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Evaluation of Acetaminophen and Aspirin in the Relief of Preoperative Dental Pain
Through direct questioning o f 113 patients and by recording preoperative dental pain at 15-minute intervals, investigators w ere able to exam ine the efficacy of two analgesics and a placebo.
Evaluation of acetaminophen and aspirin in the relief of preoperative dental pain B arb ara H. Korberly, Pharm D Glenn F. Schreiber, DMD A rthur Kilkuts Richard K. O rkand, PhD Herm an Segal, DDS
a
"ften there is an unavoidable delay between the onset of dental pain and treatment. In the interim, patients frequently take nonprescription m edica tions or are given a prescription by the dentist. The effectiveness of this therapy has not been studied under controlled conditions. The problem of evaluating analgesics is complex because of the difficulty of defining pain except as each person individually perceives it. Moreover, pain of pathologic origin apparently differs from experimental pain in the relative contributions of the perception of the original sensation and the reac tion to that sensation.1 Controlled studies on use of analgesics by humans have been done for various types of postoperative, acute, and mixed chronic pain.2'11 Recently, Cooper and Beaver7 devised a successful study of outpatients to evaluate mild analgesics for relief of postoperative dental pain. Their results demonstrated the superiority of aspirin (650 mg) and acetam inophen (600 mg) over codeine (60 mg) and a placebo in the relief of pain after extraction of a tooth. In this study, their model has been modified for use in a preoperative population. There has not been a controlled trial to determine the preoperative effectiveness of nonprescription analgesics in the relief of preoperative dental pain. This study was designed to determine the benefit of
two nonprescription analgesics used for relief of preoperative dental pain. Moreover, we hoped to establish a methodology to evaluate the efficacy of many preparations used for relief of oral pain.
Methods This study was undertaken in the emergency wait ing room of the dental clinic of a large urban univer sity dental school. Patients were screened by the senior attending practitioner (H.S.), according to the established procedure, to determine the cause and urgency of dental treatment. Participation in the study did not affect the waiting time for treatment. After initial screening, dental students working on the study (G.F.S., A.K.) interviewed the patients waiting to be treated to determine their degree of pain. Each patient was asked to record pain as slight, moderate, or severe. Patients were excluded from the study if they had previously been receiving nar cotic drugs or m edications that might interfere in quantitating analgesia. A complete medical history was obtained from each patient to determine any long-term underlying disease process. A complete history of drug use was also taken to determine previous allergic or adverse reactions to drugs or current use of medications. Patients were excluded JADA, Vol. 100, January 1980 ■ 39
Table ■ Summary of characteristics of patients. Age Aspirin Acetaminophen Placebo Total
Gender
Race
Starting pain
16 to 25
26 to 35
36 to 45
46 to 55
55 to 75
Male
Female
White
Black
Other
Slight
Moderate
Severe
12 15 19 46
11 10 13 34
7 5 4 16
2 4 2 8
4 4 1 9
15 16 19 50
21 22 20 63
8 11 12 31
27 25 22 74
1 2 5 8
9 10 20 39
20 20 14 54
7 8 5 20
from the study if they reported.previous allergies to any salicylate or analgesic. Patients with peptic ulcer disease or kidney disease, sickle cell disease, or diabetes were not included. Patients taking a drug that m ight interfere adversely with the administered analgesic (for example, sulfonylureas and anticoag ulants) were excluded from the study. If there were no contraindications, patients were advised of the purpose, potential benefits, and risks of the study, and they were asked to sign a standard consent form (10% did not sign) that classified risk as none or minimal. Patients were asked to quantify pain as slight, m oderate, or severe. This was recorded as starting pain and given a score of 2, 3, or 4. The drugs administered were in white, opaque no. 0 capsules; they contained either 0.5 gm aspirin, 0.5 gm acetam inophen, or lactose. Each dose consisted