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Fentanyl buccal tablets for the treatment of breakthrough pain

Practice Points

Sebastiano Mercadante† „„ Starting dose: in patients with chronic pain controlled by background analgesia, and presenting episodes

of breakthrough pain, doses of fentanyl buccal tablets (FBT) should be titrated starting with the lowest dose (100 µg) in patients with chronic pain receiving at least 60 mg or oral morphine equivalents. Dosing could be repeated after 30 min if analgesia is insufficient. This process, however, may result in losing time for patients who receive higher doses of opioids for treating chronic pain. „„ Discontinuation: there are no recommendations available, only anecdotal experience, particularly in

noncancer patients receiving FBT long term who developed a withdrawal syndrome. „„ Time course of efficacy: short-term studies have shown that FBT provides efficient analgesia within

10–15 min. „„ Initial tolerability profile: FBTs produce adverse effects that are often indistinguishable from those

induced by chronic opioid analgesia. Most adverse effects are mild and generally occur during the titration process. „„ Safety with other medication: FBT have been successfully used in patients receiving different types of

opioids, including morphine, fentanyl, oxycodone, hydromorphone and methadone. The effect of a combination therapy has not been formally examined. It is reasonable that interactions with other drugs are unlikely to appear clinically. Caution should be used with drugs known to compete with or inhibit cytochrome CYP3A4. „„ Warning: FBT should be guarded from inadvertent use by family members and should be avoided in

drug addicts.

SUMMARY

Fentanyl buccal tablets (FBT) have been designed to treat breakthrough pain (BTP) in patients who are already receiving, and who are tolerant to, opioid therapy for their underlying persistent pain. FBT are a formulation that uses an effervescent drug delivery system to enhance penetration across the buccal mucosa. OraVescent technology provides an effervescent reaction that liberates carbon dioxide in the buccal cavity. This reaction causes an initial decrease in pH, which facilitates solubilization, thus driving fentanyl into solution. Subsequently, carbon dioxide increases the local pH, which facilitates permeation of unionised fentanyl across the buccal mucosa. In clinical studies of opioid-tolerant patients Pain Relief & Palliative Care Unit, La Maddalena Cancer Center, Via San Lorenzo 312, 90146 Palermo, Italy; Tel.: +39 091 680 6521; Fax: +39 091 680 6110; [email protected]

10.2217/PMT.11.52 © 2011 Future Medicine Ltd

Pain Manage. (2011) 1(6), 533–538

ISSN 1758-1869

533

Review  Mercadante with cancer and noncancer-related BTP, FBT have provided consistent and clinically relevant improvements in pain intensity and pain relief relative to placebo and oral opioids like oxycodone. The safety and tolerability profile is generally typical of that observed with other opioids. The pharmacokinetic properties of FBT allow for a meaningful clinical efficacy, with an onset of action that closely matches the onset of BTP. FBT, as with any other transmucosal preparations of fentanyl, should not be used in patients who are not opioid-tolerant. Most patients with advanced cancer experience some degree of pain. In addition to background or persistent pain, about 65% of patients also experience episodes of breakthrough pain (BTP); the incidence varies according to the population surveyed, setting and the definition of BTP used [1–3] . BTP is commonly described 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] . While there are slight differences with previous definitions [5,6] , all stress the transient nature of BTP against a background of stable and controlled baseline pain. The profile of different episodes of BTP are represented in Figure 1. Breakthrough pain is associated with a significant negative impact on both quality of life (including activities of daily living, sleep, social relationships and mood) and medical outcomes [7] . Although orally administered opioids offer convenience, simplicity and are cheap, the onset of action of an oral supplemental opioid may not be fast enough to overlap the temporal profile of BTP [8] . In recent years, several products have been developed to ensure better treatment of BTP, including various formulations of fentanyl, a highly potent opioid that has no pharmacologically active metabolites. Fentanyl is a µ-receptor agonist analgesic with a potency approximately

Numerical scale rating

10

5 Background analgesia

0

Figure 1. Profile of breakthrough pain episodes with different pain intensities.

