1 s2.0 S0099239916306148
1 s2.0 S0099239916306148
1 s2.0 S0099239916306148
Abstract
Introduction: Nonsteroidal anti-inflammatory drugs experiencing adverse events such as drowsiness, dizziness, nausea, and emesis; 2
(NSAIDs) have been commonly used to treat endodontic studies reported that patients experienced no adverse events. Conclusions: A combi-
postoperative pain. The purpose of this study was to nation of ibuprofen 600 mg and acetaminophen 1000 mg is more effective than placebo
address the following Population, Intervention, Compar- but not significantly different than ibuprofen 600 mg at 6 hours postoperatively.
ator, Outcome, Timing, Study design and setting ques- Ibuprofen 600 mg is more effective than placebo at 6 hours postoperatively; however,
tion: in patients with preoperative pain who undergo there are insufficient data to recommend the most effective NSAID, dose amount, or
initial orthograde endodontic treatment, what is the dose interval for the relief of postoperative endodontic pain of longer duration in pa-
comparative efficacy of NSAIDS compared with non- tients with preoperative pain. (J Endod 2017;43:7–15)
narcotic analgesics or placebo in reducing postoperative
pain and the incidence of adverse events. Methods: Key Words
Ovid MEDLINE (1946–December 15, 2015), the Co- Acetaminophen, endodontics, ibuprofen, meta-analysis, nonsteroidal anti-
chrane Database of Systematic Reviews (2005– inflammatory drugs, pain, systematic review
December 15, 2015), and the Cochrane Central Register
of Controlled Trials (to December 15, 2015) were
searched using included drugs, indications, and study
designs as search terms. Hand searches in texts were
T he primary reason
people seek endodon-
tic treatment is for the re-
Significance
This systematic review provides evidence that
also conducted. Two independent reviewers assessed ibuprofen and ibuprofen plus acetaminophen com-
lief of pain caused by
eligibility for inclusion, extracted data, and assessed binations provide greater pain relief than placebo
bacterial infection and
quality using the risk of bias tool. L’Abbe plots were after orthograde endodontic treatment. It also em-
subsequent inflammation
used for qualitative review. Where applicable, meta- phasizes the need for increased rigor in endodontic
(1). Although pain is
analysis was conducted on the pooled effect size (ES). pain research.
diminished after treat-
Results: Two thousand two hundred eighty-four studies ment, there may be resid-
were identified through the database searches; 405 full- ual symptoms because of the effects of inflammation. Endodontic treatment includes
text articles were assessed. Fifteen articles met the in- the management of postoperative pain and symptoms that address both the patient’s
clusion criteria; qualitative analysis revealed all studies primary concern and potential long-term complications such as chronic pain (2, 3).
had a moderate to high risk of bias. Ibuprofen was the A variety of drugs have been used to manage postoperative pain and often include
most studied NSAID. The L’Abbe plots showed that nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and combinations of
NSAIDS are effective at relieving postoperative end- drugs (4).
odontic pain overall. Meta-analysis showed that Pain after endodontic treatment is largely unpreventable. NSAIDs are one of the
ibuprofen 600 mg is more effective than placebo at most recommended classes of pain relievers in dentistry today (5, 6). NSAIDs
6 hours postoperatively (ES = 10.50, P = .037), and function by inhibiting the cyclooxygenase enzymes and preventing the generation of
ibuprofen 600 mg + acetaminophen 1000 mg combina- new prostaglandin molecules, but they have no effect against existing molecules in
tion is more effective than placebo (ES = 34.89, circulation (7).
P = .000) but not significantly different than ibuprofen Systematic reviews are a way to synthesize and combine data from numerous studies
(ES = 13.94, P = .317). Five studies reported patients evaluating a common outcome (6). Holstein and Niederman (8) published a systematic
From the *Department of Endodontology, School of Dentistry and †Pacific Northwest Evidence-based Practice Center, Oregon Health and Science University, Port-
land, Oregon.