of two identical capsules containing 1 gm of either drug or placebo. The pairs of capsules were ran dom ized into three groups and w ere placed in sealed, consecutively numbered envelopes. Patients entering the study were given the capsules with 250 ml water. The degree of pain perceived by the pa tients was evaluated at 15-m inute intervals and was recorded as: 1, none; 2, slight; 3, moderate; and 4, severe. The patient’s perception of relief of pain was also recorded at these intervals as: 0, none; 1, a little; 2, some; 3, a lot; and 4, com plete. Patients were asked about the occurrence of side effects (gastroin testinal distress, drowsiness, or others) and, after treatment, the probable cause of pain and the diag nosis were recorded. Analgesia was determined by both param etric and nonparam etric statistics because of the subjectivity of the data. The pain intensity difference for each drug was calculated (for each patient by using the starting pain and subtracting the pain at 15, 30, 45, 60, 75, and 90 m inutes). The pain relief score was calculated for each drug and time as: 1, none; 2, a little; 3, some; 4, a lot; and 5, com plete, in relation to starting pain. The main difference between the methodology of this study and the postoperative study by Cooper and Beaver7 was that pain relief and intensity were determined at 15-m inute rather than hourly inter vals, and the results were gathered through direct questioning by the investigators in the dental clinic rath er th an th rou gh qu estion n aires com p leted elsewhere. 4 0 ■ JADA, Vol. 100, January 1980
Results The population of patients in regard to gender, race, age, and starting pain is described in the Table. In all cases, the specific cause of pain was inflammatory lesions of the dental hard and soft structures caused by m icroorganisms. More than 200 patients were interviewed and 113 were included in the study. Side effects did not occur with sufficient frequency to allow any meaningful statistical analysis. Results from param etric (t test) and nonpara m etric (Mann-Whitney U-test) statistical tests were essentially identical. Aspirin and acetaminophen both produced significantly more relief than the placebo, although the relief produced by acetam inophen seemed to be of shorter duration. As pa tients were admitted to dental treatment, follow-up study of the pain-relieving effect stopped. Presum a bly, greater precision at later times could be ob tained by increasing the number of patients in the study. The Illustration (A) shows mean pain relief scores for placebo, acetaminophen, and aspirin as a func tion of time after administration of the drug. A sig nificant difference (t test P < .05) was found for aspirin vs placebo at 45, 60, and 75 minutes. A t 75 minutes, aspirin also provided greater relief than acetaminophen. The Illustration (B) shows mean pain intensity differences (starting pain minus pain at tim e indicated) for placebo, acetaminophen, and aspirin for the same patients as in A and were deter mined at the same times. Significant differences (t te s tP < .05) are: 30 minutes aspirin vs placebo, 45 minutes acetaminophen vs placebo, and 60 minutes aspirin vs placebo. The average number of patients in each group was: 15 minutes, 38 patients; 30 m in utes, 36 patients; 45 minutes, 31 patients; 60 m in utes, 22 patients; and 75 minutes, 12 patients. Notice the increase in SE as the number of patients de creased. Results of the t test and Mann-Whitney U-test on the same data gave the same significant points with one exception: pain relief scores for aspirin vs placebo at 45 minutes showed U-test P = .067 vs t test P = .046.
Discussion Results dem onstrate that aspirin and acetam in ophen are both capable of providing greater relief of pain than a placebo for patients waiting in an emer-
3-
2
lot
-
a? u C
*3 Q-
little
0 - J --------1------------------- 1_____ I____________ l______L_
A spirin
_l---------- 1-------------------- 1--------- L_
Tim e-effect curve for placebo, acetam inophen 1 gm, and aspirin 1 gm. B ars ± SE of mean, assuming lin ear scale. A, pain re lie f scores. B, pain intensity differences. A sterisk indicates statistically significant differences between drug and placebo. Double asterisk in A indicates that effect of aspirin is significantly greater than both placebo and acetam inophen.
