Transbuccal fentanyl for rapid relief of orthopedic pain in the ED

Original Contribution

transbuccal fentanyl for rapid relief of orthopedic pain in the ED?,??

Melissa L. Shear a, Jonathan N. Adler MDa, Sanjay Shewakramani MDa, Jon Ilgen MDa, Olanrewaju A. Soremekun MDa, Sara Nelson MD a, Stephen H. Thomas MDb,?

aMassachusetts General Hospital Emergency Services and Harvard Medical School, Boston, MA 02114, USA

bDepartment of Emergency Medicine, OU Schusterman Center, University of Oklahoma School of Community Medicine, Tulsa,

OK 74135, USA

Received 9 February 2009; revised 11 April 2009; accepted 14 April 2009


Objectives: This study’s objectives were to assess administration of a rapidly dissolving transbuccal fentanyl tablet to patients in emergency department (ED) with orthopedic extremity pain. The main end point was time required to achieve a 2-point drop on a 0 to 10 pain scale.

Methods: In this double-blind trial, subjects received either transbuccal fentanyl, 100 ug, and a swallowed placebo, or a swallowed oxycodone/acetaminophen, 5/325-mg pill, and a nonanalgesic transbuccal comparator. pain assessment occurred every 5 minutes for an hour, and vital signs were monitored for 2 hours.

Results: Transbuccal fentanyl was associated with faster pain relief onset (median, 10 vs 35 minutes; P b .0001). Secondary end points (pain relief magnitude, Rescue medication rate, subject preference for medication on future visit) favored transbuccal fentanyl. No Vital sign abnormalities or significant side effects occurred in the ED or on 100% next-day follow-up.

Conclusions: Transbuccal fentanyl shows promise for continued investigation as a means to safely provide rapid and effective pain relief for ED patients.

(C) 2010


Analgesia practices in emergency departments (EDs)– both in the United States and abroad–are often characte- rized by pain relief that is delayed or otherwise suboptimal [1-4]. Increased scrutiny of pain care practices has helped, but improvement in analgesia care remains an important

? Unrestricted grant from the Harvard Medical School Division of Emergency Medicine.

?? Trial registration:, NCT00685295.

* Corresponding author. Tel.: +1 918 660 3822; fax: +1 918 660 3821.

E-mail address: [email protected] (S.H. Thomas).

goal. An illustrative study reports that, for patients in severe pain, the average interval between ED presentation and administration of the first pain medication was 72 minutes; the corresponding interval for patients in moderate pain was nearly 4 hours [5]. Other data indicate that there are notable problems with administration delays and suboptimal pain reduction for patients with “minor” sprains and fractures [2,6,7].

Patients with sprains and fractures constitute an important group, for potential for having pain and delayed treatment. mechanical interventions such as splinting comprise an integral part of improving comfort in this patient population, but Pharmacologic therapy remains important.

0735-6757/$ – see front matter (C) 2010 doi:10.1016/j.ajem.2009.04.011

There are a variety of available Drug therapies for ED patients with minor extremity orthopedic trauma, but each is associated with disadvantages. Nonsteroidal antiinflamma- tory drugs have well-characterized risks, and there are additional concerns (eg, bleeding, nonunion) in patients with suspected fractures [8,9]. Other nonopioid approaches, ranging from acupressure to inhaled nitrous oxide, have been tested for but are either nonefficacious or logistically nonfeasible for use in many EDs [10-12]. It is thus clear that, for some patients, opioid therapy will be indicated.

Table 1 Subjects’ demographic characteristics (n = 60)

Oral opioids represent a widely accepted ED approach for patients with suspected fractures. Among studies addressing oral opioids for ED orthopedic injuries is one that demonstrates efficacy of oxycodone (5 mg) + acetaminophen (APAP) (325 mg) [13]. This medication works well, but there remains a potential role for an alternative approach that can provide potent, rapid-onset pain relief without requiring an injection.

Intravenous fentanyl is rapidly acting and has well- described use in acute care [14]. A novel fentanyl formulation in a transbuccal tablet has been demonstrated to have rapid systemic absorption [15]. The investigators’ goal was to assess whether the fentanyl buccal tablet was associated with more rapid onset of pain relief than that achieved with the primary nonintravenous analgesic approach (Oral oxycodone/APAP) used in our ED.



The study was conducted in the ED at the Massachusetts General Hospital (Boston, Mass), where institutional review board approval was obtained. Because of the novel use of the fentanyl buccal tablet in the acute care setting, in patients who were not opioid naive, the investigators obtained an Investigational New Drug approval from the US Food and Drug Administration (Investigational New Drug no. 77096).