Address requests for reprints to Dr Christine M. Sedgley, Department of Endodontology, School of Dentistry, Oregon Health and Science University, 2730 SW Moody
Ave, Portland, OR 97201-5042. E-mail address: sedgley@ohsu.edu
0099-2399/$ - see front matter
Copyright ª 2016 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2016.09.010
JOE — Volume 43, Number 1, January 2017 NSAIDs for Managing Postoperative Endodontic Pain 7
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Review Article
review on the use of NSAIDs for treating postoperative endodontic pain in Literature Search
2002 and found the most effective analgesics were a combination of flur- The literature search of the Ovid MEDLINE and Ovid OLDMED-
biprofen and tramadol or a combined regimen of preoperative and post- LINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations,
operative flurbiprofen. The purpose of this systematic review was to EBM Reviews–Cochrane Central Register of Controlled Trials, and
update the review from 2002 using studies published over the past EBM Reviews–Cochrane Database of Systematic Reviews included
14 years, with a focus on the comparative efficacy of NSAIDs alone or articles published from inception through December 2014. The
in combination with other analgesics and other non-narcotic drugs for search criteria included key words for NSAIDs and endodontic
postoperative endodontic discomfort in patients who present with pre- postoperative pain. Hand searching was performed on reference
treatment pain. This study addresses the following Population, Interven- lists of relevant textbooks. Gray literature was also searched
tion, Comparator, Outcome, Timing, Study question: in patients with through www.clinicaltrials.gov. The search was repeated on
preoperative pain who undergo initial orthograde endodontic treatment, December 15, 2015.
what is the comparative efficacy of NSAIDS alone or in combination with Randomized controlled trials were included if they enrolled pa-
other analgesics compared with placebo or non-narcotic analgesics in tients who presented with endodontic pain and received a diagnosis
reducing postoperative pain and the incidence of adverse events. of pulpal pathosis necessitating initial nonsurgical endodontic treat-
ment, compared postoperative treatment with an NSAID or other
Materials and Methods non-narcotic analgesic or placebo, and measured pre- and postopera-
This systematic review was undertaken using recommended tive pain. Exclusion criteria included nonrandomized studies and sys-
guidelines (9). A review protocol was written and registered with the tematic reviews, animal studies, the use of a nonendodontic pain
public registry of systematic reviews PROSPERO (CRD42015019532). model, and treatment that required multiple visits.
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.
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10
Review Article
TABLE 2. Characteristics of Included Studies
Time of pain
Smith et al.
evaluation
Treatment Time of (hours Inclusion Baseline 6 H 12 H 24 H
Author, year groups (n) delivery postoperative) Outcome variable criteria Treatment* Escape drug VAS† VAS† VAS† VAS†
Arslan, Placebo (16) PRE B, 0, 6, 12, 100-mm VAS 50 VAS, NS-RCT Extra dose of 85.5 35.1 19.8 16.4
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2011 (12) Tenoxicam 20 mg (16) 24, 48, 72 DNS the treatment 82.6 7.92 9.62 4.09
Ibuprofen 200 mg (16) medication 83.2 2.83 15.3 3.49
09, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
Attar, Placebo (12) PRE B, 0, 6, 12, 100-mm VAS, 30 VAS, NS-RCT Tylenol ES 65.6 17.9 20.4 11.9
2008 (13) Ibuprofen 18, 24 170-mm HPC, DNS (McNeil 64.7 26.2 24 23.5
600-mg tablet (14) VAS-C Consumer 65.9 28.1 31.8 21.6
Ibuprofen 600-mg Healthcare
liqui-gel (13) Division, Fort
Washington, PA)
(500 mg)
Baradaran, Placebo (15) POST B, 4, 6, 12, 10-cm VAS SIP Two visit NS-RCT Acetaminophen 82.0 38.0 36.0 15.8
2014 (14) Ibuprofen 400 mg (15) 24, 48, 72 650 mg 76.0 30.0 25.3 10.7
Ibuprofen 400 mg + 82.0 23.3 23.3 13.3
alprazolam 0.5 mg (15)
Battrum, Placebo (10) Every 6 h B, 6, 24 100-mm VAS, SIP, NEC, NS-RCT Ketorolac 10 mg 12.9 14.7 — 12.9
1996 (15) Ketorolac 10 mg PO (10) 6 PIS, 4 VPR SAP 40.2 5.14 5.14
