{ O R IG IN A L C O N T R IB U T IO N S f
CRITICAL SUMMARIES
Acetaminophen plus a nonsteroidal anti-inflammatory drug decreases acute postoperative pain more than either drug alone A critical su m m ary o f Ong CK, S eym o ur RA, Lirk P, M e rry AF. C om bining p a ra c e ta m o l (a c e ta m in o p h e n ) w ith n on s te ro id a l a n tiin fla m m a to ry drugs: a q u a lita tiv e s y s te m a tic re v ie w o f analgesic effic a c y fo r a c u te p o s to p e ra tiv e pain. A n esth A nalg 2 0 1 0 ;1 1 0 (4 ):1 1 7 0 -1 1 7 9 .
F e m e Kraglund, DDS
System atic review conclusion. Current evidence suggests that a combination of acetaminophen, also known as paracetamol, and a nonsteroidal anti-inflammatory drug (NSAID) may offer superior analgesia than does either drug alone. Critical sum m ary assessm ent. The authors of this high-quality review of 21 double-masked randomized controlled trials deter mined that the combination of acetaminophen and an NSAID reduced acute postoperative (including dental) pain scores and the need for supplemental analgesics more than did acetaminophen or an NSAID alone. Evidence quality rating. Good.
Clinical question. In the treat ment of acute postoperative pain, does combining acetaminophen with a nonsteroidal anti-inflammatory drug (NSAID) provide superior efficacy when compared with either drug alone? R eview m ethods. The reviewers searched four databases for ran domized controlled trials (RCTs) in English from January 1988 to June 2009. They retrieved full reports for double-masked RCTs in which investigators compared acetaminophen/NSAID combinations with one or both of the drugs alone for pain relief. In addition, they searched the reference lists of retrieved publica tions for additional trials. Exclusion criteria included comparison of an acetaminophen/NSAID combination with analgesics other than acetamin
966
JADA 145(9)
h ttp ://ja d a .a d a .o rg
ophen or an NSAID; pain models other than acute postoperative pain; and retrospective, nonrandomized or nonmasked trials. The primary outcome measures used to test dif ferences between test groups were pain intensity (in the form of pain scores) and supplemental postopera tive analgesic requirements. The re viewers expressed these measures as mean and standard deviation. They graded each study for quality by using a validated scale. In addition, they used a Mann-Whitney U test to assess the relationships between the trials with positive and nega tive results and the quality scores. The reviewers performed subgroup analyses by means of a surgical mod el, as well as according to NSAID type. They evaluated qualitative and quantitative heterogeneity by using
S eptem ber 2014
the funnel plot and Cochran Q test, respectively. M ain results. The search yielded 32 studies; 11 were excluded because of inadequate randomization, nonmasking, chronic pain evalu ation, and examination of different classes of analgesics. The reviewers included in the analysis 21 RCTs of acute postoperative pain models, with a total of 1,909 patients. The evaluated NSAIDs were ibuprofen (n = 6), diclofenac (n = 8), ketoprofen (n = 3), ketorolac (n = 1), aspirin (n = 1), tenoxicam (n = 1) and rofecoxib (n = 1). The pain models included dental surgery (n = 6), orthopedic surgery (n = 5), gynecologic/inguinal surgery (n = 6) and ear, nose and throat surgery (n = 4). The acetaminophen/NSAID combi nation was more effective than was
{ ORIGINAL CONTRIBUTIONS f
acetaminophen or the NSAID alone in 85 percent and 64 percent of rel evant studies, respectively. The mean (standard deviation) pain intensity and supplemental postoperative analgesic requirement was 35.0 per cent (10.9 percent) and 38.8 percent (13.1 percent) lower, respectively, for the combination group versus the acetaminophen group, and 37.7 per cent (26.6 percent) and 31.3 percent
(13.4 percent) lower, respectively, for the combination group versus the NSAID group. The reviewers found no statistically significant difference between experimental groups with regard to the median quality scores. Conclusions. The results of small, multiple, high-quality doublemasked RCTs suggest that the combination of acetaminophen and an NSAID effectively lowers pain
intensity and decreases the need for supplemental postoperative analge sics better than do either drug alone, with minimal adverse effects, for the treatment of acute postoperative pain. Dr. Merry received grants from AFT Phar maceuticals, Sydney, for research into a combi nation of acetaminophen and ibuprofen.