The study population comprised a convenience sample (enrolled during a 6-month period commencing August 2008) of adult patients 18 to 60 years who presented to the ED with a chief complaint of extremity injury and who were judged to need extremity radiography to rule out fracture (Table 1). To participate in the study, patients had to indicate that their pain was of sufficient severity to receive pain medication stronger than acetaminophen or ibuprofen. Patients were ineligible if they were judged by treating providers to require intravenous analgesia or if there were concerns that study participation would interfere with the provision of required care.


Fentanyl group

Oxycodone group






Median, 40

Median, 34


(IQR, 29-49)

(IQR, 27-45)

Male (%)




Baseline pain

Median, 9

Median, 8


(IQR, 8-10)

(IQR, 8-10)



African American












Fracture or dislocation





IQR indicates interquartile range.

Other exclusion criteria were allergy to any of the drugs being administered as part of the study or concurrent therapy with medications (phenothiazines, monoamine oxidase inhibitors, Selective serotonin reuptake inhibitors) or inge- stants that could interact with opioids. Patients were excluded if they had already receivED analgesia (including before ED arrival). Other exclusions were pregnancy (Negative urine pregnancy test required), current breastfeed- ing, or history of Opioid abuse.


Study subjects each received a pair of study medications

–an active analgesic and a nonanalgesic comparator. In double-blind fashion, subjects received either transbuccal fentanyl, 100 ug (Fentora, Cephalon, Frazer, Pa), and oral/ swallowed placebo, or transbuccal nonanalgesic “placebo” (see later) and oral/swallowed oxycodone/APAP (5/325 mg). Because of inability to obtain the nonopioid vehicle “base” for the fentanyl transbuccal tablet, the investigators used an active but nonanalgesic comparator to serve as the transbuccal “placebo” tablet. The comparator used was lansoprazole, 15 mg (Prevacid SoluTab, Wyeth, Madison, NJ), which is available in a transbuccal formulation physically similar to that of the fentanyl buccal tablet. Blinding was maintained by having each pair of study medications sealed by the hospital’s research pharmacy; medications were opened and administered by a physician not involved with assessing end points (and investigators confirmed that no study patients had ever seen either

transbuccal fentanyl or lansoprazole).

After study medication administration, study staff mon- itored patients’ pain levels every 5 minutes for an hour. A 0 to 10 Numeric rating scale was used for all pain assessments. Hemodynamics and side effects were monitored for an additional hour. Vital signs including pulse oximetry were

assessed every 5 minutes for the first hour and every 15 minutes for the second hour. Study staff accompanied patients outside the ED (ie, to radiology) to assure on- schedule assessments.

Study patients could receive Rescue analgesia, based upon patient request and treating Clinician judgment, at any point during the study period. Timing and nature of rescue analgesia were recorded by study staff.

At the 60-minute time point, subjects will be asked if they would want the same level of pain relief they attained from the initial study medication, in case of future similar injury. Subjects indicated their preference on a 1 to 5 Likert scale, with the ratings corresponding to answers to the question “Would you want to receive this study medication for future similar pain?” as follows: 1 (definitely yes), 2 (probably yes), 3 (maybe), 4 (probably no), and 5 (definitely no).

The day after study participation, all study subjects were contacted. Any side effects or problems were noted.


Descriptive analysis was used to assess data such as subjeCT characteristics. For continuous and ordinal data, descriptive techniques included calculation of medians with interquartile range.

The study’s primary end point was the time at which subjects’ pain levels dropped significantly from the initial pain level. Clinically significant pain score reduction was defined a priori as a drop of at least 2 points on the numeric rating scale used in the study. This is slightly greater than the 1.3-unit change generally accepted as defining a clinically significant reduction [16,17].

The primary end point, time to significant analgesia, was analyzed using the Kaplan-Meier product-limit procedure, with pairwise comparisons executed using log-rank testing. This approach, which emphasizes the importance of time to analgesia, rather than depth of analgesia, has been used in other pain studies [18]. The secondary end point of depth of analgesia was analyzed with nonparametric techniques (Kruskal-Wallis testing).

Sample size calculations for the study were based upon the primary end point. Most of the relevant variables were well characterized or accurately estimated based upon clinical experience and available pharmacokinetic data. Power and sample size calculations were based upon the method of Freedman, as outlined in the clinical trials by Piantadosi [19]. It was anticipated that 90% of the subjects in the study would have events (ie, pain scores reduced by at least 2) and that the event occurrence would be roughly twice as fast for fentanyl. To account for potential dropouts, the study aimed to enroll 120 subjects, with a single interim assessment at the halfway point.

Other analyses of categorical end points included ?2 and Fisher exact testing (for instances in which cell counts were 5 or fewer). Statistical significance was set at the 0.05 level for

all tests, and all tests were calculated using STATA/MP version 10.0 (StataCorp, College Station, Tex).