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75–100 times greater than that of parenteral morphine, possibly because of the highly lipophilic nature of fentanyl, enabling it to transfer rapidly across both mucosal barriers and the blood–brain barrier [9] . Oral transmucosal fentanyl citrate (OTFC) has become a mainstay in the management of BTP because it provides faster absorption of fentanyl than achieved by regular oral formulations of opioids [10] . A second generation of delivery systems provided a refinement of the transmucosal route. These systems allow better drug absorption and are less dependent on the individual use of the lozenge of OTFC and active collaboration. This article will focus on the role of fentanyl buccal tablets (FBT) in the management of BTP. Characteristics of the product Fentanyl buccal tablets have been designed to treat BTP in patients who are already receiving, and who are tolerant to, opioid therapy for their underlying persistent pain. FBT are a formulation that uses an effervescent drug-delivery system to enhance penetration across the buccal mucosa. Although the lipophilicity of fentanyl allows it to pass readily through the buccal mucosa, this same characteristic renders it less soluble in an aqueous solution, such as saliva. Fentanyl is a weak base and dissolution requires a relatively low pH, where the ionized, hydrophilic form of the drug predominates. In contrast, permeation and absorption of fentanyl through a cellular membrane, such as the buccal mucosa, requires a higher pH, where the nonionized, lipophilic from of the drug predominates. The clinical efficacy of fentanyl can be enhanced by improving dissolution and passage of the drug into the circulation by selectively modifying the local pH and permeability at the mucosal wall [11] . OraVescent technology was developed to enhance drug delivery. FBT formulation contains sodium bicarbonate, sodium carbonate and citric acid, which induce a sequence of pH changes and an accompanying liberation of CO2. As the tablet begins to dissolve, the local environment becomes more acidic because of the dissolved citric acid and CO2. In this acid environment, the available fentanyl becomes almost completely unionized and its

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Fentanyl buccal tablets for the treatment of breakthrough pain  aqueous solubility is high. As the reaction progresses, CO2 is released and the pH increases in the presence of a larger number of basic cations, rendering the dissolved fentanyl nonionized. The accompanying CO2 liberation is thought to improve membrane permeation of fentanyl. As the pH increases, the gradient of nonionized fentanyl promotes the passage through the lipid barrier of the buccal mucosa (Table 1) [11,12] . Pharmacokinetics Fentanyl is rapidly and extensively absorbed from FBT across the buccal mucosa and into the bloodstream. A number of studies have shown that the area under the curve (AUC) of fentanyl delivered by FBT is characterized by the rapid absorption of fentanyl into the systemic circulation, followed by a triexponential decline from Cmax, first with a rapid distribution of fentanyl from blood into highly perfuse tissues; second, elimination and absorption of the swallowed portion of fentanyl; and finally, the redistribution of fentanyl to the deep tissue compartments and subsequent elimination. With doses of 100–810 µg; Cmax values increased dose-proportionally and increases were less than dose-proportional with higher doses [13] . FBT were observed to have a greater absolute bioavailability (67%) than OTFC (47%) or ingested FBT (31%) based on ratios of the respective AUC value to the AUC value of intravenous fentanyl. The observed greater absolute bioavailability is a result of the higher proportion of fentanyl being absorbed across the oral mucosa. A total of 48% of the total dose was absorbed across the buccal mucosa and became systematically available for facing the temporal pattern of BTP. The remaining half of the total FBT dose is swallowed and slowly absorbed from the gastrointestinal tract (52%); it is not functional to the management of BTP. The median time to peak plasma concentration is about 50 min, possibly due to a large dose absorbed transmucosally [11,14] . According to the relative availability, FBT doses should be reduced by 30–50% compared with the dose of OTFC to achieve comparable maximum systemic fentanyl exposure [12] . The dwell time (the time it takes FBT to disappear completely once placed in the buccal cavity) varies among patients, ranging from 14–25 min. Any remaining portion probably consists of the residue of excipients [15] . Sublingual FBT placement is an alternative to buccal placement. Tmax values were similar after buccal and sublingual administration [16] .

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Table 1. Characteristics of fentanyl buccal tablet. Dose strength (µg) Route

Frequency

100–800

As needed for episodes of BTP. Administration can be repeated once for a single episode after 30 min if pain control is insufficient

Buccal, sublingual

BTP: Breakthrough pain.