gency denftal clinic. Because of the conditions, it was expected that anxiety would contribute to pain and that, correspondingly, the placebo would have a greater effect 12 for pretreatment rather than post operative pain. A com parison of the pain relief scores in this study with those of Cooper and Bea ver 7 shows a greater placebo response occurred under current conditions. However, relief obtained with aspirin and acetaminophen was similarly in creased. We cannot rule out the fact that the some what larger doses used in the current study (1 gm vs 0.6 or 0.65 gm) contributed to the greater relief .2,7
We used both parametric (t test) and nonparam etric (U-test) tests in the analysis of results and obtained essentially the same significant points. The latter analysis was used because it does not require assu m ptions as to the lin earity of the measuring scale or a normal distribution of the populations . 7 A major limitation of this study was that the large variation in responses necessitated populations of 20 to 30 patients per group to disclose significant differences. Furthermore, as patients were treated, our attempt to study the time-course effect of the Korberly—others : EVALUATION OF ACETAMINOPHEN AND A SPIRIN ■ 41
drug was limited. Finally, the administration of a placebo did pro duce sign ifican t relief; this effect co m p licated evaluation of drugs used for relief of preoperative pain .12 A dditional controlled studies are clearly needed to establish the efficacy of the variety of analgesics currently recom m ended or prescribed for dental pain.
Summary The effectiveness of nonprescription analgesics— acetam inophen and aspirin— in providing subjec tive relief of preoperative dental pain was evaluated in a varied population of adults. This study dem on strates for the first time the feasibility of evaluating preoperative analgesic efficacy in preoperative den tal pain and provides evidence that acetam inophen (1 gm) and aspirin (1 gm) can alleviate dental pain better than a placebo. T he authors thank Dr. Stephen Cooper for constructive criticism of an earlier draft of this paper and M cNeil Laboratories for the unmarked capsules and a sm all grant for supplies. Support was also provided by Grant no. N S-12253 from the U S Public Health Service. Dr. Korberly is assistant professor, department of pharmacy practice, Philadelphia College of Pharmacy and Science, and adjunct professor,
42 ■ JADA, V ol. 100, January 1980
department of pharmacology, University of Pennsylvania, School of Den tal M edicine. Dr. Schreiber is resident, Hospital of the University of Penn sylvania; Mr. Kilkuts is a senior dental student; Dr. Orkand is professor, department of physiology and pharmacology; and Dr. Segal is assistant professor, department of oral m edicine, U niversity of Pennsylvania, School of Dental M edicine. Address requests for reprints to Dr. Korberly, f Department of Pharmacy Practice, Philadelphia College of Pharmacy and I Science, 43rd St, Woodland Ave, and Kingsessing M all, Philadelphia, ! 19104. 1. Beecher, H.K. T he assessment of pain in man and anim als. In Keele, C.A., and Sm ith, R. (eds.). UFAW Symposium, 1961. 2. Beaver, W .T. M ild analgesics. A review of their clin ical pharm acol ogy. Am J Med S c i 250:577-604, 1965. 3. Beaver, W .T. M ild analgesics. A review of their clin ical pharmacol ogy. Am J Med Sci 251:576-599, 1966. 4. Brenman, H.S. Oral analgesics: preoperative vs postoperative use. JADA 67:23-27, 1963. 5. Cantor, M.A. A comparison of propoxyphene HC1 (Darvon) and an analgesic m ixture (Percogesic) in pain relief after gingivectomy. J Oral Ther 4:224-228, 1967. 6. Chilton, N.W., and Beaver, W.T. Clinical evaluation of a sustained released aspirin preparation in postextraction dental pain. J Oral Ther 4:165-174, 1967. 7. Cooper, S.A ., and Beaver, W.T. A m odel to evaluate m ild analgesics in oral surgery outpatients. Clin Pharmacol Ther 20(2):243-250, 1976. 8. Cooper, S.A.; Needle, S.; and Kruger, G.O. Comparative analgesic potency of aspirin and ibuprofen. J Oral Surg 3 5 (ll):8 9 8 -9 0 3 , 1977. 9. Dionne, R.A., and Cooper, S.A. Evaluation of preoperative ibuprofen for postoperative pain after removal of third molars. Oral Surg 45(16):8518 5 6 ,1 9 7 8 . 10. M oertel, C.G., and others. A comparative evaluation of marketed analgesic drugs. N Engl ] Med 286:813-815, 1972. 11. M oertel, C.G., and others. R elief o f pain by oral m edications. Con trolled evaluation of analgesic combinations. JAMA 229:55-59, 1974. 12. Beecher, H.K. The powerful placebo. JAMA 159:1602-1606, 1955.
