Pain is a common feature of cancer that presents a significant clinical challenge. The prevalence of pain increases as the condition progresses1 and it affects over 80 % of patients with advanced disease.2 Opioids remain the best front-line treatment for providing pain relief (PR), but even when these agents effectively control background pain, patients often experience breakthrough cancer pain (BTcP).3 This may be defined as ‘a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain’.4
BTcP is a heterogeneous entity that varies both between individuals and within individuals over time.5 In a recent study that enrolled 1,000 European oncology patients, the median number of BTcP episodes was three per day, with >95 % of subjects rating the intensity of pain as either ‘moderate’ or ‘severe’.6 Median time to peak intensity was 10 minutes, and the median duration of episodes was 60 minutes.6 The negative effect on quality of life can be significant, as a result of personal suffering and interference with the activities of daily living.6
BTcP may be classified as either spontaneous pain (episodes are unpredictable and not related to an identifiable precipitant) or incident pain (episodes are related to a specific identifiable precipitant).4 There are three sub-classifications of incident pain: volitional (brought on by a voluntary act such as movement), non-volitional (brought on by an involuntary act such as coughing) and procedural (related to a therapeutic procedure such as wound dressing).4 Episodes of pain that occur shortly before the administration of ‘around-the-clock’ (ATC) opioid analgesics (‘end of dose failure’) should not be regarded as BTcP, since the background pain is not controlled in this situation.
This review article summarises the available data on a new fast-acting fentanyl formulation for treating breakthrough pain, which has been developed to accelerate absorption of fentanyl and reduce the time to onset of analgesia.
Management of Breakthrough Cancer Pain
There is currently no ‘gold standard’ for the pharmacological symptomatic treatment of BTcP, but the most common strategy is the use of supplemental analgesia, or ‘rescue medication’.4 The ideal rescue medication should not only be safe and effective, but also have a rapid onset of action, a relatively short duration of effect7 and be suitable for use both reactively (i.e. at the onset of pain) and prophylactically (i.e. prior to the onset of pain in patients with predictable incident pain). These properties would enable BTcP to be rapidly controlled, while avoiding opioid accumulation and minimising adverse effects.8 Currently, BTcP is widely treated with supplemental doses of oral opioids – often immediate-release formulations of morphine. The time to onset of analgesia for these agents is 20–30 minutes, and the time to full effect 60–90 minutes.4 This is not ideal for managing many BTcP episodes.
The requirement for an agent with a faster onset of effect led to the development of transmucosal formulations of fentanyl citrate. Fentanyl is well suited to transmucosal administration because it is highly lipophilic.9 Currently available formulations include oral transmucosal fentanyl citrate (OTFC), fentanyl buccal tablet (FBT), orally disintegrating tablet (ODT), fentanyl buccal soluble film (FBSF), intranasal fentanyl spray (INFS) and fentanyl pectin nasal spray (FPNS). Randomised controlled trials have shown that these formulations can produce analgesia within 15 minutes, and are generally well tolerated.10–15 Recent recommendations published by the European Association for Palliative Care state that ‘BTP can be effectively managed with oral, immediate-release opioids or with buccal or intranasal fentanyl preparations. In some cases the buccal or intranasal fentanyl preparations are preferable to immediate-release oral opioids because of more rapid onset of action and shorter duration of effect’.16
A continuing area of concern with transmucosal fentanyl formulations is that aberrant drug-related behaviour is likely to emerge in about 10 % of patients,17 so continuous monitoring is required. It is generally agreed that the best approach to this problem is not by limiting the availability of these agents, but by the proper assessment and management of both pain and addiction.18
A New Formulation
The conventional approach to tablet formulation is to distribute the active ingredient uniformly throughout the whole tablet, which means that the total dose is not available until the tablet has completely dissolved. In the context of BTcP, the rapid onset of effect is of paramount importance, and a new formulation of sublingual fentanyl citrate tablet (FE tablet) has been developed with the aim of accelerating absorption. It has a unique three-layer structure with a neutral central core surrounded by the fentanyl citrate layer (see Figure 1). This, in turn, is surrounded by an alkaline outer buffering layer, which provides the optimal pH for dissolution and subsequent absorption (see Figure 2). Following dissolution of the surface layer, the total dose of fentanyl is rapidly available, in contrast to a conventional tablet, where the whole amount of fentanyl will only become available after complete dissolution.
The small triangular FE tablet has a neutral taste [data on file]. In vitro testing has shown that it takes approximately 10 minutes for 80 % of the FE tablet to dissolve compared with approximately 1 hour for the OTFC lozenge (Actiq®; see Figure 2; data on file). Six dosages are available: 67, 133, 267, 400, 533 and 800 μg. The tablet is placed under the deepest part of the tongue and allowed to completely dissolve without chewing or sucking. Any remnants may be swallowed after 30 minutes. The optimal dose is determined by upward titration on an individual patient basis, with a maximum of two tablets for each BTcP episode. The range of dosages allows dose escalation in 133 or 267 μg increments until adequate analgesia is achieved. Once an appropriate dose has been established, this should be administered for subsequent BTcP episodes, up to a maximum of four doses per day. If the response to this dose changes markedly, it may be increased or decreased by one increment to maintain an optimal effect.
The pharmacokinetics of the new FE tablet have been investigated in four phase I trials in healthy adult volunteers under fasting conditions.19–22 The OTFC lozenge was selected where an active comparator was required, as this product has been on the market for the longest period of time.
A drug is said to be dose-proportional if its concentration (usually in plasma) at any given time is proportional to the dose administered. This property is of clinical importance in predicting the effect of dose adjustments, because it means, for example, that doubling the dose will double the plasma concentration. Drugs that lack dose-proportionality are more difficult to use, particularly if the therapeutic window is narrow.
The dose-proportionality of three different doses (133, 400 and 800 μg) of the FE tablet has been investigated in an open-label, randomised, three-way crossover, six sequence, dose-proportionality study.19 Thirty-three subjects were included in the statistical analysis. They received a different single dose on each of three occasions and were then followed up for approximately 2 days, with a 14-day washout phase between doses. Blood samples were collected at various time intervals up to 36 hours after dosing, and the plasma concentration of fentanyl determined using a validated liquid chromatography– tandem mass spectrometry (LC/MS/MS) method. From the area under the plasma concentration-time curve (AUC) (see Figure 3), pharmacokinetic parameters including AUC0-t, AUC0-t’, AUC0-inf and the maximum concentration (Cmax) were then derived. Analysis of these parameters and a linearity analysis performed using a regression approach, demonstrated that these three doses have linear and doseproportional pharmacokinetics after single-dose administration.19