Doroschak, Placebo (12) Every 6 h B, 6, 24, 4 PIS, 100-mm 30 VAS, SIP, Pulpectomy Acetaminophen 66.2 42.8 — 26
1999 (16) Flurbiprofen 50 mg (12) 36, 48, 60 VAS, HP NEC, 650 mg 70.6 36.6 20
NORM, AAP,
SAP, AAA
Flath, Placebo (29) PRE, 3 h B, 3, 7, 24, hours 4 PIS, 100-mm DNS Pulpectomy — 48.97 — — 30
1987 (17) Preoperative placebo, POST after initial VAS, 5 VPR 37.06 11.91
postoperative flurbiprofen dose 33.09 18.53
100 mg (30) 41.03 6.18
Pre-operative flurbiprofen
100 mg, post-operative
placebo (28)
Flurbiprofen (29)
Gopikrishna, Placebo (15) PRE B, 4, 8, 12, 100-mm VAS 30 VAS, Pulpectomy Acetaminophen 72.6 — 55.4 35.3
2003 (18) Rofecoxib 50 mg (15) 24, 48, 72 DNS 650 mg 76.3 21.7 13.1
Ibuprofen 600 mg (15) 75.1 45.9 25.0
Mehrvarzfar, Placebo (25) POST B, 6, 12, 24 10-point VAS SIP, Pulpectomy — 4.7 4.8 3.7 3.2
2012 (19) Naproxen 500 mg (25) NORM 5.8 0.8 0.5 0.7
Ibuprofen 200 mg + 4.8 0.6 0.7 0.4
acetaminophen 325 mg +
JOE — Volume 43, Number 1, January 2017
40 mg caffeine (25)
Menhinick, Placebo (19) PRE B, 1, 2, 3, 100-mm VAS 50 VAS, SIP, Pulpectomy Acetaminophen 80.0 35.8 — —
2004 (20) Ibuprofen 600 mg (20) 4, 6, 8 NEC, NORM, 300 mg + 69.0 20.8
Ibuprofen 600 mg + SAP, AAP codeine 30 mg 81.0 0.0
acetaminophen
1000 mg (18)
Nekoofar, Placebo (17) POST B, 8, 24 9-cm VAS 5-cm VAS. NS-RCT — 6.4 — — 1.2
2003 (21) Meloxicam 15 mg (17) DNS 7.3 1.0
Piroxicam 20 mg (17) 6.7 1.9
Rogers, Placebo (12) POST B, 6, 12, 24, 48 150-mm VAS SIP, normal pulp NS-RCT — 23.6 39.4 28.3 18.3
1999 (22) Ibuprofen 600 mg (12) 28.4 28.8 22.1 12.5
Review Article
system. Other side effects were noted (eg, xerostomia, rash, and
scale; NEC, pulpal necrosis; NORM, normal periapical tissues; PIS, pain intensity scale; POST, postoperative dose; SAP, symptomatic apical periodontitis; SIP, symptomatic irreversible pulpitis; VAS, visual analog scale; VAS-C, visual analog scale–categoric; VPR, verbal pain relief scale.
3-cm VAS, pain $3 on a 10-cm VAS; 5-cm VAS, pain $5 on a 9-cm VAS; 30 VAS, pain $30 on 100-mm VAS; 50 VAS, pain $50 on 100-mm VAS; AAA, acute apical abscess; AAP, asymptomatic apical periodontitis; B, baseline; DNS, diagnoses not specified; HPC, Heft Parker categoric
27.4
12.4
26.8
2.05
62.7
54.6
2.4
wheezing) (Table 4). In studies that analyzed the side effects by
4.2 treatment group, the placebo group had the same or greater inci-
3.5
47.9
18.2
25.8
1.77
dence of side effects as at least one of the experimental drug
4.2
—
groups (17–19, 21, 26).
4.9
49.5
17.0
25.3
2.79
Nine studies reported supplying or recommending a rescue medi-
5.3
—
cation or ‘‘escape drug’’ including varying doses of acetaminophen,
acetaminophen 300 mg + codeine 30 mg, and acetaminophen
118.3
130.1
7.6
70.7
68.0
62.6
61.6
8.44
*VAS scores are for patients with endodontic pain and a diagnosis of pulpal pathosis necessitating initial nonsurgical endodontic treatment and who underwent pulpectomy/cleaning and shaping or completion of single-visit RCT.
Hydrocodone
Ibuprofen
5 mm +
600 mg
500 mg
Quantitative Review
—
NS-RCT
NS-RCT
NS-RCT
SAP
were significant.
10-cm VAS
Modified
reduced pain by 13.94 VAS points more than ibuprofen, but it was
B, 6, 12, 18, 24,
96, 120
18, 24
Discussion
The goal of this study was to consolidate the available informa-
tion on NSAID use for treating postoperative endodontic pain. To the
every 6 h
every 6 h
every 6 h
every 6 h
POST,
PRE,
For Torabinejad (25), data are available for placebo and ketoprofen groups only.
Acetaminophen 325 mg +
Ketoprofen 50 mg (53)
2014 (24)
2011 (26)
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and that pain may have undergone centralization and progressed
from acute to chronic (30, 31). Analgesic drug regimens that are
effective in cases of acute pain may not be as helpful in cases of
chronic pain. The endodontic pain studies looked at a variety of
NSAIDs separately but rarely compared them with each other. In
addition to differences in the quality of pain, analgesic research
studies using an oral surgery model tend to have different baseline
population characteristics than for an endodontic model; patients
seeking third molar extraction are more likely to be young and
healthy and have no or mild preoperative pain.
