Blackwell Science, LtdOxford, UKPMEPain Medicine1526-2375American Academy of Pain MedicineJuly 200564305314Original ArticleOral Transmucosal Fentanyl CitrateAronoff et al.
PA I N M E D I C I N E Volume 6 • Number 4 • 2005 RESEARCH ARTICLE
Evidence-Based Oral Transmucosal Fentanyl Citrate (OTFC®) Dosing Guidelines Gerald M. Aronoff, MD,* Michael J. Brennan, MD,† Douglas D. Pritchard, MD,‡ and Brian Ginsberg, MD§ *Carolina Pain Associates, Presbyterian Orthopedic Hospital, Charlotte, North Carolina; †Pain Center of Fairfield, Fairfield, Connecticut; ‡Statesville Pain Associates, Statesville, North Carolina; §Duke University Medical Center, Durham, North Carolina, USA
ABSTRACT Abstract
Objective. To review the evidence for dosing and efficacy of oral transmucosal fentanyl citrate in the management of pain and produce dosing guidelines. Design. The scientific literature pertaining to oral transmucosal fentanyl citrate was reviewed, focusing upon its pharmacology and clinical experience with use in cancer and noncancer pain. Emphasis was upon published, peer-reviewed English language articles. Results. Information was crucially examined and synthesized into guidelines for use and dosing of oral transmucosal fentanyl citrate in cancer and noncancer pain. Conclusions. Oral transmucosal fentanyl citrate is a potent opioid delivery system, which, when used appropriately, is an effective treatment option for pain. Adherence to guidelines should promote its safe and efficacious use in a variety of clinical pain management settings.
Key Words. Opioid; Fentanyl; Oral Transmucosal; Dosing; Guidelines
The Clinical Problem The greatest evil is physical pain. St. Augustine (354–430)
M
any clinical situations require knowledge of pain management. In certain circumstances, such as limb fractures, pain may be acute and generally resolves over the course of treatment. In other circumstances, such as pain associated with cancer, it may be unrelenting. Sometimes changes occur in the nervous system leading to peripheral and/or central sensitization. Such patients experience chronic pain long after the initial insult has healed. Pain may be nociceptive, neuropathic, mixed, or at times, the pathophysiology may be uncertain. Regardless of the etiology, physicians have a duty to help those in pain. To adequately fulfill this obligation, they Reprint requests to: Gerald M. Aronoff, MD, Metroview Building, 1900 Randolph Road; Suite 606, Charlotte, NC 28207, USA. Tel: 704-347-3447; Fax: 704-347-3440; E-mail:
[email protected].
must not only ascertain and treat the underlying cause of the pain, but concurrently use effective strategies to rapidly relieve suffering. Opioids are an established class of analgesic agents with well-known therapeutic effects; however, there are certain complexities associated with their use that may affect the decision to treat pain and dosing strategies. Physicians are concerned with adverse side-effects, the most serious of which is respiratory depression. Other issues of concern, although uncommon, which are monitored during treatment, include opioid abuse, addiction, and diversion. Opioids can be administered in a number of different ways. Parenteral administration includes intravenous, intramuscular, and intrathecal routes. Transdermal delivery systems are also available. However, the oral route is generally the preferred route because of ease of administration. Recently, an oral transmucosal delivery system, oral transmucosal fentanyl citrate (OTFC®; Actiq®) has emerged as highly effective for rapid onset of analgesia. Advantages of this route relate
© American Academy of Pain Medicine 1526-2375/05/$15.00/305 305–314
306 to the physiology of the oral mucosa and pharmacology of fentanyl, both of which will be discussed below. The pharmacodynamics of OTFC are comparable to intravenous administration of hydrophilic opioids such as morphine [1,2], but because intravenous access is not necessary, OTFC has the advantages of convenience in terms of portability and ease of use that are similar to pills and liquids. Oral transmucosal fentanyl citrate is available as Actiq in six dosage strengths (200, 400, 600, 800, 1,200, and 1,600 mg) to allow individualized dosing. The OTFC delivery system was first approved as Fentanyl Oralet®, which was available in four dosage strengths (100, 200, 300, and 400 mg). Fentanyl Oralet was indicated for premedication before surgery and as sedation/analgesia prior to procedures in monitored care settings in patients who were typically not opioid tolerant. Fentanyl Oralet and Actiq were bioequivalent at the two dosage strengths they had in common, namely, 200 mg and 400 mg. Fentanyl Oralet is no longer marketed. Oral transmucosal fentanyl citrate has a proven