COM M ENTARY Importance and context. Most patients experi ence some pain after surgery; thus, management of postoperative pain is a critical component of patient care. In most circumstances, the pain can be treated with oral analgesics.1Acetaminophen and ibuprofen are widely available and inexpensive, with a wellestablished reputation for safety and efficacy. They frequently are used in combination in clinical practice and are available in some countries as an overthe-counter fixed-dose combination tablet. In the treatment of acute pain, drugs may be used synergistically to provide additive analgesic effects with fewer adverse effects than those with a single drug. There has been a trend to combine NSAIDs with acetamino phen for the management of acute postoperative pain. This trend has been met with controversy, however, as the evidence is limited regarding the therapeutic superiority of this combination of drugs over either drug used alone. Strengths and weaknesses of the systematic re view. The reviewers conducted a high-quality system atic review that included a comprehensive search of multiple databases and reference lists. They used only double-masked RCTs and well-defined inclusion and exclusion criteria. The reviewers provided reasons for rejecting some studies (such as absence of masking, inadequate randomization). Unfortunately, they did not seek out non-English language or unpublished articles. They graded each study for quality by using a validated instrument—the Jadad scale2—and sum marized the results in a table. Another weakness of the systematic review was that the reviewers had to estimate some study results from graphs. They did not mention whether they had attempted to contact the study authors to obtain the raw data. The review ers performed subgroup analyses to ensure that the overall results were not different from specific surgi cal and drug model findings. They evaluated statisti cal heterogeneity across the studies qualitatively by means of the funnel plot and quantitatively by using the Cochran Q test. One of the reviewers received
funding from a pharmaceutical company to research a combination of acetaminophen and ibuprofen. Strengths and weaknesses of the evidence. The reviewers analyzed 21 double-masked RCTs enroll ing 1,909 patients for this review. The results confirm previous findings that a combination of acetamino phen and an NSAID provided analgesia superior to that provided by either drug alone.3'5 One limitation of the evidence is that studies with negative findings may not have had adequate sensitivity to detect a difference in pain scores between groups, because the pain scores were relatively low in the control groups (that is, one drug or the other). In all studies, analge sics were administered before surgery or immediately afterward, but before pain had developed. In addition, some studies with small sample sizes may not have had adequate power to detect a difference if one was present. Implications for dental practice. Researchers in four studies in this systematic review (389 patients) compared the efficacy of an acetaminophen and NSAID combination with that of an NSAID alone in the management of acute pain after tooth extractions. In three of the studies, patients reported decreased pain intensity when using a combination of acet aminophen and an NSAID compared with that when using an NSAID alone. Ibuprofen, one of the most commonly used analgesics in dentistry, was one of the NSAIDs evaluated most widely in this review. The value of combining ibuprofen with acetaminophen was confirmed in all five studies in which investiga tors compared the combination with acetaminophen alone, including a tooth extraction pain model involv ing 200 patients. The results of a 2013 systematic review by Derry and colleagues1 that included three clinical trials involving 1,647 people with moderate or severe pain after undergoing third-molar extrac tion confirmed that a combination of ibuprofen and acetaminophen provided better analgesia, with fewer adverse events, than did either drug alone. To prevent severe liver damage, the U.S. Food and Drug Admin-