Fentanyl is highly protein bound, mainly to a-1-acid glycoprotein, but also to albumin and lipoproteins to a limited extent. The free fraction of fentanyl is related to pH. Fentanyl is prevalently metabolized in the liver and intestinal mucosa to norfentanyl by cytochrome CYP3A4. Fentanyl is eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites excreted in the urine. The median terminal half-life for FBT has been shown to be 22  h following multiple dosing and 12 h following a single dose; and is consistent with redistribution of fentanyl between plasma and a deep-tissue compartment. Despite fentanyl’s long half-life, the duration of action is short as the rapid and extensive uptake of fentanyl in highly perfused tissues coupled with the redistribution into a deep-tissue compartment and plasma result in a timely decline of plasma concentrations below clinical relevant threshold [17] . Characteristics of FBT are listed in Table 2 . Clinical efficacy Short-term, randomized, controlled clinical studies of FBT in patients with cancer pain and noncancer pain have shown the efficacy of FBT in the management of BTP. The efficacy was also confirmed in long-term studies on the safety and tolerability of FBT. Short-term studies included an open-label dose-titration phase prior to the start of a randomized, placebo-controlled, double-blind treatment. In patients with cancer pain, significant improvement of BTP was observed when compared with placebo in pain intensity difference, summed pain intensity difference, pain relief scores, and clinically significant improvements in pain scores at 15, 30, 45 and 60 min [18,19] . In Table 3, the percentages of patients with a decrease in pain intensity of ≥33%, ≥50% or increase of ≥2 points in pain relief as compared with placebo are reported. More recently, the efficacy and safety of FBT was compared with an active agent such as immediate-release oxycodone, in opioid-tolerant patients with cancer and noncancer chronic

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Review  Mercadante Table 2. Characteristics of fentanyl buccal tablets. Mean plasma concentration (ng/ml)

Tmax (h)

AUC (ng h/ml)

Half-life (h)

1.6

0.7

9.2

11.7

AUC: Area under the curve.

pain. Pain intensity difference at 15 min was significantly greater after FBT versus oxycodone. Secondary efficacy measures, including pain intensity difference at 5  min and pain relief at 10  min were in favor of FBT. Also, summed pain intensity differences (SPID)30´ and SPID60´ were greater with FBT than with oxycodone. Finally FBT was preferred by 52% of patients, and oxycodone by 33% [20] . Similar results were obtained in noncancer populations with chronic neuropathic pain and chronic low back pain [21,22] . Safety The most common adverse effects reported in short-term studies are often indistinguishable from those induced by chronic opioid therapy and include nausea, dizziness, headache, fatigue, vomiting, somnolence and asthenia. FBT was also generally safe and well tolerated in long-term studies in both cancer and noncancer populations. In a long-term, open-label study in opioid-tolerant patients with chronic cancer pain, after patients had been successfully titrated they entered a maintenance phase of ≥12 months. Adverse effects resulted in discontinuation of therapy for 33% of 77 patient, but all serious adverse effects were considered to be related to the patients’ underlying conditions. Fifteen patients experienced local adverse effects related to FBT [23] . In noncancer populations a continued efficacy of FBT versus placebo was demonstrated for SPID60´ with a meaningful pain relief by ≥10 min. Adverse events and patient discontinuation were generally typical of clinical opioid use [24] . An ana­lysis of long-term safety from combined clinical trials Table 3. Efficacy of fentanyl buccal tablet versus placebo in cancer patients with breakthrough pain after 30 min of administration in two randomized placebo-controlled studies. % of episodes of BTP

FBT (%)

Placebo (%)

≥33 decrease in PI at 30 min ≥50 decrease in PI at 30 min ≥2 points of PR score at 30 min

50 31 46

28 16 27

BTP: Breakthrough pain; FBT: Fentanyl buccal tablet; PI: Pain intensity; PR: Pain relief. Data taken from [18,19].

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of FBT in opioid-tolerant noncancer patients has been reported recently. The majority of patients (88%) had one or more adverse effects, which were typical of adverse effects associated with opioid use in a noncancer chronic pain population. In 43% of these patients adverse effects were considered to be causally related to treatment. Application site adverse effects were recorded in 13% of patients. A total of 11% of 646 patients discontinued FBT because of adverse effects. Two patients reported accidental overdose and four patients experienced drug dependence. Drug withdrawal syndrome occurred in 4% of patients after discontinuation of FBT alone or in combination with other opioid medications. BTP functional factors and pain interference scores showed only slight improvements. Consistent improvements were noted in functional measures [25] . In noncancer opioid-tolerant patients, 80% of 925 enrolled patients developed adverse effects that generally occurred within 1 week of starting treatment and lasted ≥2 days. Adverse effects discontinuation occurred in 14% of patients [26] . Dosing Fentanyl buccal tablets are indicated for the management of BTP in patients who are already receiving opioid therapy for their chronic pain in doses of ≥60 mg of oral morphine equivalents. FTB is available as tablets in strengths of 100, 200, 400, 600 and 800 µg. It is commonly recommended that administration be tailored though dose titration that should be started with multiples of the 100 µg tablet. During this phase, if pain is not controlled by FBT, dosing may be repeated after 30 min [9] . However, the dose of FBT to be administered for better efficacy for BTP still remains to be determined. Trials of FBT suggest a lack of relationship between the effective fentanyl dose and a fixed-schedule opioid regimen, regardless of the opioid used. According to this information, doses should be titrated starting with the lowest doses to find the effective dose [4] . However, in these studies, a substantial proportion of patients failed dose titration, often an unclear distinction between the basal pain of mild–moderate intensity and BTP of moderate–severe intensity made the interpretation provided by these studies difficult. Moreover, none of these studies assessed doses higher than 800 µg of FBT. Reviewing,

