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9 Articles in Volume 13, Issue #3
Comprehensive Rehabilitation of the Cancer Pain Patient
Neuropathy in the Cancer Patient: Causes and Cures
The Basics of Breakthrough Pain: Transmucosal Fentanyl
The Use of Botulinum Toxin in Migraines: A Review
Complex Regional Pain Syndrome: Systemic Complications
Diagnostic Ultrasound in Carpal Tunnel Syndrome: A Helpful Additional Tool
The Homebound Adolescent Headache Patient
Editor's Memo: Neurosteroids—Gaining Ground In Pain Management Research
Ask the Expert: Monitoring Liver Function

The Basics of Breakthrough Pain: Transmucosal Fentanyl

Breakthrough pain is common, occurring in 30% to 65% of cancer patients and approximately 70% of patients with chronic noncancer pain.

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.

Sublingual Fentanyl Spray
The sublingual fentanyl spray (Subsys) was approved in January 2012, and offers 34% greater maximum plasma concentration (Cmax) and 38% greater systemic exposure (AUC) compared to oral transmucosal fentanyl. A single 400-μg dose has mean absolute bioavailability of 76% as measured by AUC.11

Intranasal Spray With Pectin
The nasal mucosa is about 2 to 4 mm thick and heavily vascularized, allowing drugs to avoid first-pass metabolism from the gastrointestinal tract.23 However, nasal mucosa is easily irritated; therefore, drugs administered via this route must be delivered in very small doses. Lipophilic drugs, such as fentanyl, diffuse passively through the epithelium, allowing rapid onset. The only fentanyl nasal spray available in the United States has a pectin base (Lazanda); a non-pectin intranasal spray is available in Europe (Instanyl, Nycomed).

The pectin-based intranasal spray extends the duration of time in which the drug resides in the nasal cavity, allowing for a rapid Tmax value without surpassing therapeutic serum concentration levels. In pharmacokinetic studies, the Cmax of 100 μg of pectin-based fentanyl intranasal spray ranged from 337 to 352 pg/mL and the Tmax was 20 minutes.24 The bioavailability of the pectin-based intranasal spray is 89%,25 about 20% greater than TIRF buccal tablets.


The optimal dosing regimen for treating BTP has yet to be established. BTP, regardless of whether the patient has cancer or noncancer pain, is often treated by adding a rescue analgesic at a percentage of the total opioid dose, typically around 10% to 20%—with the rescue drug available every couple of hours, as needed.26 Immediate-release formulations of oral oxycodone or hydrocodone are commonly used, but have a longer onset of action than the TIRF products. This benefit of TIRF is particularly important when dealing with episodes of BTP that last only 30 or 40 minutes. End-of-dose BTP is treated with an increased dose of the opioid analgesic.

Transmucosal fentanyl products represent an important new option; all TIRF products are labeled to start with the lowest available dose initially, and then titrated as needed. It should be noted that a dose found to be effective with one formulation may not be effective when administered by another route. There is no μg to μg equivalence when changing from one TIRF formulation to another; when changing products, one must start anew with the lowest dose. Different TIRF products require individualized regimens based on patient response.27

Efficacy/Benefits of TIRF

Overall, transmucosal fentanyl products can have an onset of action as rapid as 5 to 10 minutes, and have equivalent analgesia to parenteral opioids for 30 minutes, but not beyond.1,27 The onset of action of OTFC was significantly more rapid than morphine, oxycodone, hydromorphone, and methadone (P<0.001).28 There are several placebo-controlled trials of various TIRF products that illustrate efficacy over placebo, but few head-to-head comparative studies. To follow is a review of some of the published studies.

Oral Transmucosal Fentanyl Citrate

The clinical efficacy of OTFC was established in a double-blind multicenter clinical trial of opioid-tolerant cancer patients.29 The researchers found that patients treated with OTFC experienced significantly greater pain relief from 15 minutes to 1 hour compared to placebo (P<0.0001).29 In another study, the fentanyl lozenge significantly decreased pain intensity at 15 minutes compared to intravenous morphine (41.4% vs 51.7%, P=0.026), but the difference lost significance at 30 minutes (65.9% vs 73.8%, P=0.136).30 Compared to oral immediate-release morphine, the fentanyl lozenge provided significantly greater reductions in pain intensity difference (PID) at all time points.31

Effervescent Buccal Tablets
The effervescent buccal tablet has been shown to be more effective than placebo in reducing pain from 10 minutes to 60 minutes.32,33 When compared with immediate-release oxycodone, effervescent buccal tablets provided significantly greater PID values at 5 minutes (P=0.0081) and 60 minutes (P<0.001).34 In this study, the buccal tablets were preferred by 52% of patients, whereas oxycodone was preferred by 33%.

