ‘meaningful’ pain relief with INFS than with OTFC, with INFS producing a significantly greater PID as early as 5 min post-dosing. Furthermore, a significantly higher proportion of patients preferred INFS over OTFC. In all clinical studies, including a 10-month follow-up, INFS was well tolerated. INFS should be considered a significant advance for the management of BTP.

To compare the efficacy of intranasal fentanyl spray (INFS), oral transmucosal fentanyl citrate (OTFC), fentanyl buccal tablet (FBT) and oral morphine (OM) for the treatment of breakthrough cancer pain (BTCP).A systematic literature review (Medline, EMBASE, BIOSIS; 1996-2007) identified six randomised controlled trials (RCTs) investigating the effects of INFS, OTFC, FBT and OM for the treatment of BTCP. The endpoint of interest was pain intensity difference (PID, reported on a 0-10 numeric rating scale [NRS]) up to 60 minutes after intake. Results of all trials were analysed simultaneously with a mixed treatment comparison (extended meta-analysis). MTC can be considered a valid method when included studies are comparable regarding effect modifying baseline patient and study characteristics.INFS provided the greatest reduction in pain relative to placebo: PID 1.7 points (95% CrI: 1.4; 1.9) at 15 minutes, 2.0 (1.6; 2.3) at 30 minutes, 2.0 (1.5; 2.4) at 45 minutes and 1.9 (1.5; 2.4) at 60 minutes. PID for OTFC and FBT relative to placebo were 0.4 (0.0; 0.8) and 0.5 (0.3; 0.7) at 15 minutes. Both treatments provided a reduction in pain superior to placebo at other time points. INFS displayed a more than 99% probability of providing the greatest pain reduction out of all interventions compared at 15 minutes after intake. This was maintained for any measured time point before 45 minutes when compared to FBT and for any measured time point before 60 minutes when compared to OTFC. Only from 45 minutes onwards did OM show a greater pain reduction than placebo.Based on currently available evidence, INFS is expected to provide the greatest improvement in the treatment of BTCP. Due to its slow onset to effect OM cannot be considered an efficacious treatment for BTCP.

Objective:To review the pharmacology, pharmacokinetics, clinical efficacy, adverse events, dosing, and administration of intranasal fentanyl spray in the treatment of breakthrough cancer pain (BTCP) in adults.Data Sources:Relevant published data were identified using PubMed from inception to April 2012 using the search terms fentanyl nasal spray, intranasal fentanyl, intranasal fentanyl cancer pain, and fentanyl pectin cancer pain. Only articles evaluating the use of intranasal fentanyl spray for cancer pain were selected.Study Selection and Data Extraction:All articles evaluating the pharmacokinetics of intranasal fentanyl or the clinical efficacy of intranasal fentanyl spray for the treatment of BTCP were considered; references of selected articles were manually reviewed to identify further articles. The manufacturer of intranasal fentanyl spray was also contacted to obtain information.Data Synthesis:Intranasal fentanyl spray gained Food and Drug Administration approval for the treatment of BTCP in adults with cancer receiving stable BACKGROUND opioid therapy for chronic pain. In doses ranging from 100 to 800 μg/spray, intranasal fentanyl spray was found to be more effective than placebo and more effective than oral morphine or oral fentanyl formulations in reducing pain for up to 15–45 minutes; onset of analgesia was also improved with intranasal fentanyl spray. The most commonly observed adverse events included nausea, vomiting, vertigo, and dizziness.Conclusions:For the treatment of BTCP, intranasal fentanyl spray offers improved onset of analgesia compared to other oral therapies; this improved onset of analgesia may closely mimic the typical time course of a BTCP episode. Nasal administration may overcome problems such as nausea, vomiting, or xerostomia that may complicate oral administration of analgesics. Potential disadvantages include uncertainty in treating more than 4 BTCP episodes per 24 hours and a higher cost compared to generically available oral opioid analgesics.

The efficacy of intranasal fentanyl spray (INFS) was compared with that of oral transmucosal fentanyl citrate (OTFC) for the relief of cancer-related breakthrough pain (BTP) in an open-label, crossover trial.Adult cancer patients receiving stable background opioid treatment and experiencing BTP episodes were recruited from 44 study centres in seven European countries (Austria, France, Germany, Italy, Poland, Spain and the United Kingdom); of the 196 patients enrolled, 139 were randomised to receive INFS followed by OTFC, or vice versa. Patients were titrated to an effective dose of one agent (50, 100 or 200 microg INFS; 200, 400, 600, 800, 1200 or 1600 microg OTFC) to treat six BTP episodes, then titration and treatment were repeated with the other agent. The primary outcome was patient-recorded time to onset of 'meaningful' pain relief. Secondary outcomes included pain intensity difference (PID) at 10 and 30 minutes (PID(10), PID(30)), sum of PID at 15 and 60 minutes (SPID(0-15), SPID(0-60)), ease of administration, treatment preference and relationship between background opioid dose and effective INFS dose. Additional outcome measures included proportions of episodes withor =33% andor =50% pain intensity (PI) reduction, and PID at additional time points.NCT00496392.Among the intention-to-treat population (n = 139), median time to onset of 'meaningful' pain relief was 11 minutes with INFS versus 16 minutes with OTFC; 65.7% of patients attained faster time to 'meaningful' pain-relief onset with INFS (p0.001). PID was statistically significantly greater for INFS than OTFC from 5 minutes post-dosing. Significantly more INFS-treated breakthrough pain episodes achieved clinically important pain relief (or =33% andor =50% PI reduction) up to 30 minutes post-dosing. The proportions of episodes treated with INFS and OTFC achieving a PI reduction ofor =33% at 5 minutes were 25.3% versus 6.8% (p0.001), and at 10 minutes were 51.0% versus 23.6% (p0.001), respectively; the proportions of episodes treated with INFS and OTFC achieving aor =50% PI reduction at 5 minutes were 12.8% versus 2.1% (p0.001), and at 10 minutes were 36.9% versus 9.7% (p0.001), respectively. Higher SPID(0-15) and SPID(0-60) scores were achieved with INFS (p0.001). More patients preferred INFS than OTFC (p0.001) and more patients found it very easy/easy to use. Both treatments were well tolerated. In the safety population (n = 139), 56.8% (n = 79) of patients experiencedor =1 AE during the trial. The only AE that occurred inor =5% of patients in either treatment group was nausea. Among those patients who experienced serious AEs (13.7%, n = 19), none were considered to be related to either study medication. There was a weak correlation between effective INFS doses and background opioid doses.In this open-label, randomised, crossover trial, significantly more patients attained faster 'meaningful' pain relief with INFS than OTFC, and more patients preferred INFS to OTFC.