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Fentanyl buccal tablets for the treatment of breakthrough pain  in detail, studies of cancer patients, the mean effective dose of FBT was 475 µg (mostly in the range of 400–800  µg). The calculated proportional dose was 300–400  µg of FBT, which is even less than the dose achieved after titration [18] . In the second study [19] , the mean effective dose of FBT was 544 µg (60% of patients had an effective dose in the range of 600–800 µg). The calculated proportional dose was 400–500 µg, a dose lower than that achieved after titration. In other words, the dose to be calculated as a proportional dose could be low and necessitates further titration, suggesting that titration with the lowest dosage may be inconvenient, at least in patients receiving medium-high doses of opioids for background analgesia, or that titration should be started from the proportional dose calculated [27] . Further studies with an appropriate design should define the question comparing titration process with the proportional  approach. Special patient groups Patients receiving high doses of opioids as background medication are challenging. Information about this topic is poor, as most studies assessed only the maximum existing dose of 800  µg. Recently, patients receiving mean doses of 1340  mg (range 720–2400  mg) of oral morphine equivalents as background analgesia and having pain under control for most daily hours, were given doses of FBT proportional to the basal opioid regimen. For example, patients receiving 600 mg of oral morphine were given 1000 µg of FBT, and so on. The mean dose of FBT administered was 2233 µg (range 1200–4000 mg). This approach was effective in most events treated within 15 min, and in all the cases, adverse effects were mild and undistinguishable from those associated with basal opioid analgesia, independent of the dose administered [28] . Efficacy of FBT was evaluated in cancer patients receiving methadone for background analgesia, who potentially may be particularly resistant to other opioids added on for the management of BTP. FBT in doses proportional to methadone doses, was effective as BTP medication in patients receiving methadone for their background analgesia, confirming that this group of patients are not inevitably resistant to other opioids [29] . Comorbidities and functional status should be taken into account when selecting analgesics for elderly patients. The frequent polypharmacy associated with comorbidities in this population

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Review

increases the possibility of drug interactions. Older patients with hepatic or renal impairment may require dose modifications of FBT, as it is not well understood the influence of age on breakthrough doses of fentanyl [30] . Patients with advanced cancer may suffer from a dry mouth or nose; taking oral medications with a drink or the use of salivary substitutes or stimulants can help patients with dry mouth [31] . Sublingual administration of FBT could be an alternative [14] . High-risk patients (those with addictive personality traits or with a recent history of substance dependence or misuse) require particular attention. Conclusion In clinical studies of opioid-tolerant patients with cancer and noncancer-related BTP, FBT has provided consistent and clinically relevant improvements in pain intensity and pain relief relative to placebo and oral opioids, like oxycodone. The safety and tolerability profile is generally typical of that observed with other opioids. The pharmacokinetic properties of FBT allow for a meaningful clinical efficacy, with an onset of action that closely matches the onset of BTP. FBT, as with any other transmucosal preparations of fentanyl, should not be used in patients who are not opioid-tolerant. Future perspective Further refinements and new technologies are going to be developed in the coming years to provide easy and effective analgesia for BTP. Regardless of the effectiveness of the different products, patients’ preference will still have a prominent role in the use and choice of the these delivery systems, able to provide analgesia in 5–15 min. Patients’ education remains of paramount importance in this context for appropriate use of BTP medications. Financial & competing interests disclosure In the last 3 years, S Mercadante acted on the advisory board and received consultation and lecture fees from Cephalon, Archimedes, Nycomed, Grunenthal, Janssen, Mundipharma, Pfizer, Dompè, GW Pharma, Qx Pharma and Prostrakan. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Review  Mercadante of a task group of the science committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur. J. Pain 13, 331–338 (2009).

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Fentanyl buccal tablets for the treatment of breakthrough pain.

SUMMARY Fentanyl buccal tablets (FBT) have been designed to treat breakthrough pain (BTP) in patients who are already receiving, and who are tolerant ...
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