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Analgesic Effect of Sustained-Release Flurbiprofen Administered at the Site of Tissue Injury in the Oral Surgery Model

From the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland (Dr Dionne, Dr Brahim, Ms Rowan); Pharma-Logic, Miami, Florida (Dr Haynes); and SkyePharma Canada, Quebec, Canada (Dr Guivarc'h).

Address for reprints: Raymond A. Dionne, DDS, PhD, NIDCR, NIH, 10 Center Drive, 1N-103, Bethesda, MD 20892-1197.

	ABSTRACT

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Nonsteroidal anti-inflammatory drugs produce their analgesic and adverse effects through interaction with cyclooxygenase in a variety of tissues. The authors evaluated the therapeutic potential of administering a sustained-release formulation of flurbiprofen into a surgical wound following oral surgery to produce analgesia at the site of injury while minimizing exposure to potential targets for toxicity. Subjects (N = 98) received 1 of 8 treatments: flurbiprofen in a microparticle formulation in doses of 3.125 mg, 6.25 mg, 12.5 mg, 25 mg, or 50 mg; PO flurbiprofen 25 mg or 50 mg; or placebo. The flurbiprofen microparticle formulation or matching placebo was placed into the extraction sites at the end of surgery (removal of 2 lower impacted third molars). The sum of the pain visual analog scale over the 6-hour observation period demonstrated significantly less pain (P < .05) for flurbiprofen microparticle in comparison with placebo. Fewer subjects remedicated in the flurbiprofen microparticle drug groups, primarily for the 12.5-mg and higher doses. The incidence of adverse effects and local complications did not differ across groups. These data suggest that direct administration of flurbiprofen in a microparticle formulation at a site of tissue injury delays the onset and lowers the intensity of postoperative pain at lower doses than usually administered orally.

Key Words: Nonsteroidal anti-inflammatory drugs • flurbiprofen • analgesia • postoperative pain

One approach to overcoming these therapeutic limitations is to maximize drug levels at the site of action and minimize systemic exposure by administering the drug directly to the site of tissue injury. Local application of aspirin and acetaminophen at subtherapeutic doses (50 mg) has been demonstrated to produce analgesia in comparison with placebo and systemic administration of the same dose.¹⁰ Aspirin solution applied topically in the oral cavity produces an analgesic effect on experimental and clinical pain, which appears to be mediated locally, not by systemic absorption.¹¹ Topical application of ketorolac tromethamine for ankle sprain results in analgesia and reduced swelling superior to both placebo and oral administration of an NSAID¹² while resulting in plasma drug levels lower than those associated with oral administration of a 10-mg dose of ketorolac. A gel formulation of ketoprofen (10 mg) administered into third molar extraction sites suppressed postoperative pain to a greater extent than oral administration but with lower circulating drug levels and no increase in systemic or local adverse effects.¹³ Topical NSAIDs also have been evaluated for experimental gingivitis in humans,¹⁴ acute soft tissue injuries,¹⁵ and as a route of administration for rheumatoid arthritis.¹⁶

The present study evaluated the administration of an NSAID in a microparticle formulation directly into surgical extraction sites to determine the analgesic efficacy and safety of peripheral administration. The results of this dose-ranging study provide evidence for a peripheral site of action, greater analgesia in comparison with the same doses given orally, and lower plasma drug levels suggestive of less potential for systemic toxicity.

	METHODS

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Subjects for this investigation were oral surgery outpatients undergoing the surgical removal of 2 mandibular impacted third molars with parenteral sedation and local anesthesia. The study design consisted of a single-dose, double-blind, parallel group comparison to evaluate the analgesic efficacy of a sustained-release formulation of flurbiprofen administered directly into the surgical sites in comparison with a placebo control and oral administration of 2 doses of flurbiprofen. Parallel collection of blood samples permitted evaluation of pharmacokinetic properties of the formulation in comparison with oral flurbiprofen administration. Subjects were 16 years of age or older, were free of systemic disease, had no history of psychiatric illness, and had no history of allergy to aspirin or NSAIDs. Additional exclusion criteria included (1) concomitant medication with NSAIDs or antihistamines and (2) pregnant or lactating females. Subjects were informed of possible risks of oral surgery and the investigational treatments, and they signed a consent form approved by the NIDCR Institutional Review Board.

The study compared suppression of postoperative pain with 5 dose strengths of flurbiprofen (3.12, 6.25, 12.5, 25, and 50 mg) in a proprietary microparticle formulation to a placebo formulation when placed submucosally into 2 mandibular extraction sites. Two additional groups were randomized to receive either 25 or 50 mg of flurbiprofen in oral capsules, for a total of 8 treatment groups. The drugs were formulated such that 0.5 mL of the flurbiprofen microparticle formulation or matching placebo was administered into each extraction site impregnated on an approximately 0.5-cm³ piece of Gelfoam absorbable gelatin sterile sponge. The drug-impregnated gelatin sponge was placed into each of the mandibular third molar extraction sites, and a suture was placed and gauze retained over each extraction site for 1 hour to promote hemostasis.