Evaluation of acetaminophen and aspirin in the relief of preoperative dental pain B arb ara H. Korberly, Pharm D Glenn F. Schreiber, DMD A rthur Kilkuts Richard K. O rkand, PhD Herm an Segal, DDS
a
"ften there is an unavoidable delay between the onset of dental pain and treatment. In the interim, patients frequently take nonprescription m edica tions or are given a prescription by the dentist. The effectiveness of this therapy has not been studied under controlled conditions. The problem of evaluating analgesics is complex because of the difficulty of defining pain except as each person individually perceives it. Moreover, pain of pathologic origin apparently differs from experimental pain in the relative contributions of the perception of the original sensation and the reac tion to that sensation.1 Controlled studies on use of analgesics by humans have been done for various types of postoperative, acute, and mixed chronic pain.2'11 Recently, Cooper and Beaver7 devised a successful study of outpatients to evaluate mild analgesics for relief of postoperative dental pain. Their results demonstrated the superiority of aspirin (650 mg) and acetam inophen (600 mg) over codeine (60 mg) and a placebo in the relief of pain after extraction of a tooth. In this study, their model has been modified for use in a preoperative population. There has not been a controlled trial to determine the preoperative effectiveness of nonprescription analgesics in the relief of preoperative dental pain. This study was designed to determine the benefit of
two nonprescription analgesics used for relief of preoperative dental pain. Moreover, we hoped to establish a methodology to evaluate the efficacy of many preparations used for relief of oral pain.
Methods This study was undertaken in the emergency wait ing room of the dental clinic of a large urban univer sity dental school. Patients were screened by the senior attending practitioner (H.S.), according to the established procedure, to determine the cause and urgency of dental treatment. Participation in the study did not affect the waiting time for treatment. After initial screening, dental students working on the study (G.F.S., A.K.) interviewed the patients waiting to be treated to determine their degree of pain. Each patient was asked to record pain as slight, moderate, or severe. Patients were excluded from the study if they had previously been receiving nar cotic drugs or m edications that might interfere in quantitating analgesia. A complete medical history was obtained from each patient to determine any long-term underlying disease process. A complete history of drug use was also taken to determine previous allergic or adverse reactions to drugs or current use of medications. Patients were excluded JADA, Vol. 100, January 1980 ■ 39
Table ■ Summary of characteristics of patients. Age Aspirin Acetaminophen Placebo Total
Gender
Race
Starting pain
16 to 25
26 to 35
36 to 45
46 to 55
55 to 75
Male
Female
White
Black
Other
Slight
Moderate
Severe
12 15 19 46
11 10 13 34
7 5 4 16
2 4 2 8
4 4 1 9
15 16 19 50
21 22 20 63
8 11 12 31
27 25 22 74
1 2 5 8
9 10 20 39
20 20 14 54
7 8 5 20
from the study if they reported.previous allergies to any salicylate or analgesic. Patients with peptic ulcer disease or kidney disease, sickle cell disease, or diabetes were not included. Patients taking a drug that m ight interfere adversely with the administered analgesic (for example, sulfonylureas and anticoag ulants) were excluded from the study. If there were no contraindications, patients were advised of the purpose, potential benefits, and risks of the study, and they were asked to sign a standard consent form (10% did not sign) that classified risk as none or minimal. Patients were asked to quantify pain as slight, m oderate, or severe. This was recorded as starting pain and given a score of 2, 3, or 4. The drugs administered were in white, opaque no. 0 capsules; they contained either 0.5 gm aspirin, 0.5 gm acetam inophen, or lactose. Each dose consisted of two identical capsules containing 1 gm of either drug or placebo. The pairs of capsules were ran dom ized into three groups and w ere placed in sealed, consecutively