The 60 study subjects’ demographics and results are outlined in the tables. The patients had a relatively high pain scores and high frequency of fracture diagnosis.

Analgesia end points

With respect to the primary end point of time to achieve a pain score reduction of 2 units (on a 0 to 10 scale), the fentanyl subjects had a significant advantage (Fig. 1 and Table 2). The results with respect to the secondary end point of degree of analgesia also favored the fentanyl group (Fig. 2 and Table 2).

Rescue medication

Overall, rescue medication was required in 22 subjects; rescue analgesia was more frequently administered to those in the oxycodone/APAP group (Table 2). The most common rescue Medication administered was oxycodone/APAP (19 cases or 86% of those receiving rescue analgesia). One subject each received 3 other medications as follows: hydromorphone (intravenous), morphine (intravenous), and ibuprofen (oral). The 2 intravenous rescue analgesics were both administered (at 30 and 35 minutes into the 60-minute study period) to patients in the oxycodone/APAP group.

Subject preference to receive same study medication

As compared with oxycodone subjects, those in the fentanyl group were far more likely to be satisfied with the

Fig. 1 Time to significant analgesia.


Table 2 Results


Fentanyl group

Oxycodone group


Minutes to 2-point

Median, 10

Median, 35


pain reduction

(IQR, 5-15)

(IQR, 20-40)

Minutes to maximal

Median, 40

Median, 55


pain reduction

(IQR, 30-50)

(IQR, 40-60)

Maximal pain score

Median, 6

Median, 3



(IQR, 4-7)

(IQR, 2-5)

Achieving significant




pain reduction (%)

Guessing correct study




medication (%)

Receiving rescue




medicines (%)

analgesia provided by the study drug. This was true regardless as to whether preference was measured as a median of the 1 to 5 rating scale (P = .0001) or as a proportion of subjects indicating either 1 or 2 (meaning strong or probable preference to receive similar analgesia in the future; P b .001).

3.4. Unblinding

There was no indication that unblinding played a significant role in this trial (Table 2). For both groups, more than half of subjects were able to correctly guess the active study medication received.

Medication side effects“>3.5. Medication side effects

There was a single instance of vomiting, occurring 40 minutes into the study in a patient in the oxycodone/APAP group. Including the instance of vomiting, there were episodes of nausea in 13% of cases overall. The nausea was described in all cases except for one (in which the vomiting occurred) as “slight.” This slight nausea did occur more frequently (P = .005) in the oxycodone group (27%) as compared to the fentanyl group (0%). Other minor adverse effects, variably described by subjects as being “dizzy” or “woozy,” occurred with approximately equal frequency in oxycodone/APAP and fentanyl subjects (20% vs 13%; P = .71).

The monitoring of vital signs identified no adverse effects in any subject in either group. There were no instances of significant decrement in heart rate, blood pressure, respira- tory rate, or pulse oximetry (in no case did any vital sign change significantly, and in no case did pulse oximetry drop b96%). No hemodynamic or respiratory interventions were required for any patient, and no patients received intravenous fluids or supplemental oxygen as part of their routine care during the study period.

Analgesia remains an important therapeutic goal for the acute care setting. For patients with suspected orthopedic injuries, properly titrated intravenous Opioid analgesia is safe and desirable for its acute care profile [20-23]. Although much of the reported opioid experience with prehospital and ED pain management deals with opioids other than fentanyl, fentanyl offers particular advantages for acute care pain relief [6,7,14,21,24-34]. Fentanyl, like any potent opioid, clearly has attendant risks, but the consistent message from almost 2 decades of literature is that when used appropriately the drug is both safe and effective for relieving pain in a variety of Acute care settings [35].

The barrier of placing intravenous access is not a critical one in the ED, but it is nonetheless the case that clinicians and patients would benefit from an easily administered, rapidly effective mechanism for delivering pain medication. Intranasal and inhaled nebulized fentanyl have been shown to have some promise for postoperative analgesia and for pain relief in children in the ED [36,37]. These routes may be useful, but limitations in comfort and logistics have led to assessment of intraoral delivery systems for fentanyl.

The most commonly used such administration method, the “lollipop” or lozenge, has been used to facilitate pediatric procedures including those performed in the ED [38]. The fentanyl lozenge has been associated with some occasional pruritis and postprocedure nausea [38,39]. The standard oral transmucosal lozenge may in fact be well suited for evaluation in a trial such as this one, but the investigators chose to use the transbuccal tablet for its simplicity of delivery and rapidity of effect. Although the fentanyl buccal tablet’s medication delivery rate will not match that of intravenous fentanyl, it is preferable to the fentanyl lozenge in that it enters the systemic circulation more rapidly and to a significantly greater extent [15].