benefit in treating cancer-associated breakthrough pain in opioid-tolerant patients with cancer, which is the Food and Drug Administration (FDA)approved indication for Actiq [3]. Pain medicine physicians have also used OTFC successfully to provide rapid pain relief in moderate to severe noncancer pain in both opioid-tolerant and opioid-nontolerant patients. Dosing strategies are a key aspect of optimal opioid therapy in general. The purpose of this manuscript is to review the existing evidence supporting the efficacy of OTFC, as well as its dosing guidelines. We present dosing guidelines for the use of OTFC in both opioid-tolerant patients already taking longer acting opioids for persistent pain and patients with acute pain who are not opioid tolerant. Evidence for Efficacy of Transmucosal Fentanyl
Oral Transmucosal Fentanyl Citrate Oral transmucosal fentanyl citrate (OTFC®; Actiq®) is a noninvasive fentanyl dosage form currently marketed in the United States and Europe for the management of breakthrough pain in opioid-tolerant patients. Each OTFC unit consists of a fentanyl-containing lozenge attached to a handle. As the lozenge dissolves during OTFC administration, approximately 25% of the total fentanyl dose is rapidly absorbed across the oral mucosa and becomes systemically available. The
Aronoff et al. remaining 75% of the total dose is swallowed, and approximately one-third of that amount (25% of the total dose) escapes hepatic and intestinal firstpass metabolism and is absorbed more slowly in the intestine. The rapid oral transmucosal absorption of fentanyl combined with fast diffusion across the blood–brain barrier contributes to its swift onset of effect.
Pharmacology of OTFC Fentanyl is strongly lipophilic with an noctanol : water partition coefficient at pH 7.4 of 816 : 1 [3]. By comparison, the n-octanol water partition coefficient for morphine is 1.4 and for oxycodone is 0.7. In OTFC, fentanyl is conjugated with citric acid to enhance water solubility. These low octanol/water partition coefficients for morphine and oxycodone help explain why these drugs are not well absorbed across the oral mucosa and why they take longer than fentanyl to move across the blood–brain barrier to enter the central nervous system (CNS). The oral mucosal route of delivery offers several advantages. The oral mucosa is highly permeable—20 times more permeable than the skin— and is highly vascularized. Lipophilic, unionized compounds (e.g., fentanyl) pass through the cellular membranes easily, traveling rapidly through the mucosa into the blood stream. The oral cavity has a relatively uniform temperature and a large surface area, further optimizing this delivery route [4]. Not all drugs are suitable for oral transmucosal administration [5]. Overall, lipophilic drugs are better absorbed than hydrophilic drugs. In a study of normal volunteers using sublingual absorption, morphine was only 18% bioavailable, whereas fentanyl was 51% bioavailable [6]. The limited efficacy of sublingual morphine has recently been reviewed [7]. Morphine is poorly absorbed across the oral mucosa due to its low lipid solubility and extensive ionization at the pH of the mouth. In addition to easily crossing mucosal membranes, opioid medications must cross the blood– brain barrier to reach the opioid receptors in the CNS to provide pain relief. The rate constant for the equilibrium of fentanyl between blood and the CNS is six minutes [8], whereas the same rate constant for morphine is approximately 17 minutes [9]. Pharmacokinetics of OTFC The single-dose pharmacokinetics of 15 mg/kg OTFC were examined in a study in 12 male volun-
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Oral Transmucosal Fentanyl Citrate teers [10]. On separate days the volunteers received the same dose of fentanyl intravenously, as OTFC, or as an oral solution of dissolved OTFC. Mean plasma fentanyl concentrations following the three routes of administration are presented in Figure 1. The peak plasma concentration (Cmax) was greater (2.68 ± 0.34 vs 1.58 ± 0.22 ng/mL) and occurred sooner after OTFC administration compared with the oral solution (median Tmax, 22 vs 90 minutes). Absolute bioavailability of OTFC was 50% compared with intravenous (IV) fentanyl. Bioavailability of the oral solution of dissolved OTFC was 32% compared with IV fentanyl. Serum fentanyl levels achieved with OTFC are proportional to the dose administered [11], and the administration of multiple doses at fixed intervals does not alter absorption pharmacokinetics [12]. A study comparing the bioavailability of two simultaneously consumed 400 mg OTFC doses with one dose of 800 mg OTFC demonstrated that the two treatments were bioequivalent [13]. OTFC was generally well tolerated, and adverse events were comparable between treatments. The adverse events were typical of those observed following opioid administration in opioid-naive healthy subjects. These results suggest that opioid-tolerant patients could consume two units of OTFC simultaneously during titration to explore response to a single OTFC unit of the summed dosage, although this approach should be restricted to the two lowest OTFC doses during titration. For example, patients starting titration at 200 mg who do not experience adequate analgesia or intolerable side-effects could administer two