numbered envelopes. Patients entering the study were given the capsules with 250 ml water. The degree of pain perceived by the pa tients was evaluated at 15-m inute intervals and was recorded as: 1, none; 2, slight; 3, moderate; and 4, severe. The patient’s perception of relief of pain was also recorded at these intervals as: 0, none; 1, a little; 2, some; 3, a lot; and 4, com plete. Patients were asked about the occurrence of side effects (gastroin testinal distress, drowsiness, or others) and, after treatment, the probable cause of pain and the diag nosis were recorded. Analgesia was determined by both param etric and nonparam etric statistics because of the subjectivity of the data. The pain intensity difference for each drug was calculated (for each patient by using the starting pain and subtracting the pain at 15, 30, 45, 60, 75, and 90 m inutes). The pain relief score was calculated for each drug and time as: 1, none; 2, a little; 3, some; 4, a lot; and 5, com plete, in relation to starting pain. The main difference between the methodology of this study and the postoperative study by Cooper and Beaver7 was that pain relief and intensity were determined at 15-m inute rather than hourly inter vals, and the results were gathered through direct questioning by the investigators in the dental clinic rath er th an th rou gh qu estion n aires com p leted elsewhere. 4 0 ■ JADA, Vol. 100, January 1980
Results The population of patients in regard to gender, race, age, and starting pain is described in the Table. In all cases, the specific cause of pain was inflammatory lesions of the dental hard and soft structures caused by m icroorganisms. More than 200 patients were interviewed and 113 were included in the study. Side effects did not occur with sufficient frequency to allow any meaningful statistical analysis. Results from param etric (t test) and nonpara m etric (Mann-Whitney U-test) statistical tests were essentially identical. Aspirin and acetaminophen both produced significantly more relief than the placebo, although the relief produced by acetam inophen seemed to be of shorter duration. As pa tients were admitted to dental treatment, follow-up study of the pain-relieving effect stopped. Presum a bly, greater precision at later times could be ob tained by increasing the number of patients in the study. The Illustration (A) shows mean pain relief scores for placebo, acetaminophen, and aspirin as a func tion of time after administration of the drug. A sig nificant difference (t test P < .05) was found for aspirin vs placebo at 45, 60, and 75 minutes. A t 75 minutes, aspirin also provided greater relief than acetaminophen. The Illustration (B) shows mean pain intensity differences (starting pain minus pain at tim e indicated) for placebo, acetaminophen, and aspirin for the same patients as in A and were deter mined at the same times. Significant differences (t te s tP < .05) are: 30 minutes aspirin vs placebo, 45 minutes acetaminophen vs placebo, and 60 minutes aspirin vs placebo. The average number of patients in each group was: 15 minutes, 38 patients; 30 m in utes, 36 patients; 45 minutes, 31 patients; 60 m in utes, 22 patients; and 75 minutes, 12 patients. Notice the increase in SE as the number of patients de creased. Results of the t test and Mann-Whitney U-test on the same data gave the same significant points with one exception: pain relief scores for aspirin vs placebo at 45 minutes showed U-test P = .067 vs t test P = .046.
Discussion Results dem onstrate that aspirin and acetam in ophen are both capable of providing greater relief of pain than a placebo for patients waiting in an emer-
3-
2
lot
-
a? u C
*3 Q-
little
0 - J --------1------------------- 1_____ I____________ l______L_
A spirin
_l---------- 1-------------------- 1--------- L_
Tim e-effect curve for placebo, acetam inophen 1 gm, and aspirin 1 gm. B ars ± SE of mean, assuming lin ear scale. A, pain re lie f scores. B, pain intensity differences. A sterisk indicates statistically significant differences between drug and placebo. Double asterisk in A indicates that effect of aspirin is significantly greater than both placebo and acetam inophen.
