Analgesic efficacy of flurbiprofen in comparison with acetaminophen, acetaminophen plus codeine, and placebo after impacted third molar removal

J Oral Maxillofac Surg

52:919-924.1994

Analgesic Efficacy of Flurbiprofen in Comparison With Acetaminophen, Acetaminophen Plus Codeine, and Placebo After Impacted Third Molar Removal RAYMOND A. DIONNE, DDS, PHD,* JAMES SNYDER, DDS,t AND KENNETH M. HARGREAVES, DDS, PHD+ Purpose: The analgesic efficacy of 50 and 100 mg flurbiprofen was compared with acetaminophen 650 mg, acetaminophen 650 mg plus codeine 60 mg, and placebo. Patients and Methods: Subjects undergoing the surgical removal of impacted third molars were randomly administered one of the five treatments after the onset of moderate to severe postoperative pain. Pain intensity, pain relief, and side effects were evaluated for 6 hours after drug administration. Results: Both doses of flurbiprofen resulted in significant analgesia in comparison with placebo, acetaminophen, and acetaminophen plus codeine as measured by pain intensity difference, pain relief, and global evaluation. The greatest incidence of side effects occurred in the group receiving acetaminophen plus codeine, and the fewest side effects were reported by subjects administered flurbiprofen. Conclusion: The results of this study indicate that flurbiprofen is more effective and causes fewer effects than acetaminophen and codeine when used for postoperative dental pain, in ambulatory patients.

oforal surgery. Surgical trauma activates a biochemical cascade resulting in the synthesis or release of prostaglandins, bradykinin, substance P, histamine, and other substances that interact to produce plasma extravasation leading to edema, one of the clinical signs of inflammation. These local mediators also have several effects on peripheral nerve endings: they excite and sensitize peripheral nerve endings, which results in the clinical manifestation of hyperalgesia, (ie, spontaneous pain, reduced pain threshold, and increased pain perception to noxious stimuli). In addition these local mediators stimulate the release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings, which act synergistically with other inflammatory mediators to induce further plasma extravasation. The interactions of these inflammatory mediators with the neural release of substance P and the process of extravasation forms a positive feedback loop that is thought to continually refuel the inflammatory process, maintaining the clinical signs of inflammation for days after the initial stimulus.

The management of acute postsurgical pain with nonsteroidal anti-inflammatory drugs (NSAIDs) has become widely accepted since the introduction of ibuprofen as an analgesic. I The NSAID drug class has proven to be superior to single-entity analgesics such as aspirin and acetaminophen in providing pain relief, with fewer side effects, than opioid-mild analgesic combinations.i" NSAIDs are particularly well suited for the management of acute pain because they also interfer with inflammation that is the normal sequela

* Chief, Clinical Pharmacology Unit, National Institute of Dental Research, Bethesda, MD. t Associate Professor, Division of Endodontics, School of Dentistry, University of Minnesota, Minneapolis, MN. In private practice, Alexandria, VA. Supported in part by a grant to Dr Snyder from the Upjohn Company. Address correspondence and reprint requests to Dr Dionne: Building 10, Room IN-103, 9000 Rockville Pike, Bethesda, MD 20892.

*

© 1994 American Association of Oral and Maxillofacial Surgeons 0278-2391/94/5209-0004$3.00/0