JADA 145(9)
http://jada.ada.org
September 2014
967
{ ORIGINAL CONTRIBUTIONS \
istration recommends that practitioners prescribe or dispense drug products that contain no more than 325 milligrams of acetaminophen per tablet, and that the maximum dose for adults be no more than 4,000 mg of acetaminophen daily.6 ■ doi:io.i42i9/jada.20i4.39 Dr. Kraglund is an assistant professor, Faculty of Dentistry, Dalhousie University, 5981 University Ave., P.O. Box 15000, Halifax, Nova Scotia, Canada, B3H 4R2, e-mail [email protected]. She also is an evidence reviewer for the American Dental Association. Address correspondence to Dr. Kraglund. Disclosure. Dr. Kraglund did not report any disclosures. These summaries, published under the auspices of the Ameri can Dental Association Center for Evidence-Based Dentistry, are prepared by practitioners trained in critical appraisal of published systematic reviews who work under the mentorship of experts. The summaries are not intended to, and do not, express, imply or sum marize standards of care, but rather provide a concise reference for dentists to aid in understanding and applying evidence from the referenced systematic review in making clinically sound decisions as
968
JADA 145(9)
http://jada.ada.org
September 2014
guided by their clinical judgment and by patient needs. For more information on the evidence quality rating provided above and additional critical summaries, please visit http://ebd.ada.org. 1. Derry CJ, Derry S, Moore RA. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. Cochrane Database Syst Rev 2oi3;6:CDoi02io. 2. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials I996;i7(i):i-i2. 3. Mehlisch DR. The efficacy of combination analgesic therapy in relieving dental pain. JADA 2002;i33(7):86i-87i. 4. Ong CK, Seymour RA. An evidence-based update of the use of analgesics in dentistry. Periodontol 2000 2008;46:143-164. 5. Lange H, Kranke P, Steffen P, Steinfeldt T, Wulf H, Eberhart LH. Combined analgesics for postoperative pain therapy: review of effectivity and side-effects (in German). Anaesthesist 2007;56(io ): 1001-1016. 6. U.S. Food and Drug Administration. Questions and answers about oral prescription acetaminophen products to be limited to 325 mg per dosage unit, www.fda.gov/drugs/drugsafety/ informationbydrugclass/ucm23987i.htm. Accessed July 31, 2014.
Copyright of Journal of the American Dental Association (JADA) is the property of American Dental Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
CRITICAL SUMMARIES
Acetaminophen plus a nonsteroidal anti-inflammatory drug decreases acute postoperative pain more than either drug alone A critical su m m ary o f Ong CK, S eym o ur RA, Lirk P, M e rry AF. C om bining p a ra c e ta m o l (a c e ta m in o p h e n ) w ith n on s te ro id a l a n tiin fla m m a to ry drugs: a q u a lita tiv e s y s te m a tic re v ie w o f analgesic effic a c y fo r a c u te p o s to p e ra tiv e pain. A n esth A nalg 2 0 1 0 ;1 1 0 (4 ):1 1 7 0 -1 1 7 9 .
F e m e Kraglund, DDS
System atic review conclusion. Current evidence suggests that a combination of acetaminophen, also known as paracetamol, and a nonsteroidal anti-inflammatory drug (NSAID) may offer superior analgesia than does either drug alone. Critical sum m ary assessm ent. The authors of this high-quality review of 21 double-masked randomized controlled trials deter mined that the combination of acetaminophen and an NSAID reduced acute postoperative (including dental) pain scores and the need for supplemental analgesics more than did acetaminophen or an NSAID alone. Evidence quality rating. Good.
