The Basics of Breakthrough Pain: Transmucosal Fentanyl
First described in cancer patients in 1990, the clinical definition of breakthrough pain (BTP) is broad: "Any transient and clinically important pain that flares over baseline pain in a patient whose baseline pain is adequately controlled by a chronic analgesic regimen."1 Studies have shown that BTP is common among pain patients and can occur in 30% to 65% of cancer patients2,3 and approximately 70% of patients with chronic noncancer pain.4
The personal and institutional burdens of BTP are enormous. Cancer patients with BTP have significantly higher rates of hospitalization (36.9%), poorer outcomes, and vastly higher healthcare costs ($1.7 million) than cancer patients without BTP (22.5% and $192,000, respectively).5,6 The vast majority of chronic noncancer pain patients also report that BTP has a negative effect on their ability to work, activity levels, and enjoyment of life.7
The good news is that recent advancements in rapid-onset opioids offer important ways to manage BTP in opioid-tolerant patients. One of the newest "go-to" product categories for BTP is transmucosal immediate-release fentanyl (TIRF), available in various formulations. Fentanyl, a pure agonist of the μ-opioid receptor, is highly lipophilic in nature, which allows for ready absorption through mucosal surfaces.8 This review will highlight the unique pharmacokinetic properties of several TIRF products.
Identifying Breakthrough Pain
Broadly speaking, the three most common subtypes of BTP are incident, idiopathic/spontaneous, and end of dose—although BTP can present in many different forms (gradual onset, paroxysmal, etc).9 Incident BTP is provoked by movement or activity, and accounts for nearly 50% of BTP occurrences, while spontaneous BTP is characterized as unpredictable pain without a readily identifiable cause (Table 1). The third subtype, end of dose, is just as it is described—worsening pain before the next scheduled dose of opioid for chronic pain. Identifying the types of BTP can help shape treatment approaches.
Diagnosing BTP requires patient education about the nature of BTP and good communication with the patient. Incident BTP can be anticipated and treated prophylactically, such as knowing that a patient will experience BTP when moved. Patients with end-of-dose BTP should be re-evaluated to eliminate analgesic gaps; inpatients may benefit from patient-controlled analgesia systems.
ecause of the nature of BTP, the characteristics of lipophilic opioids—their rapid absorption and concomitant rapid onset of action—make them ideal agents for the treatment of this type of pain. Lipophilic opioids include fentanyl, sufentanil (Sufenta), and methadone.9 Fentanyl, a potent fast-acting opioid agent that is about 80% nonionized, is particularly suitable for transmucosal formulations (sublingual sprays and tablets, buccal film, nasal sprays, and lozenges). The bioavailability of transmucosal fentanyl varies considerably by product type. In the case of the oral transmucosal fentanyl citrate (OTFC) lozenge (Actiq), 25% of the total dose is absorbed by the buccal mucosa and the rest is swallowed, where it undergoes first-pass metabolism in the gastrointestinal tract.10 Thus, the bioavailability of the OTFC formulation is approximately 50%9 compared to 76% for the sublingual fentanyl spray (Subsys)11 and 89% for intranasal fentanyl (Lazanda).12
The analgesic effects of these products are related to serum blood concentration: the minimum effective analgesic serum concentration of fentanyl ranges from 0.3 to 1.2 ng/mL, and levels in excess of 10 to 20 ng/mL are associated with surgical anesthesia and respiratory depression.13 A highlight of several commercially available TIRF products follows and is summarized in Table 2.
Oral Transmucosal Fentanyl Citrate
OTFC was the first TIRF approved by the FDA in 1998 for management of BTP in adult cancer patients. The lozenge is designed like a lollipop, requiring the patient to move the medication across the inside of the cheek until it is dissolved (total time required is approximately 15 minutes). About three-quarters of the OTFC dose is swallowed, reducing its relative bioavailability, which was reported to be about 50% in a multiple-dose study in healthy adults.14 In that study, OTFC was given in doses ranging from 200 to 1,600 μg to healthy volunteers. The authors reported the mean maximal plasma concentration (Cmax) was 0.4 ng/mL to 2.5 ng/mL for the lowest and highest dose, respectively. The mean time to peak plasma concentration (Tmax) was 40 minutes at the 200 μg dose and 20 minutes at the 1,600 μg dose, with a mean half-life (T1/2 ) for the two doses of 3.2 and 6.4 hours, respectively.14
Effervescent Buccal Tablets
The fentanyl buccal tablet (Fentora) was approved in 2006 for BTP in adult cancer patients. The tablet is left in the mouth for 14 to 25 minutes until it dissolves. The specially designed tablet results in a greater proportion of fentanyl being absorbed transmucosally (approximately 50%), rather than being swallowed. Thus, these fast-dissolving products have higher bioavailability than OTFC (65% vs 50%).15 The Tmax for effervescent fentanyl tablets is approximately 35 to 45 minutes, considerably less than oral fentanyl; and the area under the curve (AUC) and Cmax are proportional to doses from 100 to 800 μg, but not proportional at doses above 800 μg.16, 17 Mucositis in cancer patients did not affect dissolution of the product or its absorption.18
Buccal Soluble Film
Approved in 2009, the fentanyl buccal soluble film (Onsolis) is adhered to the inside of the cheek and dissolves within 15 to 30 minutes, allowing patients to remain passive during drug administration. In a study comparing 800 μg OTFC to 800 μg buccal soluble films at pH 6, 7.25, and 8.5, the buccal soluble films offered both greater Cmax values (1.0 ng/mL vs 1.4 to 1.7 ng/mL, respectively) and greater systemic exposure (AUC∞ 10.3 ng•h/mL vs 13.1 to 14.5 ng•h/mL).19 In clinical trials, the median Tmax of the buccal films was 1 to 2 hours, with Tmax for pH 7.25 half that of other formulations.20 The bioavailability of the buccal films was measured at 71%.21
Sublingual Fentanyl Tablet
The sublingual fentanyl tablet (Abstral) was approved in 2011, and uses water-soluble carrier particles coated with fentanyl and a mucoadhesive agent to help fix the tablet under the tongue. The highly vascularized nature of the sublingual mucosa permits rapid permeation, allowing the tablet to dissolve rapidly under the tongue. The first detectable plasma concentration was observed 8 to 11 minutes after administration.22 The Cmax is dose proportional (100 μg, 0.24 ng/mL; 200 μg, 0.41 ng/mL; and 400 μg, 0.91 ng/mL). Tmax ranged from 40 minutes at 100 μg to about 57 minutes at 400 μg.