919

920

ANALGESIC EFFICACY OF FLURBIPROFEN

Drugs that block the actions or synthesis of th ese mediators possess analgesic activity for pain of in flammatory origin. NSAIDs are thought to act by interfering with the inflammatory process by inhibiting cyclooxygenase, the enzyme that catalyzes the synthesis of prostaglandins from arachidonic acid.' Flurbiprofen, an NSAID, has been shown to suppress tissue levels of both prostaglandin Ez and bradykinin after oral surgery.6.7 The onset of activity of orally administered NSAIDs, such as ibuprofen, is usually slow, with peak analgesic activity not reached until I to 2 hours after administration. 1 Administration ofeither ibuprofen or flurbiprofen before a surgical procedure can delay the onset and reduce the magnitude of postoperative pain. 8•9 Practical considerations, however, often prevent medicating ambulatory patients before a procedure, requiring postoperative administration of a drug with a reasonably rapid onset of activity, minimal side effects, and an oral route of administration. Flurbiprofen has been evaluated extensively for the management of rheumatoid arthritis'P'!' and osteoarthritis," as well as for analgesic indications.F':'! Although approved by the FDA for use in the management of arthritis.!" flurbiprofen has never received formal approval as an analgesic. The use ofsuch a drug for an indication outside of the package labeling is then based on professional judgment and a body of scientific literature documenting its clinical utility. The current study evaluated the analgesic efficacy of two different 'doses offlurbiprofen in comparison with two standard analgesics: acetaminophen and acetaminophen plus codeine. A parallel control group received placebo medication as a measure of assay sensitivity and for comparison of side effects. This article reports the analgesic superiority of orally administered flurbiprofen, and its fewer side effects, in comparison with two standard analgesic drug regimens for postoperative pain. These observations add to the large body of evidence that supports the efficacy and safety of flurbiprofen as a n oral analgesic for use in dentistry.

Methods The study consisted of a single-dose, parallel-group, double-blind evaluation offlurbiprofen in the oral surgery model of acute pain. Subjects were 135 patients undergoing the surgical removal of impacted third molars in a private dental practice. Patients were explained the nature of the surgical procedure and the possible adverse effects of the medications and signed an institutionally approved consent form . Eligible patients were males and females, 16 years of age or older, reporting moderate or severe postoperative pain. Patients were excluded if they were pregnant, lactating, or not following an effective birth control regimen; had a history of drug or alcohol abuse; were suffering from

any malignancy, renal , hepatic, or hematologic disease; or if they had experienced allergic reactions to any of the drugs to be used or related drugs. Oral surgery was performed under either local anesthesia only (43 % of patients), local anesthesia plus intravenous sedation (28 %), local anesthesia plus nitrous oxide (17 %), or general anesthesia (12 %). The distribution ofthe various sedative regimens and drugs used was similar across treatment groups. Local anesthesia consisting of 2% lidocaine with I: 100,000 epinephrine or 3% mepivacaine was administered intraorally to block the innervation to the maxillary and mandibular third molars and overlying mucosa. The third molars then were removed with standard surgical techniques, sutures were placed if a mucoperiosteal flap had been elevated, and gauze was held in place with biting pres-' sure for a minimum of I hour postoperatively. Subjects were eligible for entry into the study when postoperative pain reached moderate to severe intensity and a minimum of at least 4 hours had elapsed since administration of any drug with analgesic properties other than the local anesthetic. Subjects then completed a category scale for pain intensity that rated pain as none (scored as 0), mild (I), moderate (2), or severe (3). A study drug then was administered orally containing one of five possible medications: flurbiprofen 50 mg, flurbiprofen 100 mg, acetaminophen 650 mg, acetaminophen 650 mg plus codeine 60 mg, or placebo. Patients were allowed to leave the clinic a minimum of 2 hours after the study medication was given and instructed to record their pain intensity and pain relief hourly up to 6 hours postdrug. Pain relief was categorized as none (scored as 0), a little (I), some (2), a lot (3), or complete (4). Subjects also were asked to record any other effects of the medication. A standard " rescue" analgesic medication (650 mg acetaminophen plus 60 mg codeine) was provided to take if the test medication proved inadequate. Comparability of the treatment groups at baseline was tested using the chi-square test for discrete variables and analysis of variance (ANOVA) for continuous variables. Subject who terminated the study before the second-hour observation were considered dropouts and were replaced. Patients who remedicated after 1.5 hours because of inadequate pain relief completed the 2-hour observation, and this score was used as the 2-hour observation. For statistical purposes, patients' initial pain level was used for the remaining hours of the observation period and the pain relief scores assumed to be zero. The difference between the pain at each observation and the starting pain was calculated as the pain intensity difference (PID) and summed over the entire observation period as a summary measure of analgesic activity, the sum of pain intensity difference scores (SPID). The hourly pain reliefscores were also summed as an overall measure of analgesia, the total pain relief

921

DIONN E. SNYDER, AND HAR GREAVES

score (TOTPAR). The categorical data, as well as the derived indices of analgesic effect, were analyzed by the Kruskal-Wallis test followed by a non parametric multiple comparison procedure to determine differences between groups. IS The frequency of adverse effects was analyzed by chi-square analysis.