Plasma fentanyl (ng/mL) ± SEM
35 30
IV fentanyl 15 mg/kg
25 20 15 3
OT fentanyl 15 mg/kg
2.5 2 1.5 1
Oral fentanyl 15 mg/kg
0.5 0 0
20
40
60
80
100
120
140
Time (minutes)
Figure 1 Pharmacokinetics of oral transmucosal, IV, and oral fentanyl administration. Plasma fentanyl levels are shown after volunteers received 15 mg/kg of IV fentanyl, oral transmucosal (OT) fentanyl, and oral fentanyl (OTFC dissolved in water and swallowed) on three separate days. Adapted from Streisand et al. [10] and clinical trial data [3].
units of 200 mg simultaneously to test the response to a 400 mg dose. Similarly, two units of 400 mg could be administered simultaneously to test the response to 800 mg. In a multidose study in chronic cancer pain patients, there was no unexpected accumulation of fentanyl [14]. These patients were titrated to an OTFC dose and dosing interval to control their persistent, around-the-clock pain. The effective dosing intervals ranged from four to six hours, and the mean total daily dose of fentanyl was 3,078 mg. The steady-state serum fentanyl levels remained relatively constant, and the peak levels were those predicted from the single-dose pharmacokinetics. This study also demonstrated expected tolerance to adverse side-effects in patients chronically exposed to opioids. None of the 18 patients withdrew from the study or experienced unusual or severe adverse events despite serum fentanyl levels as high as 6–8 ng/mL. Patients typically use OTFC on an as needed basis to manage flares of breakthrough pain and not on a regularly scheduled, around-the-clock basis, as they did in this study. There are, however, implications for breakthrough pain management. Patients using OTFC as frequently as every four to six hours to manage their breakthrough pain have the potential to achieve serum fentanyl levels that contribute to managing their persistent pain.
Relative Potency of OTFC Compared with IV Morphine Understanding relative potency is an important issue when considering how to safely choose a starting dose of OTFC. Comparisons of the relative potency of OTFC and IV morphine have been made in a postoperative pain model that assessed analgesic effects averaged over several hours and in a respiratory depression model in volunteers that assessed more acute opioid effects. Respiratory depression was assessed because it is the key safety issue defining the therapeutic window for opioids. Although relative potency estimates based on the administration of single doses of opioids may have limited utility in predicting equianalgesic opioid doses for multidose, chronic applications [15], the data from these two controlled studies are relevant when assessing the relative safety of various starting doses of OTFC. Relative Potency in a Postoperative Pain Model The relative potency ratio of OTFC to IV morphine was initially evaluated in a randomized, double-blind study in patients recovering from lower abdominal surgery [1]. Patients were
308 assigned to one of four treatment groups, low- or high-dose IV morphine (2 mg or 10 mg) or lowor high-dose OTFC (200 mg or 800 mg). The design was parallel; every patient received one of the four active treatments and a placebo of the other delivery modality (e.g., patients receiving active OTFC also received a saline infusion) on the first day following surgery. One hundred and thirty-three patients (65 test treatment, 68 reference treatment) enrolled in the study. Both 800 mg OTFC and 10 mg IV morphine produced similar durations of analgesia; the mean time until additional analgesia was requested was approximately 3.5 hours (220 minutes vs 210 minutes, respectively). The duration of analgesia for the 800 mg OTFC and 10 mg IV morphine were significantly longer (P < 0.04) than the duration of analgesia for the 200 mg OTFC and 2 mg IV morphine (159 minutes vs 153 minutes, respectively). Based on calculation of pain intensity, pain relief, and duration of analgesia, a relative potency ratios of 8–14 : 1 were determined. Mean time to onset of meaningful pain relief was similar in all patient groups—about five minutes—and was less than 10 minutes in approximately 80% of all patients.