The drug formulation consists of micro- to nano-particles of drug stabilized by surface-modifying agents such as phospholipids with or without other surface modifiers. Such size-reduced, stabilized particles can be incorporated into a variety of dosage forms to facilitate both administration and bioabsorption of the therapeutic agent. In the present manifestation, flurbiprofen particles so prepared were rendered sterile by gamma irradiation and thus suitable for administration. The presence of the phospholipid onto the freshly generated drug surface provides a capsule domain that prevents particle growth by aggregation, flocculation, agglomeration, or Ostwald ripening during production and shelf life storage.

Subjects were randomly allocated to receive any one of the 5 doses of flurbiprofen administered into the 2 mandibular extraction sites, a 25- or 50-mg flurbiprofen oral capsule, or placebo. The microencapsulated drug formulation and matching placebo were supplied as sterile, lyophilized microparticles in vials by the manufacturer (SkyePharma Canada, Inc, Quebec, Canada) and randomly allocated by the NIH Pharmaceutical Development Service (PDS) to consecutive subjects. The drug formulation was reconstituted with sterile water as a flurbiprofen suspension and dispensed in a 3-mL syringe labeled by patient number for absorption onto the gelatin sponge immediately prior to placement into the extraction site.

The oral capsules were prepared by the PDS from bulk drug (Novopharm USA, Inc, Schaumburg, Ill) and packaged in #2 pink opaque gelatin capsules. Matching lactose placebo capsules were allocated such that every subject received an oral dose of either active drug or placebo immediately prior to surgery and had a sponge placed into each of the 2 mandibular extraction sites after surgery (double-dummy design). Placebo patients received inactive treatment via both routes of administration.

Two partial or full bony impacted mandibular molars were extracted using 2% lidocaine with 1:100 000 epinephrine and intravenous sedation with midazolam. At the completion of the procedure, the microencapsulated drug or placebo formulation absorbed onto the gelatin sponge was placed gently into each of the 2 mandibular extraction sites. Primary closure was obtained using 3-0 chromic gut suture and sterile gauze placed bilaterally and held in place with firm biting pressure for 1 hour. Rescue analgesia, provided upon patient request, consisted of 2 tablets of acetaminophen 300 mg plus codeine 30 mg for moderate to severe pain or IV ketorolac for severe pain and agitation. Subjects were remedicated upon request but were encouraged to complete at least 2 postoperative observations (60 minutes total) following the loss of anesthesia to evaluate the investigational treatment's effect on postoperative pain.

Pain was rated at the end of surgery, at 15 minutes after surgery, and at 30-minute intervals starting 30 minutes after surgery for up to 6 hours using a 100-mm visual analog scale (VAS) with anchors of no pain and worst possible pain. Pain was categorized by the subjects at the same time points as none (0), slight (1), moderate (2), or severe (3). Duration of anesthesia was evaluated to ensure that postoperative pain was not influenced by residual mandibular anesthesia. Patients were instructed to tap their lower lip and categorize the sensation as normal (0), tingling (1), or numb (2). Hemostasis was assessed at each observation by the research nurse and categorized as no bleeding (0), slight ooze (1), persistent ooze (2), bleeding controlled with pressure (3), or uncontrolled bleeding (4). The presence of side effects was also evaluated at each observation; the words used by the subjects to describe the effect that they were experiencing were classified into categories such as drowsy, dizzy, headache, nausea, or other adverse effects to permit post hoc comparison across treatments.

Blood samples for the determination of flurbiprofen levels were collected into chilled, heparinized tubes prior to drug administration (0 time) and at 15, 30, 60, 90, 120, 150, 180, 240, 300, and 360 minutes following drug and centrifuged under refrigeration (4°C). The plasma was decanted and frozen in dry ice for storage at -70°C until shipped on dry ice for analysis (PharmaKinetics Laboratory, Inc, Baltimore, Md). Flurbiprofen plasma levels were measured following extraction of the drug and an internal standard (meclofenamate sodium) by protein precipitation. The residue was reconstituted in the mobile phase (acetonitrile and phosphate buffer) prior to analysis by high-pressure liquid chromatography (Hewlett-Packard model 1050) on a C-8 column with fluorescence detection (Waters 474 Scanning Fluorescence Detector). The relationship between concentration and peak height was linear within the range of 0.25 to 10.0 µg/mL, with a limit of quantification of 0.25 µg/mL in 0.2 mL of heparinized plasma. The mean recovery for flurbiprofen was 96.7%.