ferences existed between treatment groups at all time points after the first hour (P < .0 I), through the second to fifth hours (P < .00 I), and persisted at the sixth hour (P < .0 I). Both doses of flurbiprofen were similar to each other and significantly better than placebo for hours I through 6. Rurbiprofen 100 mg was significantly more efficacious than acetaminophen and acetaminophen plus codein e at hours 3 through 6. Flurbiprofen 50 mg provided significantly greater analgesia than acetaminophen from 2 through 6 hours and was more efficacious than acetaminophen plus codeine at the 2-hour observation. These data indicate that all four active treatments had similar efficacy at I hour after administration, but that flurbiprofen resulted in greater analgesia and longer duration than the other active treatments over the remainder of the observation period. The sum of the pain intensity difference scores (SPID) demonstrate that the overall analgesic effect differed significantly (P < .00 I) among treatments (Fig IB). Both doses of flurbiprofen were significantly better than placebo, acetaminophen, and acetaminophen plus codeine. Acetaminophen plus codeine was significantly better than placebo, but not distinguishable from acetaminophen alone. The SPID score for acetaminophen 650 mg was not statistically different from placebo. Pain relief, as measured by a five-point categorical scale, was significantly different (P < .01) among treatment groups at all hourly observations (Fig 2A). Both doses of flurbiprofen were similar to each other, but significantly more efficacious than placebo at all times. Flurbiprofen 100 mg resulted in significantly greater pain relief than acetaminophen plus codeine for hours

Results

A total of 135 patients received a study medication; II of these were judged not to be evaluable for a variety of reasons: previously enrolled in the same study (4), remedicated before 2-hour observation (3), lost to follow-up (2), asleep during observations (I), and ineligible. because ofcodeine sensitivity (I). The final study sample consisted of 124 subjects in five treatment groups that were similar in terms of age, sex, race, weight, and height (Table I). The treatment groups were also similar in the type ofextractions performed, number ofsutures placed, and rating of surgical trauma (data not shown) . The cumulative dropout rate was greatest in the placebo group (68% by 6 hours) and the acetaminophen 650 mg group (68%), intermediary for acetaminophen plus codeine (54%) and flurbiprofen 50 mg (40%), and least for the flurbiprofen 100 mg group (14%). These differences presumably were related to the efficacy of the treatments and not to other variables, which were similar across groups. Starting mean pain intensity scores, rangingbetween moderate and severe because of the inclusion criterion for study entry, were similar across treatment groups. Pain intensity difference scores increased to a variable degree in all groups over time (Fig IA). Significant dif-

Table 1. Summary of Demographic Characteristics of 124 Subjects Included in the Efficacy and Safety Analysis Treatment Group

N

Age

F1urbiprofen 50 mg

26

26.4

Flurbiprofen 100 mg

22

29.5

10 M F

29.6

12 14 13

M F

Acetaminophen 650 mg

27

Sex 9 17

M F

M F

Acetaminophen 650 mg + cod eine 60 mg

24

29.4

9 15

Placebo

25

28.2

15 M 10 F

Abbreviations for race: W, white; B, black; Or, oriental; 0, other.

Race

Weight (Ibs)

Height (inches)

19 W I B 4 Or 2 0 15 W 7 B 22 W 4 B I Or 20 W 2 B I Or 1 0 20 W 2 B I Or 2 0

143.2

66.9

148.0

67.4

149.2

66.9

145.4

66.9

155.9

68.4

922

ANALGESIC EFFICACY OF FLURBIPROFEN

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FL 100

APAP a COD APAP ISO

80

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ference in side effects between treatment groups (Table 2). The greatest incidence of side effects (36%) was reported for acetaminophen plus codeine, primarily reports of drowsiness. Conversely, the lowest incidence of side effects was reported after flurbiprofen 100 mg, one incidence of drowsiness plus one other. The concurrent use of sedative and anesthetic drugs for the oral surgery procedure and the sample size, however, limit interpretation of these differences in the incidence of side effects between groups.