Relative Potency in a Respiratory Depression Model The relative potency of OTFC to IV morphine was also assessed in a study that measured the time course and magnitude of acute opioid respiratory depressant effects along with other central opioid effects, including sedation and miosis [2]. In a randomized, double-blind, double-dummy manner, 38 healthy adult subjects received 400, 800, or 1,600 mg OTFC or 4, 8, or 16 mg IV morphine (N = 6 per dose group). A CO2 rebreathing challenge using a modified Read rebreathing circuit was used to evaluate the respiratory effects. Minute ventilation was plotted against end-tidal CO2 and the slope of the resulting curve was analyzed. Safety assessments included a Respiratory Intervention Scale (RIS) with interventions based on continuous pulse oximetry values and vital signs. In this study, a statistically significant doserelated depression of the slope of the ventilatory response to CO2 rebreathing challenge was observed for both OTFC and IV morphine. The mean (95% confidence intervals) OTFC : IV morphine relative potency ratio was 22 : 1 (11–45 : 1) for minimum ventilatory slope and 15 : 1 (6– 36 : 1) for average ventilatory slope (zero to eight hours). The OTFC : IV morphine relative potency ratios for miosis and sedation ranged from
Aronoff et al. Table 1 Relative potency of common OTFC starting doses compared with other opioids* Opioid (Route of Administration)
Dose
Dose
OTFC Morphine (IV) Morphine (oral) Oxycodone (oral) Hydromorphone (oral) Hydrocodone (oral)
200 mg 2–4 mg 6–12 mg 4–8 mg 1.5–3 mg 6–12 mg
400 mg 4–8 mg 12–24 mg 8–16 mg 3–6 mg 12–24 mg
* The relative potency of OTFC to IV morphine is based on the results of Lichtor et al. [1] and Lu and Bailey [2]. The oral data have been inferred from the IV morphine data assuming a 1 : 3 dose conversion of IV : oral morphine. Dose conversion to other oral opioids based on recommendations from the American Pain Society [27].
11 to 23 : 1 and from 10 to 15 : 1, respectively, depending on the variable assessed (minimum, maximum change from baseline, and mean over zero to eight hours). Adverse events that occurred were typical of opioids administered to healthy volunteers (i.e., nausea, vomiting, and pruritus). Median RIS score at each assessment was 0 for all treatment groups, meaning that no interventions were required for low oxygen saturations or decreased respiratory rates. No subject had vital signs that constituted an adverse event. Considering the data from both of these studies, it is reasonable to consider a range of 10–20 : 1 for the relative potency of OTFC to IV morphine. Estimates of the relative potency of the two lower doses of OTFC, which are typical starting doses, compared with commonly used oral opioids are listed in Table 1. Relative potency should not be used to convert from another opioid to OTFC, but rather as a guide for choosing a starting dose. In the interests of being cautious, especially when considering dosing in opioid-naive patients, it is recommended to use the higher end of the relative potency range when making comparisons with IV morphine to avoid overdosing (e.g., 200 mg of OTFC being equivalent to 4 mg of IV morphine).