Patients were released from the clinic 6 hours after surgery and supplied with 24 tablets of acetaminophen 300 mg plus codeine 30 mg and instructed to administer 2 tablets every 4 to 6 hours as needed for pain. Subjects recorded the number of tablets and time ingested on a medication diary. The total number of tablets taken over the first 24 hours and from 24 to 48 hours was used as a measure of any residual effects of the investigational drugs on pain. Patients were contacted by telephone on the seventh postoperative day to evaluate the incidence of complications and subjective symptoms suggestive of alveolar osteitis.

Pain intensity over the entire 6-hour observation period was evaluated by repeated-measures analysis of variance. Post hoc comparison between treatment groups was based on the total pain scores for the entire 6 hours as measured by VAS using a 1-way analysis of variance and Duncan's multiple-range test. The incidence of complications for the different doses and routes of administration was compared by Fischer's exact test for the 8 groups.

	RESULTS

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A total of 107 patients underwent oral surgery as candidates for inclusion in the study. Six patients were not randomized to drug at the end of surgery: 3 had ingested an NSAID within 24 hours prior to surgery, and 3 were rated by the oral surgeon as having excessive surgical difficulty resulting in prolonged duration of surgery. Two patients failed to return for 24- or 48-hour observations, and 1 patient was removed from the study in the immediate postoperative period at the patient's request due to a complaint of abdominal pain. The remaining 98 subjects were included in the analyses for efficacy and safety; plasma samples were analyzed from 80 subjects for levels of flurbiprofen over the 6-hour observation period.

The duration of mandibular anesthesia was similar across groups, with virtually all patients reporting return of normal sensation by 3 to 4 hours from the end of surgery. Treatment groups were also similar for the doses of local anesthetic and midazolam, the difficulty of the surgical procedure, and demographic characteristics (Table I).

Pain onset occurred over the first 2 hours (Figure 1, upper panel), coincident with the loss of mandibular anesthesia, and was attenuated in a dose-dependent manner (P < .05) by administration of the flurbiprofen formulation at the surgical site. The 3 lower doses administered at the surgical site did not separate from the placebo dose; the administration of flurbiprofen at the surgical site demonstrated a leftward shift of the dose-response relationship (Figure 1, lower panel) indicative of greater efficacy for administration at the site of injury. Administration at the surgical site also produced a dose-related increase (P < .01) in the time to request for postoperative rescue medication (Figure 2). Similar results were seen for the category scale (data not shown).

View larger version (18K): [in this window] [in a new window]   Figure 1. Pain intensity determined by a 100-mm visual analog scale (VAS) measured over the first 6 hours postoperatively for placebo and 5 strengths of flurbiprofen in a microparticle (MP) formulation (upper panel); sum of the pain intensity scores for 25- and 50-mg flurbiprofen MP and administered orally (lower panel).

View larger version (11K): [in this window] [in a new window]   Figure 2. Time to rescue medication postoperatively following oral surgery for placebo (0-mg dose) and 5 strengths of flurbiprofen in a microparticle (MP) formulation (upper panel); dose-response suppression of pain over the 6-hour observation period (lower panel).

Plasma flurbiprofen was detectable in 43.8% of the samples collected over the first 6 hours postoperatively; the number of samples at each time point ranged from n = 5 to 10. Peak plasma concentrations were detected between 1 and 3 hours, depending on the dose and route of administration (Figure 3). The AUC increased in a dose-related manner, but comparable doses (25 and 50 mg) of flurbiprofen administered at the surgical site were significantly lower (P < .05) than the same dose administered orally. Drug was detectable in plasma at 24 hours in 4 subjects administered 25 or 50 mg flurbiprofen orally and in 3 subjects receiving 50 mg of the flurbiprofen formulation at the surgical site; all samples collected at 48 hours were below the limit of detection.

View larger version (18K): [in this window] [in a new window]   Figure 3. Plasma levels of flurbiprofen over the first 6 hours postoperatively and at 24 and 48 hours illustrated for 6.25, 12.5, 25, and 50 mg flurbiprofen in a microparticle (MP) formulation or administered orally (PO) in doses of 25 or 50 mg.

The incidence of adverse events did not differ across treatment groups, with the 2 most common symptoms reported, drowsiness and dizziness, most likely attributable to the sedative effects of the midazolam and lidocaine (Table II). Postoperative bleeding, manifesting as an ooze from the extraction site for greater than 60 minutes following surgery, was similar across treatment groups (Table II); flurbiprofen administered into the surgical site (7.9%) having a rate of postoperative bleeding similar to oral flurbiprofen (8.0%), with both being lower than placebo (25%). Complications associated with the surgical procedure itself, such as alveolar osteitis and persistent paresthesia (4/98) to the lingual or mandibular nerve, were also similar between treatment groups.