In an open-label, long-term, multicenter study of the safety and tolerability of effervescent buccal fentanyl tablets, pain scores remained stable over 18 months and functional scores improved in opioid-tolerant patients with BTP.35 A cross-over study of 323 patients with BTP randomized for treatment with immediate-release oral oxycodone or fentanyl buccal tablets found that the fentanyl product was associated with significantly greater PIDs; fentanyl buccal tablets were preferred by 52% of patients over the oral oxycodone in this study.36

Buccal Soluble Film
Fentanyl buccal film was found to reduce significantly PID over 30 minutes compared to placebo.37 In this study, patient satisfaction with the film was reported to be excellent in 67.1% and very good in 47.1%. No comparative studies of fentanyl buccal film to other fast-acting opioid analgesics are known to the authors.

Sublingual Fentanyl
Following a dose-titration phase, sublingual fentanyl tablets provided a greater PID than placebo (49.5 vs 36.6, P=0.0004), which was maintained for 1 hour after dosing. PID improved over placebo after 10 minutes and remained significant for 1 hour.38 The authors are not aware of any comparative studies of sublingual fentanyl versus other rapid-onset opioid analgesics.

In a randomized, double-blind, placebo-controlled study of fentanyl sublingual spray (n=130), the spray was associated with an improved summed PID score from 5 to 60 minutes after administration (P<0.0001) and offered greater pain relief from 5 to 60 minutes than placebo (P<0.0001).39

In a study of 11 hospice inpatients administered sublingual fentanyl for BTP, patients were asked to rate their pain, using a visual analogue scale, before treatment, then after 3, 5, 10, 15, 30, 45, and 60 minutes. Six patients (55%) had reductions in pain scores at 10 minutes, and 9 patients (82%) at 15 minutes.40 In addition, 46% of patients rated the sublingual tablet better than their usual BTP medications; 18% rated it "very good" and 36% "good." In this study, 2 patients reported that the product tasted bitter, but did not wish to discontinue its use.

Intranasal Spray With Pectin
The intranasal fentanyl spray with pectin provided significant pain relief within 10 minutes versus placebo.41,42 In a double-blind crossover study, the intranasal spray offered more patients clinically significant pain relief (defined as at least 2 points in reduction on an 11-point visual analog scale) than immediate-release oral morphine (P<0.05).43

In a study of 12 hospice inpatients with cancer-related BTP, intranasal fentanyl was reported to produce reduction in pain scores in 8 patients (66%)—4 within 5 minutes and 7 within 10 minutes.44 Forty-two percent of patients evaluated the spray as "very good" and 25% rated it as "good."

It should be noted that some patients may not achieve adequate pain relief with fentanyl, even when it is appropriately titrated. While this represents a small subset of patients, such nonresponders should be rotated to other rapid-onset opioids.24 Fentanyl response/nonresponse is not well understood and clear risk factors for nonresponse have not been elucidated.

Precautions/Adverse Events

Fentanyl is a powerful opioid analgesic and shares with other opioids the risk of certain side effects including, but not limited to, respiratory depression, somnolence, nausea, vomiting, constipation, dizziness, headache, pruritus, and lethargy. Dosing must be carefully controlled and products limited; since self-administration of these products is possible outside of a clinical setting, thorough patient and caregiver education is necessary. The proper formulation should be selected to meet the individual patient's need and preferences.

Risk Evaluation and Mitigation Strategies (REMS)

Fentanyl is a schedule II controlled substance. To mitigate its potential for abuse, rapid-onset fentanyl has been the subject of REMS efforts. This includes close clinical supervision of the patient's drug therapy, identifying patients at high risk for opioid misuse and abuse, and educating patients on the proper use of the drug and its associated risks. In December 2011, the FDA allowed a single, shared REMS for TIRF dosage forms.45

Prescribing Considerations

The use of TIRF products to treat noncancer BTP is off label, but the control of BTP is essentially the same in cancer and noncancer patients. The most important consideration in control of BTP is rapid onset of action. Effective BTP control requires patient education and ongoing communication between patient and clinician so the BTP can be characterized, anticipated if possible, and properly treated.

The choice of TIRF product is based on many factors, including patient and clinician preferences. The TIRF lozenge is preferred by many patients but contains sugar and is not suitable for diabetic patients; it has been associated with dental caries. Further, the lozenge requires that the patient hold the lollipop in the mouth against the cheek; patients unable to follow these instructions should not take the lozenge. It takes about 10 or 15 minutes to consume the lozenge.

The buccal and sublingual tablets can be taken by more passive patients, but should be administered to patients who can follow instructions about their use. Patients with dry mouth or mucositis may have difficulty with these products; the use of other formulations should be considered.

For patients with dysphagia, dry mouth, or the inability to follow instructions for taking the sublingual, buccal, or lozenge formulations, the sublingual and intranasal spray products require no particular activity on the part of the patient, have a rapid onset of action, and appear to meet with patient acceptance. These spray products may be the appropriate choice for patients with dysphagia. Intranasal fentanyl should not be used in patients with a particular nasal pathology.


The pharmacokinetics of transmucosal fentanyl make it particularly suitable for treating BTP in opioid-tolerant patients. A variety of innovative formulations are available aimed at allowing for rapid and convenient dosing in this population.


Last updated on: May 19, 2015
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