Efficacy of OTFC Use of OTFC in Breakthrough Cancer Pain: Controlled Clinical Trials Oral transmucosal fentanyl citrate has been studied for the management of breakthrough pain in chronic cancer pain patients. Breakthrough pain was defined in these trials as a transient flare in pain, rising to moderate to severe intensity, occurring in conjunction with a persistent pain that is controlled and of no more than mild or moderate intensity. Two randomized, double-blind, dose titration studies of OTFC were designed to find the opti-
Oral Transmucosal Fentanyl Citrate mal dose for patients treated concomitantly with either transdermal fentanyl [16] or oral morphine [17,18]. These dose titration studies with OTFC were the first to assess breakthrough pain dosing in controlled clinical trials. Of note, in both studies the successful dose of OTFC was not correlated with the dosage of around-the-clock opioid that patients also used for their persistent pain. This was an important finding because the previous dosing recommendation had stated that the breakthrough medication dose should be a fixed percentage (i.e., 10–20% or 1/6) of the aroundthe-clock opioid dose. The recommended dosing for OTFC in breakthrough pain is to start at a low dose (200 mg is the FDA-approved starting dose) and titrate upward until efficacy is achieved or intolerable side-effects are experienced. This recommendation from the controlled titration studies was shown to be effective in a double-blind, placebo-controlled, crossover study [3]. OTFC produced significantly lower pain intensity difference scores (P < 0.0001) than placebo at every postadministration time point in the study (15, 30, 45, and 60 minutes following the beginning of administration) [18]. Pain relief scores were also significantly better following OTFC compared with placebo at every time point measured (P < 0.0001). Patients were treated for significantly fewer episodes of breakthrough pain with additional rescue medication when they used OTFC than when they used placebo (15% vs 34%, respectively, P < 0.0001). In this study involving an open-label titration with all patients starting titration at 200 mg, the time to titrate OTFC was reported with a median of five days, a mode of three days, and a range of 1– 22 days [19]. The efficacy of OTFC was also assessed in a multicenter, double-blind, double-dummy, multiple crossover study that compared OTFC in doses of 200–1,600 mg with morphine sulfate immediate release (MSIR) in doses of 15–60 mg for treatment of breakthrough pain [19]. OTFC produced significantly better pain relief than MSIR at each time point evaluated in the double-blind phase of the study, including 15 minutes (the first time point assessed). The faster onset of pain relief with OTFC than MSIR was associated with greater patient satisfaction, as indicated by significantly higher mean global medication performance ratings for OTFC than MSIR. Additionally, 94% of patients chose to continue using OTFC, compared with 6% for MSIR, during an open-label extension trial.
309 Overall, clinical studies of OTFC in doses ranging from 200 mg to 1,600 mg have shown that OTFC is an effective analgesic for breakthrough pain in patients already receiving maintenance opioid therapy for chronic pain. The successful OTFC dose is determined by titration and is not predicted by the dose of the longer acting opioid used to manage the persistent pain. Patient satisfaction is high, efficacy does not appear to decrease over time, and most patients (61%) did not require dose escalation during treatment in a long-term safety study [20]. The unique pharmacodynamic properties of OTFC combined with its noninvasive delivery form offer advantages over current medications available for the treatment of breakthrough pain.
Patient OTFC Tolerability Oral transmucosal fentanyl citrate as Actiq was studied in outpatients with cancer, who were not monitored. Respiratory depression risk was considerably decreased because patients were taking sustained-release morphine or transdermal fentanyl, and thus, were opioid tolerant. The adverse events associated with OTFC in studies of patients with chronic cancer pain were typical opioid side-effects. Some of the adverse events may have been attributable to patients’ underlying disease or to other analgesics or medications patients were using at the time of the study. The most common adverse events observed during the clinical trials of OTFC, reported by at least 10% of patients, included nausea, somnolence, and dizziness [3]. Other common adverse events include asthenia, constipation, and confusion (3–10% of patients). Headache, abdominal pain, dyspepsia, mouth ulceration, dry mouth, vasodilatation, hallucinations, vertigo, dyspnea, pruritus, and sweating were reported by 1–3% of patients in the clinical trials. Additional clinical experience has shown that side-effects of OTFC will frequently cease or decrease in severity with continued use of OTFC. The most serious adverse effects associated with all opioids are respiratory depression, circulatory depression, hypotension, and shock [21,22]. Patients who are regularly receiving opioid analgesic drugs are typically less susceptible to these serious adverse effects than opioid-naive patients. In particular, caution should be used when titrating OTFC in patients with medical conditions that predispose them to respiratory depression. Developing OTFC dosing guidelines for patients who have not been exposed to opioids is
310 Table 2
Aronoff et al. Number of subjects with respiratory events after four increasing doses of OTFC [11] Dose of OTFC
Respiratory rate