	DISCUSSION

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Peripheral administration of flurbiprofen was more effective than oral administration of the same dose, suggesting a local site of action. Absorption from the surgical wound and distribution to some other site of action would have resulted in analgesia comparable to the oral formulation. The greater analgesic effect for the peripheral route is presumably due to achieving a higher effective drug concentration at the site of injury without loss due to distribution to other compartments or the onset of elimination. The area under the drug concentration curve over the first 6 hours indicates that a larger portion of the orally administered flurbiprofen was in the circulation than the locally administered drug, suggesting a higher drug concentration at the surgical site for the peripherally administered flurbiprofen.

Peripheral administration of flurbiprofen at the 3.12- and 6.25-mg doses did not differ in analgesic efficacy from placebo, whereas the 12.5- and 50-mg doses administered at the surgical site resulted in significantly less pain over the entire observation period, most notably from 180 to 360 minutes after the residual effects of the local anesthetic dissipated. The 25-mg dose at the surgical site inexplicably did not differ significantly from the lower doses or placebo, possibly reflecting the small sample size for this dose-ranging study and thereby magnifying the effect of individual subjects in the group who did not achieve relief with the locally applied drug.

Flurbiprofen, like other NSAIDs, interferes with the formation of products of the arachidonic acid cascade.¹⁷ The antinociceptive actions of NSAIDs in the formalin test are 100 to 1000 times more potent when administered intrathecally in comparison to intraperitoneal administration,¹⁸ consistent with the demonstration of a central site of action for NSAID analgesia.¹⁹ The results of the present study are supportive of a peripheral site of action but do not contradict a central site of action following systemic absorption and distribution. The approximate 50% reduction in plasma flurbiprofen levels with greater analgesic efficacy for peripheral administration at the 25- and 50-mg doses in comparison to oral administration is consistent with a peripheral site of action, as lower drug levels would result in less penetration to central sites with less analgesic activity if a central site of action were the predominant mechanism in this model.

Microdialysis of the oral surgery site demonstrated that oral administration of a high dose of flurbiprofen (200 mg) did not result in drug concentrations at the extraction sites exceeding the IC₅₀ dose for cyclooxygenase-2 activity until 90 minutes postdrug.²⁰ Administration of a dose in the normal therapeutic range (50-100 mg) would likely have taken even longer to achieve inhibitory concentrations of cyclooxygenase-2 at the presumed site of action. Analgesic onset following oral administration of 25 to 100 mg flurbiprofen occurs as early as 30 minutes postdrug^21,22 and is substantial by 60 minutes.^20-22 The early analgesic onset following oral administration of NSAIDs such as flurbiprofen compared to the time course for achieving inhibitory concentrations in the periphery is suggestive of an early analgesic action at some other site, presumably the central nervous system. The ability of NSAIDs to suppress edema in the oral surgery model²³ and their well-documented effects in patients with rheumatoid arthritis are consistent with a peripheral site of anti-inflammatory action.

The administration of a drug with the ability to interfere with platelet adhesion into a surgical extraction site raises concerns regarding the potential for postoperative bleeding or interference with normal healing. Monitoring by the nurse observer over the initial 6 hours postoperatively did not reveal any increased incidence of oozing or hemorrhage at the extraction site. Patient reports over the first 48 hours and at 7 days also did not reveal any increase in the incidence of delayed healing, which normally manifests as an increased incidence of alveolar osteitis in oral surgery patients. These findings and similar safety for ketoprofen administered into the extraction sites in 3 replicate studies¹³ suggest that administration of this dose formulation is safe even when administered into a surgical wound.

The renal and gastrointestinal adverse effects associated with NSAIDs are related to distribution to these sites as a consequence of the oral or parenteral routes of administration. Although not directly assessed in this single-dose study, the demonstration of much lower plasma drug levels for the locally administered drug formulation in comparison to a normal therapeutic dose of flurbiprofen (25-50 mg) implies a decreased potential for drug toxicity. The plasma concentrations following administration into the surgical site were approximately half of the levels achieved with oral administration. The greater analgesic efficacy achieved by administration into the surgical sites in comparison with oral administration of the same doses (ie, 25 and 50 mg) resulted in lower blood concentrations predictive of less toxicity than the usual oral route of administration, likely by achieving higher drug concentrations at the site of intended drug action.

The results of the present study and a similar previous study¹³ provide a basis for the peripheral administration of NSAIDs in lower than usual doses to achieve efficacy comparable to or greater than systemic administration. Administration to a surgical site was well tolerated, suggestive of tissue compatibility at other sites less disrupted than a fresh surgical wound. The lower blood concentrations seen following peripheral administration are also predictive of less toxicity at sites normally associated with NSAID toxicity, the kidneys and GI tract, although repeated dosing is needed to be comparable to chronic administration.

	FOOTNOTES

 
DOI: 10.1177/0091270004265703

Submitted for publication December 22, 2003; Revised version accepted March 22, 2004.

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