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FL 50

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The management of postoperative pain in ambulatory patients is best accomplished by an orally effective medication with rapid onset and minimal side effects. The inflammatory origin of most postsurgical dental pain has made it useful for studying the analgesic effects of the NSAID drug class. Yet, many clinicians and patients still continue to use drugs and cornbinations without anti-inflammatory efficacy, such as acetaminophen and codeine. The results of this study demonstrate that flurbiprofen in doses of 50 or 100

PLBO

COD

FIGURE I. Pain intensity difference scores after f1urbiprofei1100 mg (FL 100), f1urbiprofen 50 mg (FL 50), acetaminophen 650 mg plus codeine 60 mg (APAP 650 & COD 60), acetaminophen 650 mg (APAP 650), or placebo (PLBO). A. Time-action curve; B. Sum of the hourly pain intensity difference scores.

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2 through 6, and greater relief than acetaminophen from 3 to 6 hours. F1urbiprofen 50 mg was also significantly better than acetaminophen at most time points after the first hour. The total pain relief score demonstrated significantly greater relief with flurbiprofen 100 mg in comparison with placebo, acetaminophen, and acetaminophen plus codeine {Fig 2B). F1urbiprofen 50 mg was statistically distinguishable from placebo and acetaminophen plus codeine, but not from acetaminophen 650 mg. Both acetaminophen and acetaminophen plus codeine were indistinguishable from placebo. Subjects also provided an overall subjective rating of the efficacy of the treatments at the end of the 6hour observation period on a categorical scale ranging from "poor" (I) to "excellent" (5). Both flurbiprofen 100 mg (mean rating, 3.8) and flurbiprofen 50 mg (3.9) were rated approximately as "very good," which was significantly better (P < .05) than the other three treatment groups. Acetaminophen 650 mg (3.0) was rated as "good", but was statistically indistinguishable from acetaminophen plus codeine (2.7) and placebo (2.5). A statistical trend (P = .06) was observed for a dif-

A

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FIGURE 2. Pain relief scores after f1urbiprofen 100 mg (FL 100), f1urbiprofen 50 mg (FL 50), acetaminophen 650 mg plus codeine 60 mg (APAP 650 & COD 60), acetaminophen 650 rng (APAP 650), or placebo (PLBO). A. Time-action curve; B. Sum of the hourly pain relief scores.

923

DIONNE, SNYDER, AND HARGREAVES

Table 2.

Incidence of Side Effects Reported

Treatment Group

Drowsiness.

Gastric Distress

Nausea or Vomiting

Flurbiprofen 100 mg Flurbiprofen 50 mg Acetaminophen 650 mg Acetaminophen 650 mg + codeine 60 mg Placebo

I 2 4

0 I 0

4 I

2 0

mg is superior to both acetaminophen alone and acetaminophen plus 60 mg codeine. Both summary measures of analgesic activity, SPID and TOTPAR, demonstrated significantly greater analgesic efficacy for flurbiprofen compared with the other three treatment groups. Differences between the active treatments were detectable by the second hour after administration and continued until the end of the 6-hour observation. Greater therapeutic effects for opioid analgesics can be achieved with greater doses, but with a parallel increase in the incidence ofside effects. Codeine at a dose of 120 mg, for example, has been shown to produce analgesia comparable to 10 mg of intramuscular morphine, but with an incidence ofside effects not generally tolerated in ambulatory patients." Similarly, 10 mg oxycodone produces significant additive analgesia in combination with acetaminophen in the oral surgery model, but with a greater than 80% incidence of side effects. I? In contrast, flurbiprofen resulted in greater analgesia than both other active treatments, with a trend toward fewer side effects. Increased analgesia with fewer side effects represents a therapeutic advantage for both pain management and return to normal function. The continued use of opioid-mild analgesic combinations in clinical practice is most likely attributable to traditional prescribing habits. Controlled comparisons of newer NSAIDs with combinations containing 60 mg codeine have repeatedly demonstrated analgesic superiority for the NSAID. NSAlDs also reduce other sequelae of inflammation such as ederna.P but without the transient adrenal suppression produced by corticosteroids. When given preoperatively, NSAIDs such as ibuprofen and flurbiprofen can suppress postoperative pain intensity to a mean of"slight" pain after the removal of impacted third molars.f-" The ability to suppress both postoperative pain and edema, with fewer side effects than with opioid-rnild analgesic combinations, should take precedence over reliance on traditional approaches to pain management in dental patients. NSAIDs have been alleged to increase the incidence ofalveolar osteitis after oral surgery.19 This observation was based on two separate studies evaluating diflunisal