gency denftal clinic. Because of the conditions, it was expected that anxiety would contribute to pain and that, correspondingly, the placebo would have a greater effect 12 for pretreatment rather than post operative pain. A com parison of the pain relief scores in this study with those of Cooper and Bea ver 7 shows a greater placebo response occurred under current conditions. However, relief obtained with aspirin and acetaminophen was similarly in creased. We cannot rule out the fact that the some what larger doses used in the current study (1 gm vs 0.6 or 0.65 gm) contributed to the greater relief .2,7
We used both parametric (t test) and nonparam etric (U-test) tests in the analysis of results and obtained essentially the same significant points. The latter analysis was used because it does not require assu m ptions as to the lin earity of the measuring scale or a normal distribution of the populations . 7 A major limitation of this study was that the large variation in responses necessitated populations of 20 to 30 patients per group to disclose significant differences. Furthermore, as patients were treated, our attempt to study the time-course effect of the Korberly—others : EVALUATION OF ACETAMINOPHEN AND A SPIRIN ■ 41
drug was limited. Finally, the administration of a placebo did pro duce sign ifican t relief; this effect co m p licated evaluation of drugs used for relief of preoperative pain .12 A dditional controlled studies are clearly needed to establish the efficacy of the variety of analgesics currently recom m ended or prescribed for dental pain.
Summary The effectiveness of nonprescription analgesics— acetam inophen and aspirin— in providing subjec tive relief of preoperative dental pain was evaluated in a varied population of adults. This study dem on strates for the first time the feasibility of evaluating preoperative analgesic efficacy in preoperative den tal pain and provides evidence that acetam inophen (1 gm) and aspirin (1 gm) can alleviate dental pain better than a placebo. T he authors thank Dr. Stephen Cooper for constructive criticism of an earlier draft of this paper and M cNeil Laboratories for the unmarked capsules and a sm all grant for supplies. Support was also provided by Grant no. N S-12253 from the U S Public Health Service. Dr. Korberly is assistant professor, department of pharmacy practice, Philadelphia College of Pharmacy and Science, and adjunct professor,
42 ■ JADA, V ol. 100, January 1980
department of pharmacology, University of Pennsylvania, School of Den tal M edicine. Dr. Schreiber is resident, Hospital of the University of Penn sylvania; Mr. Kilkuts is a senior dental student; Dr. Orkand is professor, department of physiology and pharmacology; and Dr. Segal is assistant professor, department of oral m edicine, U niversity of Pennsylvania, School of Dental M edicine. Address requests for reprints to Dr. Korberly, f Department of Pharmacy Practice, Philadelphia College of Pharmacy and I Science, 43rd St, Woodland Ave, and Kingsessing M all, Philadelphia, ! 19104. 1. Beecher, H.K. T he assessment of pain in man and anim als. In Keele, C.A., and Sm ith, R. (eds.). UFAW Symposium, 1961. 2. Beaver, W .T. M ild analgesics. A review of their clin ical pharm acol ogy. Am J Med S c i 250:577-604, 1965. 3. Beaver, W .T. M ild analgesics. A review of their clin ical pharmacol ogy. Am J Med Sci 251:576-599, 1966. 4. Brenman, H.S. Oral analgesics: preoperative vs postoperative use. JADA 67:23-27, 1963. 5. Cantor, M.A. A comparison of propoxyphene HC1 (Darvon) and an analgesic m ixture (Percogesic) in pain relief after gingivectomy. J Oral Ther 4:224-228, 1967. 6. Chilton, N.W., and Beaver, W.T. Clinical evaluation of a sustained released aspirin preparation in postextraction dental pain. J Oral Ther 4:165-174, 1967. 7. Cooper, S.A ., and Beaver, W.T. A m odel to evaluate m ild analgesics in oral surgery outpatients. Clin Pharmacol Ther 20(2):243-250, 1976. 8. Cooper, S.A.; Needle, S.; and Kruger, G.O. Comparative analgesic potency of aspirin and ibuprofen. J Oral Surg 3 5 (ll):8 9 8 -9 0 3 , 1977. 9. Dionne, R.A., and Cooper, S.A. Evaluation of preoperative ibuprofen for postoperative pain after removal of third molars. Oral Surg 45(16):8518 5 6 ,1 9 7 8 . 10. M oertel, C.G., and others. A comparative evaluation of marketed analgesic drugs. N Engl ] Med 286:813-815, 1972. 11. M oertel, C.G., and others. R elief o f pain by oral m edications. Con trolled evaluation of analgesic combinations. JAMA 229:55-59, 1974. 12. Beecher, H.K. The powerful placebo. JAMA 159:1602-1606, 1955.