In fact, the fentanyl buccal tablet’s median Tmax (Time to maximum concentration) of 52.2 minutes translates into a

Fig. 2 Pain scores over time.

time frame commensurate to that of a typical ED evaluation [40]. Because Tmax is unrelated to fentanyl buccal tablet dose [41], both benefits and side effects of the formulation should peak during the first hour after its administration. This allows for time for clinicians to get patients to x-ray, make a definitive diagnosis, and generate a plan for disposition after a single dose of transbuccal fentanyl. The results of this study are consistent with the estimate that the effects of transbuccal fentanyl can last an hour.

The study’s main results, that transbuccal fentanyl appears to be associated with faster onset time than oral oxycodone/APAP, are not surprising. Our oxycodone/APAP finding of median onset time of 35 minutes is right in line with previous data demonstrating an oxycodone/APAP (5/325 mg) median onset time of 30 to 40 minutes [13,18]. Many ED clinicians have a high Comfort level with fentanyl. The agent is commonly used, and reports of its use even in critical care patients confirm relative hemodynamic and respiratory safety [6,31-34]. It is noteworthy that in the prehospital and ED settings, patients receiving fentanyl are virtually always opioid naive (as were all of this study’s patients). Because of this, and as an additional safeguard, this study entailed administration of the lowest available dose of fentanyl transbuccal tablet (100 ug). Although transbuccal fentanyl is generally intended for use in opioid-tolerant chronic pain patients with breakthrough pain [42], the results of the current study suggest a possible role for the agent in

the ED setting.

This study had numerous limitations, which taken together mean that our results should be considered preliminary and as spurs to further research. The most important limitation was that trial size–although sufficient to clearly demonstrate difference in the timing end point– was insufficient to precisely estimate side effect rates. The overall results with respect to medication side effects were encouraging because no serious adverse events occurred in either group. However, it must be emphasized that the cessation of the study based upon clear demonstration of efficacy translates into imprecision with regard to assessment of side effect rates. Overall, the rates (for any side effects) were 13.3% (fentanyl) and 40% (oxycodone/APAP), but the binomial exact 95% confidence intervals (CIs) surrounding these estimates were broad. For fentanyl, the 95% exact CI was 3.8% to 30.7%, and for oxycodone/APAP, the 95% CI was 22.7% to 59.4%. These wide CIs, although correspond- ing to only minor side effects, nonetheless emphasize the importance of conducting further research carefully focusing on safety of buccal fentanyl use in the ED.

The convenience sampling approach used in this study was necessitated by availability of research assistants, but as with any convenience sampling, selection bias is a concern (although there are no obvious sources of such bias). The potential shortcoming of rescue medication is less of a concern in this study because administration of rescue medication occurred primarily in the oxycodone/APAP arm (and because the study found findings in favor of fentanyl).

In any event, the rescue analgesia typically given (oxyco- done) had a sufficiently prolonged onset of action that its effects would not have been expected to have too much impact on overall pain relief results. (The 2 instances in which rapid-acting intravenous analgesia rescue was admi- nistered occurred in oxycodone/APAP patients.)

An additional consideration is the issue of whether the selected dosages of oxycodone and fentanyl were truly equianalgesic. It has been noted that safety considerations prompted selection of a relatively low dose of transbuccal fentanyl. In an attempt to provide an equianalgesic level of oxycodone, the study design called for oxycodone to be administered at a lesser dose (5 mg) than commonly used by acute care clinicians. There is little precise information on equiAnalgesic doses of oral oxycodone and transbuccal fentanyl (especially when used in opioid-naive patients). Furthermore, the data that are available, such as those provided in standard emergency medicine texts, include caveats about the variability of equianalgesia estimates [43]. With that acknowledgment, equianalgesia tables from one standard text [43] suggest that 7.5 mg is the oxycodone equivalent to the study’s 100 ug of transbuccal fentanyl dose. Therefore, one of the study’s limitations is that the dose of oxycodone may have represented less opioid potency than the transbuccal fentanyl dose. This would not be expected to impact the study’s primary end point of time to analgesia, but oxycodone (or fentanyl) in larger doses would be likely to be associated with greater pain relief and lesser need for rescue analgesia.

In conclusion, the results from this pilot study suggest that transbuccal fentanyl at a relatively low dose of 100 ug has rapid onset for orthopedic pain treatment in the ED. Further study is definitely indicated, using different dosages (for increased analgesic effect) and with larger populations (to enable more precise assessment of safety). It is premature to adopt transbuccal fentanyl for routine use in the ED, but this approach does appear promising as a mechanism to quickly alleviate ED patients’ pain.


The authors thank John Vetrano, Alexis Barth, and Nancy Balch from the Massachusetts General Hospital Pharmacy Services.


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