Clinical question. In the treat ment of acute postoperative pain, does combining acetaminophen with a nonsteroidal anti-inflammatory drug (NSAID) provide superior efficacy when compared with either drug alone? R eview m ethods. The reviewers searched four databases for ran domized controlled trials (RCTs) in English from January 1988 to June 2009. They retrieved full reports for double-masked RCTs in which investigators compared acetaminophen/NSAID combinations with one or both of the drugs alone for pain relief. In addition, they searched the reference lists of retrieved publica tions for additional trials. Exclusion criteria included comparison of an acetaminophen/NSAID combination with analgesics other than acetamin
966
JADA 145(9)
h ttp ://ja d a .a d a .o rg
ophen or an NSAID; pain models other than acute postoperative pain; and retrospective, nonrandomized or nonmasked trials. The primary outcome measures used to test dif ferences between test groups were pain intensity (in the form of pain scores) and supplemental postopera tive analgesic requirements. The re viewers expressed these measures as mean and standard deviation. They graded each study for quality by using a validated scale. In addition, they used a Mann-Whitney U test to assess the relationships between the trials with positive and nega tive results and the quality scores. The reviewers performed subgroup analyses by means of a surgical mod el, as well as according to NSAID type. They evaluated qualitative and quantitative heterogeneity by using
S eptem ber 2014
the funnel plot and Cochran Q test, respectively. M ain results. The search yielded 32 studies; 11 were excluded because of inadequate randomization, nonmasking, chronic pain evalu ation, and examination of different classes of analgesics. The reviewers included in the analysis 21 RCTs of acute postoperative pain models, with a total of 1,909 patients. The evaluated NSAIDs were ibuprofen (n = 6), diclofenac (n = 8), ketoprofen (n = 3), ketorolac (n = 1), aspirin (n = 1), tenoxicam (n = 1) and rofecoxib (n = 1). The pain models included dental surgery (n = 6), orthopedic surgery (n = 5), gynecologic/inguinal surgery (n = 6) and ear, nose and throat surgery (n = 4). The acetaminophen/NSAID combi nation was more effective than was
{ ORIGINAL CONTRIBUTIONS f
acetaminophen or the NSAID alone in 85 percent and 64 percent of rel evant studies, respectively. The mean (standard deviation) pain intensity and supplemental postoperative analgesic requirement was 35.0 per cent (10.9 percent) and 38.8 percent (13.1 percent) lower, respectively, for the combination group versus the acetaminophen group, and 37.7 per cent (26.6 percent) and 31.3 percent
(13.4 percent) lower, respectively, for the combination group versus the NSAID group. The reviewers found no statistically significant difference between experimental groups with regard to the median quality scores. Conclusions. The results of small, multiple, high-quality doublemasked RCTs suggest that the combination of acetaminophen and an NSAID effectively lowers pain
intensity and decreases the need for supplemental postoperative analge sics better than do either drug alone, with minimal adverse effects, for the treatment of acute postoperative pain. Dr. Merry received grants from AFT Phar maceuticals, Sydney, for research into a combi nation of acetaminophen and ibuprofen.
COM M ENTARY Importance and context. Most patients experi ence some pain after surgery; thus, management of postoperative pain is a critical component of patient care. In most circumstances, the pain can be treated with oral analgesics.1Acetaminophen and ibuprofen are widely available and inexpensive, with a wellestablished reputation for safety and efficacy. They frequently are used in combination in clinical practice and are available in some countries as an overthe-counter fixed-dose combination tablet. In the treatment of acute pain, drugs may be used synergistically to provide additive analgesic effects with fewer adverse effects than those with a single drug. There has been a trend to combine NSAIDs with acetamino phen for the management of acute postoperative pain. This trend has been met with controversy, however, as the evidence is limited regarding the therapeutic superiority of this combination of drugs over either drug used alone. Strengths and weaknesses of the systematic re view. The reviewers conducted a high-quality system atic review that included a comprehensive search of multiple databases and reference lists. They used only double-masked RCTs and well-defined inclusion and exclusion criteria. The reviewers provided reasons for rejecting some studies (such as absence of masking, inadequate randomization). Unfortunately, they did not seek out non-English language or unpublished articles. They graded each study for quality by using a validated instrument—the Jadad scale2—and sum marized the results in a table. Another weakness of the systematic review was that the reviewers had to estimate some study results from graphs. They did not mention whether they had attempted to contact the study authors to obtain the raw data. The review ers performed subgroup analyses to ensure that the overall results were not different from specific surgi cal and drug model findings. They evaluated statisti cal heterogeneity across the studies qualitatively by means of the funnel plot and quantitatively by using the Cochran Q test. One of the reviewers received