There is pharmacologic evidence that the combination of
ibuprofen and acetaminophen is better than either drug alone for
pain relief. Ibuprofen and acetaminophen are synergistic rather than
merely additive according to a recent report by Miranda et al (32).
The findings by Miranda et al also bring to light other NSAIDs that might
benefit from coadministration with acetaminophen, and it may be worth
comparing their efficacy with ibuprofen/acetaminophen; a combination
with significant synergy may outperform ibuprofen.
Ibuprofen plus acetaminophen combinations were not more
effective than ibuprofen alone (20, 26), but they were more effective
than placebo (19, 20). The 2 studies that compared ibuprofen plus
acetaminophen with ibuprofen do not agree; this may be caused by
differences in the inclusion criteria regarding the baseline diagnosis.
One of the 2 studies that compared ibuprofen plus acetaminophen
with placebo (19) actually studied a combination of ibuprofen plus
acetaminophen plus caffeine 40 mg (Novafen; Brown & Burk, Rich-
Figure 2. Risk of bias assessment. mond, UK). In the present review, it was determined that Novafen could
be included in the meta-analysis because of findings from the Cochrane
of cyclooxygenase 1 and cyclooxygenase 2, with additional activity review that doses of caffeine less than 100 mg have no additional benefit
linked to the central nervous system via endogenous neurotransmitter to analgesics (33).
systems (27, 28). Acetaminophen is considered to have fewer The inclusion criteria were designed to identify studies that analyze
gastrointestinal and cardiovascular side effects than NSAIDs. Its analgesic treatment groups in patients for whom relief of postoperative
number needed to treat is higher than other NSAIDs, with endodontic pain that is expected to be moderate to severe and for whom
acetaminophen 500 mg having a number needed to treat of 3.5 on pain relief is more urgently required. The exclusion criteria were de-
the Oxford League table. Recent evidence suggests that combining signed to eliminate studies that did not adjust for confounding factors
ibuprofen and acetaminophen has a greater analgesic effect than that can attenuate postoperative pain. An example of this is in the num-
either drug alone (29). ber of treatment visits. The number of treatment visits does not impact
This information provides growing evidence that ibuprofen and postoperative pain (1), but the stage of treatment does; there is more
ibuprofen plus acetaminophen combinations are effective at relieving postoperative pain after cleaning and shaping of the root canal system
pain of endodontic origin in the hours after root canal therapy. Previ- than after obturation of the root canal system (25).
ously, the core of the pain literature applied to endodontics came from Several studies were included (12–14, 18–21, 23, 24, 26)
an oral surgery or medical pain perspective, which might not be that were not included in the previous systematic review (8). It
germane to pain of endodontic origin. A patient needing root canal should be noted that certain NSAIDS in included studies are no
treatment may have had preexisting pain for an extended duration longer available in the United States (Table 1) (eg, rofecoxib, a
cyclooxygenase 2 NSAID was withdrawn from the market in the ature is a severe limitation. Additionally, trial authors often did not
United States in 2004 because of reports of serious heart disease report a statistical measure of postoperative pain variability such
after use [23]). This is also the first time NSAIDs used in allevi- as standard deviation or confidence limits, which made their inclu-
ating postoperative endodontic pain have been subjected to a sion in meta-analyses difficult. Other limitations include the signifi-
quantitative comparison and meta-analysis. cant heterogeneity in the included studies; the trials differed in the
The most obvious limitation of this review is the small number timing of drug administrations, the dose, and the time after admin-
of included studies and that the sample size of all the included istration when the effect was measured. For example, although Attar
studies available for meta-analysis was small, ranging from n = 12 et al (13) administered ibuprofen liqui-gel and tablet forms at
to n = 36. The scarcity of studies available in the endodontic liter- approximately 15 and 30 minutes, respectively, before accessing
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Figure 4. Meta-analysis. Forest plots of (A) ibuprofen versus placebo at 6 hours, (B) ibuprofen + acetaminophen versus placebo at 6 hours, and (C)
ibuprofen + acetaminophen versus ibuprofen at all time points.
and instrumenting the root canal, there was much heterogeneity and This review highlights some of the needs for future endodontic
an absence of standardization regarding the timing of pretreatment pain research. Primarily, additional studies are needed that analyze
and post-treatment drug delivery. endodontic pain, with larger sample sizes for increased statistical
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