Headache

Other

None

0 I 2

0 I

I 0 2

20 20 20

2 2

0 I

2 I

15 20

3

in oral surgery patients. 19,20 The incidence of alveolar osteitis was elevated in the second study when the diflunisal was administered preoperatively in comparison with postoperative administration of diflunisal in the first study. The use of a historical control is generally recognized to be unreliable because of variability that can occur over time independent of the phenomenon under study." The incidence of alveolar osteitis in published studies is highly variable, ranging from 1% to greater than 30%.22-24 This large variability over time and between investigators can readily result in a difference in the occurrence of alveolar osteitis independent of drug administration. Retrospective evaluation of previously published data? failed to demonstrate any difference in the incidence ofalveolar osteitis after preoperative flurbiprofen (6 cases in 80 patients, 7.8%) in comparison with parallel groups of patients receiving either placebo, acetaminophen, or acetaminophen plus codeine (5/78, 6.4%). Similarly, prospective comparison of the incidence of alveolar osteitis after preoperative administration offlurbiprofen (5%) also failed to demonstrate a difference in comparison with standard drugs (5%),18 Thus, few credible data exist to mitigate use ofNSAIDs for oral surgery on the basis ofconcern over alveolar osteitis. Concern has also been raised that use of NSAIDs may increase episodes of postoperative bleeding. Ibuprofen has been shown to increase bleeding time in both normal patients and hemophiliacs, but the values remained within the normal range." Preoperative flurbiprofen also increases bleeding time but values remain within the normal range (Dionne RA, unpublished observations). Although the use of an aspirinlike drug would be difficult to justify for a patient with a known bleeding disorder, available evidence suggests that NSAIDs generally do not result in clinically significant increases in bleeding. Lastly, use of an NSAID that has not been specifically approved by the Food and Drug Administration (FDA) for an analgesic indication raises the potential of increased medicolegal jeopardy. The FDA, however, clearly limits their authority to the development and marketing of new drugs and monitoring of marketed drugs for reports of serious side effects. The use of a

924 drug for an "offlabcl indication" is left to the judgment ofphysicians and dentists and is recognized as a source of therapeutic innovation. For example, the use oftricyclic antidepressants for the management of chronic pain falls outside of their approved indication as antidepressants but has proven safe and effective for a variety of different chronic pain syndromes.P-" Oral surgeons routinely use other drug classes for parenteral sedation (ie, midazolam) that do not have approved indications for such outpatient use." In the absence of any compendium of drug use for dentistry, similar to the AMA Drug Evaluations for physicians, the use of drugs for purposes other than the narrow FDA-approved indications is a professional judgment based on expected therapeutic benefit and potential risk to the patient. The analgesic superiority demonstrated for flurbiprofen in controlled trials, and the millions of doses administered safely to patients with arthritis, strongly supports the use offlurbiprofen for acute dental pain.

References I. Cooper SA, Needle SE, Kruger GO : An analgesic relative potency assay comparing aspirin, ibuprofen and placebo. J Oral Surg 35:898, 1977 2. Cooper SA, Mardirossian G: Comparison of flurbiprofen and aspirin in the relief of postsurgical pain using the dental pain model. Am J Med 80(suppl 3A):36, 1986 3. Forbes JA, Butterworth GA, Burchfield WH, et al: Evaluation of ketorolac, aspirin, and an acetaminophen-codeine combination in postoperative oral surgery pain. Pharmacotherapy 1O:77S, 1990 4. Cooper SA, Gelb SB, Cavaliere MB, et al: An analgesic relative potency assay comparing ketoprofen and aspirin in postoperative dental pain. Adv Ther 1:410, 1984 5. Ferreira SH, Moncada S, Vane JR : Prostaglandins and the mechanism of analgesia produced by aspirin-like drugs. Br J PharmacoI49:86, 1973 6. Swift JO, Garry MG, Roszowski MT, et al: Effect offlurbiprofen on tissue levels of immunoreactive bradykinin and acute postoperative pain. J Oral Maxillofac Surg 51: 112, 1993 7. Roszowski MT, SwiftJO, Hargreaves KM: Prostaglandin E2tissue levels increase following third molar extraction. J Dent Res 71:178, 1992 (abstr) 8. Dionne RA, Campbell RA, Cooper SA, et al: Suppression of postoperative pain by preoperative administration of ibuprofen