funding from a pharmaceutical company to research a combination of acetaminophen and ibuprofen. Strengths and weaknesses of the evidence. The reviewers analyzed 21 double-masked RCTs enroll ing 1,909 patients for this review. The results confirm previous findings that a combination of acetamino phen and an NSAID provided analgesia superior to that provided by either drug alone.3'5 One limitation of the evidence is that studies with negative findings may not have had adequate sensitivity to detect a difference in pain scores between groups, because the pain scores were relatively low in the control groups (that is, one drug or the other). In all studies, analge sics were administered before surgery or immediately afterward, but before pain had developed. In addition, some studies with small sample sizes may not have had adequate power to detect a difference if one was present. Implications for dental practice. Researchers in four studies in this systematic review (389 patients) compared the efficacy of an acetaminophen and NSAID combination with that of an NSAID alone in the management of acute pain after tooth extractions. In three of the studies, patients reported decreased pain intensity when using a combination of acet aminophen and an NSAID compared with that when using an NSAID alone. Ibuprofen, one of the most commonly used analgesics in dentistry, was one of the NSAIDs evaluated most widely in this review. The value of combining ibuprofen with acetaminophen was confirmed in all five studies in which investiga tors compared the combination with acetaminophen alone, including a tooth extraction pain model involv ing 200 patients. The results of a 2013 systematic review by Derry and colleagues1 that included three clinical trials involving 1,647 people with moderate or severe pain after undergoing third-molar extrac tion confirmed that a combination of ibuprofen and acetaminophen provided better analgesia, with fewer adverse events, than did either drug alone. To prevent severe liver damage, the U.S. Food and Drug Admin-
JADA 145(9)
http://jada.ada.org
September 2014
967
{ ORIGINAL CONTRIBUTIONS \
istration recommends that practitioners prescribe or dispense drug products that contain no more than 325 milligrams of acetaminophen per tablet, and that the maximum dose for adults be no more than 4,000 mg of acetaminophen daily.6 ■ doi:io.i42i9/jada.20i4.39 Dr. Kraglund is an assistant professor, Faculty of Dentistry, Dalhousie University, 5981 University Ave., P.O. Box 15000, Halifax, Nova Scotia, Canada, B3H 4R2, e-mail [email protected]. She also is an evidence reviewer for the American Dental Association. Address correspondence to Dr. Kraglund. Disclosure. Dr. Kraglund did not report any disclosures. These summaries, published under the auspices of the Ameri can Dental Association Center for Evidence-Based Dentistry, are prepared by practitioners trained in critical appraisal of published systematic reviews who work under the mentorship of experts. The summaries are not intended to, and do not, express, imply or sum marize standards of care, but rather provide a concise reference for dentists to aid in understanding and applying evidence from the referenced systematic review in making clinically sound decisions as
968
JADA 145(9)
http://jada.ada.org
September 2014
guided by their clinical judgment and by patient needs. For more information on the evidence quality rating provided above and additional critical summaries, please visit http://ebd.ada.org. 1. Derry CJ, Derry S, Moore RA. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. Cochrane Database Syst Rev 2oi3;6:CDoi02io. 2. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials I996;i7(i):i-i2. 3. Mehlisch DR. The efficacy of combination analgesic therapy in relieving dental pain. JADA 2002;i33(7):86i-87i. 4. Ong CK, Seymour RA. An evidence-based update of the use of analgesics in dentistry. Periodontol 2000 2008;46:143-164. 5. Lange H, Kranke P, Steffen P, Steinfeldt T, Wulf H, Eberhart LH. Combined analgesics for postoperative pain therapy: review of effectivity and side-effects (in German). Anaesthesist 2007;56(io ): 1001-1016. 6. U.S. Food and Drug Administration. Questions and answers about oral prescription acetaminophen products to be limited to 325 mg per dosage unit, www.fda.gov/drugs/drugsafety/ informationbydrugclass/ucm23987i.htm. Accessed July 31, 2014.
Copyright of Journal of the American Dental Association (JADA) is the property of American Dental Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