ANALGESIC EFFICACY OF FLURBIPROFEN

9. 10. II . 12. 13.

14. 15. 16. 17. 18.

19. 20. 21. 22.

23. 24. 25. 26. 27. 28.

in comparison to placebo, acetaminophen, and acetaminophen plus codeine. J C1in Pharrnacol 23:37, 1983 Dionne RA: Suppression of dental pain by preoperative administrat ion offlurbiprofen. Am J Med 80(3A):41, 1986 Skosey JL: FIurbiprofen in rheumatoid arthritis: Duration of analgesic effect. Am J Med 80(3A):103, 1986 Brown BL, Johnson JH, Stiger TR: FIurbiprofen versus naproxen in the treatment of rheumatoid arthritis. Am J Med 80(3A): 105, 1986 Lomen PL, Lamborn KR , Porter GH , et al: Treatment of osteoarthritis of the knee: A comparison of flurbiprofen and aspirin. Am J Med 80(3A):97, 1986 Sunshine A, Marrero I, Olson N, et al: Comparative study of flurbiprofen, zomepirac sodium, acetaminophen plus codeine, and acetaminophen for the relief of postsurgical dental pain. Am J Med 80(3A):50, 1986 Flurbiprofen Package Insert. Physicians' Desk Reference (ed 47). Montvale, NJ, Medical Economics Company, 1993, p 2431 Conover WJ: Practical Nonpararnctric Statistics (ed 2). New York, NY, John Wiley & Sons, 1980, p 231 Lasagna L, Beecher HK: The analgesic effectiveness of codeine and meperidine (Demerol). J Pharmacol Exp Ther 112:306, 1954 Cooper SA, Precheur H, Rauch 0, et al: Evaluation of oxycodone and acetaminophen in treatment of postoperative pain . Oral Surg Oral Med Oral Pathol 50:496, 1980 Troullos ES, Hargreaves KM, Butler DP, et al: Comparison of nonsteroidal anti-inflammatory drugs, ibuprofen and flurbiprofen, with methylprednisolone and placebo for acute pain, swelling, and trismus. J Oral Maxillofac Surg 48:945, 1990 Petersen JK: The analgesic and anti-inflammatory efficacy of diflunisal and codeine after removal of impacted third molars. Curr Med Res Opin 5:525, 1978 Petersen JK: Diflunisal, a new analgesic, in the treatment of postoperative pain following removal ofimpacted mandibular third molars. Int 1 Oral Surg 8:102, 1979 Pocock SJ: Clinical Trials. New York, NY, John Wiley & Sons, 1983, p 54 Goldberg MH, Nemarich AN, Marco WP: Complications after mandibular third molar surgery: A statistical analysis of 500 con secutive procedures in private pract ice. J Am Dent Assoc 111:277,1985 Larsen PE: The effect of chlorhexidine rinse on the incidence of alveolar osteitis following the surgical removal of impacted mandibular third molars. J Oral Maxillofac Surg 49:932, 1991 Krekmanov L: Alveolitis after operative removal of third molars in the mandible. Int J Oral Surg 10:173,1981 Mcintyre BA, Philp RB, Inwood Ml: Effect of ibuprofen on platelet function in normal subjects and hemophiliac patients . C1in Pharmacol Ther 24:6[6, 1978 Sharav Y, Singer E, Schmidt E, et al: The analgesic effect of amitriptyline on chronic facial pain . Pain 31:199, 1987 Max MB, Culnane M, Schafer SC, et al: Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 37:589, 1987 Dionne RA: Pharmacologic consideration in the training of dentists in anesthesia and sedation. J Dent Edue 53:297, 1989